Defining the role of laminin-332 in carcinoma

Cherise M. Guess; Vito Quaranta

doi:10.1016/j.matbio.2009.07.008

Matrix Biol. Author manuscript; available in PMC 2010 May 25.

Published in final edited form as:

Matrix Biol. 2009 Oct; 28(8): 445–455.

Published online 2009 Aug 15. doi: 10.1016/j.matbio.2009.07.008

PMCID: PMC2875997

NIHMSID: NIHMS200779

PMID: 19686849

Defining the role of laminin-332 in carcinoma

Cherise M. Guess^a,^b and Vito Quaranta^b,^c,^*

Author information Copyright and License information PMC Disclaimer

Abstract

The deadly feature of cancer, metastasis, requires invasion of cells through basement membranes (BM), which normally act as barriers between tissue compartments. In the case of many epithelially-derived cancers (carcinomas), laminin-332 (Ln-332) is a key component of the BM barrier. This review provides a historical examination of Ln-332 from its discovery through identification of its functions in BM and possible role in carcinomas. Current understanding points to distinct roles for the three Ln-332 subunits (α3, β3, γ2) in cell adhesion, extracellular matrix stability, and cell signaling processes in cancer. Given the large number of studies linking Ln-332 γ2 subunit with cancer prognosis, particular attention is given to the crucial role of this subunit in cancer invasion and to the unanswered questions in this area.

Keywords: Laminin-332, Cancer, Invasion, Prognosis, Extracellular matrix

1. Introduction

1.1. Cancer: the problem defined

The overwhelming complexity of the cancer field comes from the fact that cancer is not so much a specific disease as it is a cluster of many separate but related disorders. Ninety percent of cancer cases fall into the broad classification of carcinomas, or cancers of epithelially-derived cells, which make up the majority of the lining cells of the body. Along with cell-type, the tissue or organ of origin is used to define a specific cancer further multiplying the number of sub-classifications.

At its core, cancer is best described as unregulated cellular growth and invasion; however, the path to loss of growth regulation and the extent of dysregulation of other cellular traits can vary widely, especially with respect to the cell/tissue type(s) involved. This heterogeneity, even when subtle, can have enormous impact on treatment choice and clinical response. Even with such a wide array of individual characteristics, it has been concluded that most, if not all, cancers acquire changes affecting six particular areas, or hallmarks, of cancer: namely these are self-sufficiency in growth signals, sustained angiogenesis, apoptosis evasion, insensitivity to anti-growth signals, limitless replicative potential, and the ability for tissue invasion and metastasis (Hanahan and Weinberg, 2000). While increased potential to cripple any of these hallmarks would be a welcome addition to the therapeutic arsenal, it is the ability to colonize beyond the original site that makes a cancer potentially deadly by dramatically restricting means of treatment, such as surgical removal of a primary tumor. Many research efforts focus on understanding the molecular mechanisms underlying the metastatic proclivity of cancer cells. Yet, there is a dearth of suitable molecular targets specific for metastasis treatment.

1.2. Metastasis: distant spread requires local invasion

There is a popular school of thought known as the ‘seed and soil hypothesis’, which contends that the major determinant of success in growth at a secondary site is a hospitable environment (“soil”) that matches the requirements of a metastasizing cell (“seed”). This idea was first articulated by Stephen Paget in his landmark 1889 Lancet paper to explain the observation that cancer cells (seeds) from certain organs were more likely to metastasize to particular distant sites (soil)(Paget, 1989). Several decades later, a new theory emerged from James Ewing (Ewing, 1928), who correlated these observations to the circulatory pattern from the original tumor site. In fact, it is now known that both of these theories are partially correct (see Chambers et al., 2002; Couzin, 2003; Fokas et al., 2007 for discussion), yet neither fully account for observed metastatic phenomena.

It is generally thought that the metastatic cascade requires several steps before clinical manifestations (reviewed in Fidler, 2002). Cells must escape from a primary tumor and enter into the blood or lymphatic system, survive in the circulation, extravasate from the vessel at a secondary site, and finally they must find a way to adapt and thrive at this new location (Chambers and Matrisian, 1997; Chambers et al., 2000). At several of these steps, crossing of BM must occur. For example, entry into and exit from the circulatory system absolutely require crossing of vessel BM. Furthermore, in the invasive spread to a neighboring organ, for which entering the circulation may not be an issue, the ability of a cancer cell to cross BM may be the sole obstacle for dissemination in and out of stroma. Thus, a comprehensive understanding of cancer metastasis inherently requires examination of local invasion and BM crossing by cancer cells (Fidler, 2002; Aznavoorian et al., 1993).

1.3. Local invasion: crossing the BM

Local invasion itself is primarily a composite of two main processes: enzymatic degradation of the BM that separates epithelial cells from underlying stroma, followed by migration through a newly cleared pathway (Liotta and Stetler-Stevenson, 1991). These processes can be accompanied by deregulation of normal adhesion between neighboring cells via decrease in cell–cell adhesion molecules such as E-cadherin (Bracke et al., 1996), though it has become increasingly clear that epithelially-derived cancer cells can also migrate collectively as sheets (reviewed in Friedl and Brocker, 2000). The invasion process involves metalloproteinases (MMPs) that break down the BM, the integrin family of cell receptors which function in attachment and migration, plus many additional protein families (Wittekind and Neid, 2005). MMP secretion is accompanied by formation of cell protrusions (pseudopodia, invadopodia, or other membrane extensions) and migration (reviewed in Adams, 2002; Weaver, 2006); in this way, invasive cells can bypass the normal tissue barriers confining them to one area of an organism.

1.4. BM: a barrier to invasion

The BM is a 50- to 100 nm layer of ECM components that separates all epithelial and endothelial cells from underlying stromal cells, and provides both structural support and vital signaling cues from the microenvironment (reviewed in Yurchenco and Schittny, 1990; Iozzo, 1998; LeBleu et al., 2007). BMs are vital for structural tissue integrity and can be found essentially in every organ of the body.

ECM molecules that make up the BM are secreted by surrounding stromal cells (e.g. epithelial cells or fibroblasts) and remodeled by the cells themselves to form sheets, upon which epithelial and endothelial cells rest. This serves as a physical barrier as well as a signal regulator by sequestering growth factors, chemokines, and other signaling factors, which are released upon matrix degradation (reviewed in Schenk and Quaranta, 2003).

ECM components are classified broadly as either proteoglycans or non-proteoglycans. Heparin-, chondroitin-, and keratan- sulfates make up the proteoglycans that have growth factor mimetic domains shown to stimulate fibroblast and chondrocyte proliferation; these molecules consist of a fibrous protein with long chains of unbranched polysaccharides called glycosaminoglycans (reviewed in Iozzo, 1998; Lander and Selleck, 2000).

BM non-proteoglycans come in many forms and have a wide variety of functions. Collagens are by far the most abundant and provide the bulk of structural support (reviewed in Hulmes, 1992). Fibronectins connect cells with collagens and other ECM components via cell-surface integrin receptors (reviewed in Teti, 1992). Laminins are glycoproteins that modulate adhesion and signaling through integrin binding; additionally, they adhere to other ECM molecules, including other laminins, to form a network that strengthens the membrane by resisting tensile force (reviewed in Aumailley and Smyth, 1998).

1.5. Laminins: BM structural molecules

Nearly 30 years ago, stroma from the Engelbreth–Holm–Swarm (EHS¹) tumor was purified and found to contain large amounts of a novel non-collagenous glycoprotein the researchers termed laminin (Timpl et al., 1979). Now known as Ln-111, this molecule has previously been referred to as EHS laminin, Ln-1, or simply laminin in older literature (Aumailley et al., 2005). Since Ln-111, 15 other distinct laminins have been found in mammals (Aumailley et al., 2005). All members of the laminin family are heterotrimers of an α, β and γ chain, encoded in humans by 5α, 4β, and 3γ genes (Miner and Yurchenco, 2004). Structural similarity among all laminins has been proposed, based on sequence data and theoretical heterotrimer stability (Beck et al., 1993). This configuration was shown to contain the three chains wound together to form a triple helical coiled-coil domain stabilized by disulfide bonds, termed the long-arm. Portions of the β and γ chains, as well as a portion of α extending from the long arm make up three short arms, completing a cruciform structure (Beck et al., 1990).

The key structural role of laminins in BM is underscored by distinct phenotypes in laminin subunit null mice, including those lacking α2 (Kuang et al., 1998; Miyagoe et al., 1997), α3 (Ryan et al., 1999), α5 (Miner et al., 1998), β2 (Noakes et al., 1995), or γ1 (Smyth et al., 1999) laminin chains that have a lethal phenotype. Even though many details are still being elucidated, the general trend is that laminins are crucially involved in tissue organization, including the specification of key epithelial traits like cell polarity or protection from detachment-induced cell death (anoikis) (Miner and Yurchenco, 2004; Li et al., 2003). Cancer invasion can be seen as a failure to maintain tissue organization, making laminins important molecules to consider in cancer.

Different cell types express different laminin types. Ln-332 is unique to and widespread among epithelia. Therefore, it is of high relevance for studies of carcinoma invasion.

1.6. Ln-332: the laminin formerly known as Ln-5

For the sake of clarity, especially in tracing early literature on Ln-332 and cancer, it is important to briefly recap the history of Ln-332 discovery and the evolution of its nomenclature. Ln-332 was referred to in the earlier literature as BM-600/nicein (Verrando et al., 1987; Verrando et al., 1988), GB3 antigen (Verrando et al., 1988), epiligrin (Carter et al., 1991), kalinin (Rousselle et al., 1991), and ladsin (Miyazaki et al., 1993); originally, these were all thought to be separate molecules. The common identity of some of these molecules was first suggested in the early 1990s, when strikingly similar characteristics began to emerge (Watt and Hotchin, 1992). Shortly thereafter, kalinin and nicein were found to share the same tissue distribution (Meneguzzi et al., 1992) and protease cleavage patterns (Marinkovich et al., 1993). Vailly and colleagues found that the 100-and 105-kDa subunits (γ chains) of nicein and kalinin have the same amino acid sequence, by comparing their respective cDNAs (Vailly et al., 1994). They concluded nicein and kalinin heterotrimers were identical and suggested that, based upon similar biochemical, immunological, and cell biology results from another group (Domloge-Hultsch et al., 1992), epiligrin was also the same molecule. Together with few other observations, it became accepted that all of these molecules were in fact one and the same, eventually leading to the Ln-5 unified nomenclature (Burgeson et al., 1994). Two years later, the issue was finally put to rest when Miyazaki's group released a report on the identification of their ladsin molecule as Ln-5 (Mizushima et al., 1996). A more logical and standardized nomenclature system was developed more recently, whereby current and future laminins would be named by their αβγ chain constituency regardless of discovery order (Aumailley et al., 2005), so the molecule formerly known as Ln-5 underwent a name change to Ln-332.

While the inconsistent nomenclature during the infancy of Ln-332 studies caused some confusion, there is no doubt over the identity of this laminin as an ECM protein unique to epithelial cells with crucial roles in cell adhesion, signaling and migration (reviewed in Colognato and Yurchenco, 2000). These heterotrimers consist of an α3, β3, and γ2 chain encoded by the LAMA3 (Ryan et al., 1994), LAMB3 (Gerecke et al., 1994), and LAMC2 genes (Vailly et al., 1994), respectively (Fig. 1). Due to inclusion of the truncated α3 chain, Ln-332 has 3 short arms instead of 2 (Rousselle et al., 1995).

An external file that holds a picture, illustration, etc.
Object name is nihms200779f1.jpg

Open in a separate window

Fig. 1

Laminin-332 structure and major roles. Representation of Ln-332 heterotrimer is shown. The long arm of the molecule contains all chains held in a coiled structure by disulfide linkage. The G domain, consisting of 5 LG modules (red circles beneath the long arm), of the α chain is responsible for various cellular functions. LG modules 1–3 are important for integrin binding important for cell signaling. LG modules 3 and 4 are important for proteolytic processing, and modules LG4 and LG5 interact and bind with heparin and proteoglycans (reviewed in Marinkovich, 2007). The β and γ short arms contain cleavable interaction domains with crucial ECM interaction and growth factor-like signaling functions.

1.7. Ln-332 subunits: human pathology and cancer

Although the emphasis of this review is cancer, the human pathology most commonly associated with Ln-332 is the autosomal recessive disease, junctional epidermolysis bullosa (JEB). Mutations in any of the three Ln-332 chains can result in JEB, which is characterized by severe skin blister formation (Aberdam et al., 1994; Pulkkinen et al., 1994a; Pulkkinen et al., 1994b; Pulkkinenm et al., 1995a; Vidal et al., 1995; Kivirikko et al., 1996). Clinical manifestations of JEB are due to an absence of Ln-332- containing adhesive structures known as hemidesmosomes (Pulkkinen and Uitto, 1999). Hemidesmosomes are vital for cell-matrix adhesion and involve interaction of Ln-332 with α6β4 integrin, collagen-VII, collagen-XVII, and other molecules (Borradori and Sonnenberg, 1999; Nievers et al., 1999). Knockout of α6β4 or collagen-VII in mice leads to similar blistering issues though the exact phenotype varies somewhat (van der Neut et al., 1996; Heinonen et al., 1999). Whether abnormalities in hemidesmosomes are also related to the role of Ln-332 in cancer remains an open issue. In the remainder of this review, we focus on each of the Ln-332 subunits separately, as they have each been reported to have distinct roles in cancer progression.

2. Laminin α3

The α3 chain is encoded by the LAMA3 gene, which has two transcript variants. The truncated LAMA3a variant is expressed and incorporated into heterotrimer (Ryan et al., 1994), while the other variant has thus far only been studied via overexpression of artificially produced cDNA (Kariya et al., 2004). Transcript regulation is achieved by alternative splicing and separate promoter sites (Ferrigno et al., 1997). Aside from Ln-332, α3 is also a part of Ln-311 (formerly Ln-6) and Ln-321 (formerly Ln-7) heterotrimers; all three of these molecules can be found covalently linked to each other in the stroma, strengthening adhesion of the attached epithelial cells (Champliaud et al., 1996). Integrin binding function was predicted for α3 chain once the LAMA3 gene was cloned and discovered to possess an RGD motif (residues 658–660) and an LDV motif (residues 313–315) in the α-helical domain (Ryan et al., 1994), since these sequences had been shown to mediate the binding of fibronectin to its integrin receptors (Pierschbacher and Ruoslahti, 1984; Wayner et al., 1989; Komoriya et al., 1991). However, the RGD motif is not exposed so any integrin binding function may involve other motifs.

The α3 chain is crucial for interaction with α3β1 integrin, which stimulates cell migration, adhesion, and spreading on Ln-332 (Shang et al., 2001). The α3β1 binding site was narrowed down to one of the large globular domains, LG3, using recombinant proteins. Integrin signaling, which also occurs through two other binding partners of Ln-332, α6β4 and α6β1, has critical roles in mediating actin protrusion, migration, and invasion (Mercurio et al., 2001). Recent work from the Marinkovich group (Tran et al., 2008) illustrates the vital role of the α3 chain in cancer by showing that its large globular domains 4–5, which are cleaved from normal skin cells, is highly expressed in carcinoma where it stimulates phosphoinositide 3-kinase (PI3K) and MMP activity, invasion, and tumor growth. Interestingly, these effects are countered in vivo by treatment with antibodies specific to this domain.

Interestingly, a region termed Domain IIIa in the α3 sequence contains two epidermal growth factor (EGF)-like repeats. This domain shares 46% sequence homology with the Domain IIIa sequence of Ln-111 and 48% with that of Ln-211 (formerly Ln-2) (Ryan et al. 1994). These EGF-like repeats can be found as part of each laminin chain in varying numbers, pointing to the possibility of nonintegrin-mediated signaling through growth factor receptor transactivation expanding the ability of Ln-332 to modulate cell behavior.

3. Laminin β3

The Ln-332 β3 chain was recently reported to also be a component of Ln-333 heterotrimer expressed in specialized adhesive membrane structures exclusive to germ cells in developing testis (Yan and Cheng, 2006). Like LAMA3, LAMB3 also encodes two transcript variants (Pulkkinen et al., 1995b); however, only the truncated LAMB3A form appears to be translated into protein (Hao et al., 2002). When this variant is expressed in prostate carcinoma cell lines naturally lacking its expression, cell migration and tumorigenicity are enhanced (Calaluce et al., 2004). It has previously been shown that MT1-MMP cleavage of this chain causes cell migration of prostate carcinoma cells in vitro (Udayakumar et al., 2003). Recent work has also highlighted the importance of β3 in prostate cancer by showing that hepsin, a protease overexpressed in 90% of human prostate tumors, induces cleavage of β3 chain in prostate cancer cells, leading to increased migration (Tripathi et al., 2008).

Anchoring fibrils, stalk-like structures that run orthogonal to the BM, are composed mainly of type VII collagen (Briggaman and Wheeler, 1975), while structurally similar thread-like projections called anchoring filaments are comprised of mostly Ln-332 (Sakai et al., 1986; Keene et al., 1987). One of the noncollagenous domains of type VII collagen NC1, contains a 285 amino acid subdomain, which binds Ln-332 β3, and to a lesser extent γ2, in a glycosylation-dependent manner (Rousselle et al., 1997; Chen et al., 1999). Chen and colleagues (Chen et al., 1999) showed that serum from a patient with the autoimmune form of JEB contained NC1 auto-antibodies, which blocked Ln-332 binding, indicating a likely role for collagen-VII/Ln-322 interaction in this disease and underscoring the importance of this binding event in the ECM. The site of this interaction, determined to occur within the EGF-like domain of the β3 short arm by recombinant mutant mapping, is necessary for full adhesion activity of Ln-332, yet dispensable for motility (Nakashima et al., 2005). This interaction between β3 and collagen-VII was found to promote tumorigenesis in squamous cell carcinomas via activation of PI3K signaling, which led to apoptosis protection and increased tumor invasion (Waterman et al., 2007). The signaling through PI3K was apparently related to tumorigenic increase, rather than adhesive differences caused by Ln-332. Similarly, a recent report demonstrated that addition of purified Ln-332 to esophageal squamous carcinoma cells activates the PI3K pathway resulting in increased invasion. This process can be inhibited with Ln-322 blocking antibodies (Baba et al., 2008). These studies, along with others, begin to reveal the possible role of Ln-332 as a signaling molecule in the BM that may at times outweigh its structural BM functions.

The importance of β3 chain in providing structural stability should however not be downplayed. There are more JEB-causing mutations of Ln-332 structure linked to the β3 chain than the α3 and γ2 chains combined (Schneider et al., 2007). Transduction of wt β3 cDNA into primary keratinocytes from β3-mutated JEB patients results in the generation of tissue with restored function and expression including the ability to form hemidesmosomes (Robbins et al., 2001).

4. Laminin γ2

Unlike the other two chains, γ2 is unique to the Ln-332 trimer. It also has the distinction of being the only chain of the complex that can be secreted in monomeric form (Gagnoux-Palacios et al., 2001). Like the other chains, it has two transcript variants; the full-length mRNA is broadly expressed in epithelial cells of 17-week-old human embryonic tissues, while the truncated version seems to be restricted to cerebral cortex, lung, and distal tubules of the kidney (Airenne et al., 1996). Ln-332 γ2 protein can be detected in the BM of many normal human epithelial tissues including skin, lung, small intestine, stomach, kidney, and prostate. Surprisingly, γ2 has also been reported to occur in non-epithelial tissue, namely lymphatic areas encasing the small arteries of the thymus and spleen (Mizushima et al., 1998).

Many functions of γ2 rely on proteolysis [with some exceptions, such as the integrin α2β1-mediated binding required for keratinocyte migration (Decline and Rousselle, 2001)]. Our lab first reported the migration-inducing MMP-2 cleavage of breast epithelial cell Ln-332 γ2 (Giannelli et al., 1997), which was later confirmed to have a role in sex steroid-induced tissue reorganization and maturation in vivo (Giannelli et al., 1999). The γ2 cleavage can also be carried out by a related membrane-type MMP (MT1-MMP) in colon and breast carcinoma cells (Koshikawa et al., 2000). MT1-MMP cleavage also stimulated migration, as shown in the spontaneously immortalized normal breast epithelial cell line MCF10A (Gilles et al., 2001). Migration induction and the opposing well-known functions of Ln-332 in forming static adhesive structures (hemidesmosomes) were reconciled by the hypothesis that these functions may alternate to promote tissue homeostasis, perhaps in a MMP dependent manner. A seemingly conflicting report claims that MMP-2 and MT1-MMP have no role and instead suggest that mammalian tolloid metalloproteinase is responsible for γ2 cleavage in keratinocytes (Veitch et al., 2003); however, we showed that this apparent contradiction in experimental findings is likely due to tissue specific differences (Koshikawa et al., 2004; Koshikawa et al., 2005). Furthermore, other groups have also documented physiologically relevant MMP-2 and/or MT1-MMP cleavage of γ2 (Kiyoshima et al., 2005; Oku et al., 2006; Shen et al., 2007).

There are also reports of proteolytic cleavage of the γ2 chain by other proteases. Bone morphogenetic protein-1, important for maturation of procollagen types I (Wozney et al., 1988), II and III (Hojima et al., 1985) by cleavage, was shown to cleave human (Amano et al., 2000) and murine (Sasaki et al., 2001) γ2 chain. It has been reported that MMP-3, -8, -13, -14, -20 (Pirila et al., 2003) and −19 (Sadowski et al., 2005) process γ2, inducing varying degrees of epithelial cell migration. Outside of epithelium, Ln-332 was shown to serve as a migratory substrate for mature thymocytes following cleavage of CD-44 by MMP-14 (Vivinus-Nebot et al., 2004).

It is important to note that γ2 cleavage does not always stimulate migration (reviewed in Hintermann and Quaranta, 2004). To the contrary, by a series of experiments using naturally occurring γ2-null cells transfected with cDNA of wildtype or mutant γ2 chains, γ2 processing was required for incorporation of secreted Ln-332 into the BM, where it supports formation of static adhesive structures (hemidesmosomes) (Gagnoux-Palacios et al., 2001). This same report provided evidence that γ2 is secreted and incorporated into the BM both in monomeric form and as part of Ln-332 heterotrimers. Thus, the end result of γ2 cleavage may have at least two outcomes: either regulating structural integrity or serving as a migratory substrate.

It has been proposed that signaling initiation may be an additional consequence of γ2 cleavage. This is because all of the aforementioned cleavages occur in the short arm of the molecule, which harbors a repeat of EGF-like domains. Exposure of these domains by cleavage opens the possibility that they may become ligands for cell surface signaling receptors, i.e., of the EGF receptor family. Whether or not these EGF-domain cleavage products are readily available for binding and potential signaling remains to be seen. We reported evidence for γ2 EGF signaling initiated by the products of both MT1-MMP (Koshikawa et al., 2004) and MMP-2 cleavage (Schenk et al., 2003). In the case of MMP-2, this activity led to migration and survival through a divergent EGF receptor (EGFR) signaling pathway (Schenk et al., 2003). This is an example of a separable yet related function of γ2 chain in producing microenvironment cues and is especially relevant given the well-established role of increased EGFR expression and EGFR signaling in cancers of various types. In this respect, even more enticing is the increasing volume of literature reporting coexpression of γ2 and EGFR in cancer (Kiyoshima et al., 2005; Ono et al., 2002; Katoh et al., 2002; Fukai et al., 2005; Richter et al., 2005).

5. Ln-332 γ2 and cancer: a prognostic indicator

Numerous immunohistochemistry (IHC) and in situ hybridization (ISH) studies show Ln-332 γ2 chain to be at the leading edge of invading carcinomas, where it is positively correlated with invasiveness and patient survival (reviewed in Katayama and Sekiguchi, 2004). Several concrete examples are discussed below (see Table 1 for more inclusive list).

Table 1

Ln-332 expression and cancer prognosis.

Tumor histology	Method	Chain(S)	Correlations	Reference
Bladder
Urinary bladder carcinoma	MS-PCR	α3, β3	Invasion, stage, grade	Sathyanarayana et al., 2004
Urothelial carcinoma	IHC	γ2	Invasion, recurrence	Kiyoshima et al., 2005
Urinary bladder carcinoma	MS-PCR	γ2	Survival	Sathyanarayana et al., 2004
Breast
Ductal carcinoma	ISH	γ2		Pyke et al., 1994
Ductal carcinoma	IHC, ISH	γ2		Pyke et al., 1995
Breast carcinoma	MS-PCR	α3	Size, stage	Sathyanarayana et al., 2003a
Breast carcinoma	MS-PCR	β3, γ2		Sathyanarayana et al., 2003a
Metaplastic breast Carcinoma	IHC	γ2	Initial diagnosis	Carpenter et al., 2008
Cervical
Cervical carcinoma	IHC	γ2	Invasion	Noel et al., 2005
Cervical adenocarcinoma	IHC	γ2	Invasion	Negri et al., 2006
Cervical cancer	IHC	γ2	Progression	Wang et al., 2006
Cervical squamous carcinoma	IHC	γ2		Andersson et al., 2005
Cervical squamous adenocarcinoma	IHC	γ2		Andersson et al., 2005
Intraepithelial neoplastic lesion	IHC	γ2		Tringler et al., 2007
Cervical carcinoma	IHC	γ2	Invasion	Skyldberg et al., 1999
Colorectal
Colon adenocarcinoma	ISH	γ2	Invasion	Pyke et al., 1994
Colorectal carcinoma	IHC	α3		Sordat et al., 1998
Colorectal carcinoma	IHC	β3, γ2	Invasion	Sordat et al., 1998
Colorectal carcinoma	IHC	α3	Invasion	Lohi et al., 2000
Colorectal carcinoma	IHC	β3, γ2, L n −332		Lohi et al., 2000
Colon adenocarcinoma	IHC, ISH	γ2	Invasion	Pyke et al., 1995
Colorectal carcinoma	IHC	α3		Sordat et al., 2000
Colorectal carcinoma	IHC, ISH	γ2	Invasion	Hlubek et al., 2001
Colorectal carcinoma	IHC	γ2		Habermann et al., 2001
Colon adenocarcinoma	IHC	γ2	Invasion	Lenander et al., 2001
Colorectal adenoma	IHC	γ2	Size, progression	Lenander et al., 2003
Colorectal carcinoma	IHC	γ2	Metstasis, survival	Aoki et al., 2002
Colorectal carcinoma	IHC	γ2		Masaki et al., 2003
Colorectal carcinoma	IHC	β3, γ2	Invasion	Akimoto et al., 2004
Colorectal cancer	IHC	γ2	Survival	Shinto et al., 2005
Colorectal cancer	IHC	γ2	Relapse	Lloyd et al., 2006
Colorectal cancer	IHC	γ2	Nodal involvement	Park et al., 2005
Colorectal carcinoma	IHC	β3, γ2, L n −332	invasion	Sordat et al., 2000
Gallbladder
Gallbladder carcinoma	IHC	γ2	Invasion	Eguchi et al., 2008
Gastric
Gastric carcinoma	IHC	α3	Invasion	Tani et al., 1996
Gastric carcinoma	IHC	α3		Tani et al., 1996
Gastric carcinoma	IHC	Ln −332		Tani et al., 1996
Gastric carcinoma	IHC	α3, β3		Koshikawa et al., 1999
Gastric carcinoma	IHC	γ2	Invasion	Koshikawa et al., 1999
Head and Neck
Oral squamous cell carcinoma	IHC, ISH	γ2	Invasion	Kainulainen et al., 1997
Oral squamous cell carcinoma	IHC	γ2	Invasion	Thorup et al., 1998
Oral squamous cell carcinoma	IHC	α3	Invasion	Kosmehl et al., 1999
Oral squamous cell carcinoma	IHC	γ2	Invasion	Berndt et al., 2001
Laryngeal carcinoma	IHC	γ2	Invasion, progression	Nordemar et al., 2001
Laryngeal carcinoma	IHC	γ2		Hagedorn et al., 2001
Esophageal squamous cell carcinoma	IHC	γ2	Invasion, survival	Yamamoto et al., 2001
Squamous cell carcinoma of tongue	IHC	γ2	Invasion, survival	Katoh et al., 2002
Squamous cell carcinoma of tongue	IHC	β3, γ2	Invasion	Akimoto et al., 2004
Squamous cell carcinoma of tongue	IHC	γ2	Survival	Ono et al., 1999
Squamous cell carcinoma of tongue	IHC	γ2		Lim et al., 2004
Squamous cell carcinoma of tongue	IHC	γ2		Korpi et al., 2008
Hypopharyngeal cancer	IHC	γ2	Stage, survival	Nakayama et al., 2004
Esophageal squamous cell carcinoma	IHC	γ2	Survival	Baba et al., 2006
Esophageal squamous cell carcinoma	IHC	γ2	Stage, survival	Baba et al., 2008
Oral squamous cell carcinoma	IHC	γ2	Invasion, survival	Gasparoni et al., 2007
Oral squamous cell carcinoma	IHC	γ2	Initial diagnosis	Driemel et al., 2007
Esophageal squamous cell carcinoma	IHC	γ2	Invasion, met., survival	Fukai et al., 2005
Head and neck squamous cell carcinoma	IHC	γ2	Invasion	Anderson et al., 2001
Preneoplastic oral lesions	IHC	γ2	Invasion, progression	Nordemar et al., 2003
Follicular thyroid carcinoma	IHC	α3, β3, γ2		Lohi et al., 1998
Liver
Hepatocellular carcinoma	IHC	γ2		Giannelli et al., 2001
Hepatocellular carcinoma	IHC, ISH, RT-PCR	α3, β3		Giannelli et al., 2003
Intrahepatic cholangiocarcinoma	IHC	γ2	Progression	Aishima et al., 2004
Hepatocellular carcinoma	IHC, ISH, RT-PCR	γ2	Metastasis	Giannelli et al., 2003
Lung
Lung adenocarcinoma	IHC	γ2	Invasion	Akashi et al., 2001
Lung adenocarcinoma	IHC	α3, β3		Kagesato et al., 2001
Lung adenocarcinoma	IHC	γ2	Invasion, survival	Moriya et al., 2001
Lung adenocarcinoma	IHC	γ2	Invasion	Kagesato et al., 2001
Squamous cell carcinoma of lung	IHC, ISH	γ2		Maatta et al., 1999
Large cell lung carcinoma	ISH	γ2		Maatta et al., 1999
Small cell lung carcinoma	ISH	γ2		Maatta et al., 1999
Bronchio-aveolar adenocarcinoma	ISH	γ2		Maatta et al., 1999
Pancreas
Pancreatic adenocarcinoma	IHC, ISH	γ2		Soini et al., 1996
Pancreatic ductal adenocarcinoma	IHC	γ2	Invasion	Fukushima et al., 2001
Pancreatic ductal adenocarcinoma	IHC	α3, β3, γ2		Tani et al., 1997
Pancreatic ductal adenocarcinoma	IHC	γ2	Invasion, survival	Takahashi et al., 2002
Prostate
Prostate carcinoma	IHC, ISH	γ2	Invasion	Hao et al., 1996
Prostate carcinoma	IHC	α3	Invasion	Hao et al., 1996
Prostate carcinoma	IHC, ISH	α3, β3, γ2		Hao et al., 2001
Prostate carcinoma	MS-PCR	α3, β3, γ2	Stage	Sathyanarayana et al., 2003b
Prostate carcinoma	IHC	α3		Hao et al., 1996
Other tissues
Basal cell carcinoma	IHC	Ln −332	Invasion	Schofield et al., 1998
Glioma	IHC	γ2		Fukushima et al., 1998
Leiomyosarcoma	ISH	γ2		Pyke et al., 1994
Leiomyosarcoma	IHC, ISH	γ2		Pyke et al., 1995
Melanoma	ISH	γ2		Pyke et al., 1994
Melanoma	IHC, ISH	γ2		Pyke et al., 1995
Papillary renal neoplasm	IHC	α3, β3		Lohi et al., 1996
Oncocytoma	IHC	α3, β3		Lohi et al., 1996
Squamous cell carcinoma	ISH	γ2		Pyke et al., 1994
Squamous cell carcinoma	IHC, ISH	γ2	Invasion	Pyke et al., 1995
Vaginal squamous cell carcinoma	IHC	γ2	Invasion, survival	Hellman et al., 2000
Cylindromatosis	IHC	α3, β3, γ2		Tunggal et al., 2002
Anogenital tract carcinoma	IHC	γ2	Invasion	Nordstrom et al., 2002
Ovarian clear cell carcinoma	IHC	γ2		Kato et al., 2007
Ovarian adenocarcinoma	IHC	Ln −332	Survival	Kohlberger et al., 2002

Open in a separate window

A study of 67 urothelial carcinomas revealed that γ2 over-expression is an effective independent prognostic indicator of intravesical recurrence (Kiyoshima et al., 2005). In hepatocellular cancers, γ2 is involved in epithelial to mesenchymal transition (Giannelli et al., 2005) and its detection is strongly associated with metastasis (Giannelli et al., 2003). Intriguingly, circulating γ2 fragments in serum are elevated in pancreatic ductal adenocarcinoma patients having liver metastases, particularly compared to those whose cancer has not spread, suggesting that circulating γ2 fragment may be useful as a prognostic indicator (Katayama et al., 2005).

Expression of Ln-332, particularly γ2, is implicated in progression of several types of head and neck cancer. MT1-MMP interaction with γ2 correlates with both metastasis and depth of invasion in esophageal squamous cell carcinomas (Shen et al., 2007). Transcrip-tome analysis unveiled LAMC2 among a panel of upregulated genes in oral tongue squamous cell carcinoma specimens (Ye et al., 2008). In colorectal (Sordat et al., 1998), anal (Nilsson et al., 2005), pancreatic (Soini et al., 1996), and gastric cancers (Koshikawa et al., 1999), differential γ2 localization or expression levels have been shown to be of prognostic value.

Fascinating observations have also been made concerning the role of Ln-332 in “vascular or vasculogenic mimicry”, defined as the ability of tumor cells (especially uveal melanoma) to take on endothelial-like morphology and produce functional vessels that anastomose with capillaries (Seftor et al., 2001; Hendrix et al., 2003). Seftor et al. previously showed that this phenomenon occurs in tumors that produce monomeric γ2 chain (Seftor et al., 2001), which has been shown to correlate with enhanced invasiveness in vivo (Koshikawa et al., 1999). Molecular and cellular mechanisms, however, remain to be elucidated.

Overall, these reports point to a possible role of Ln-332 γ2 as an indicator for prognosis in several types of cancer. In most cancer types, the general trend appears to be that overexpression of Ln-332 or one of its subunits, especially γ2, correlates with poor prognosis (Table 1). However, there are exceptions, such as breast and colon cancer, in which the presence of γ2 appears to predict better outcomes (Table 1). Clearly, more in-depth, perhaps standardized studies are necessary to solidify these trends.

6. Ln-332 γ2 and cancer: unanswered questions

A basic issue with reports of increases in Ln-332 γ2 staining in cancer specimens is that it is uncertain whether these are increases in protein level or simply reflect differential γ2 localization or cleavage within a tumor. Since γ2 is specific to Ln-332, it is frequently used as a surrogate marker for presence of the heterotrimer, thus examining expression of the other two chains is often neglected (see Table 1). The problem with this approach is that γ2 can be secreted as a monomer (Gagnoux-Palacios et al., 2001). Therefore, without verifying the presence of the other two chains, there remains ambiguity over the context of γ2 chain expression. This issue should be solved in future studies, since an antibody specific for the monomeric form of γ2 has been reported (Koshikawa et al., 2008).

Another area of concern is the wide variation in assessment techniques (see Table 1). For protein expression studies in human cancer tissue specimens, IHC has been widely used. It is well known that IHC methods are somewhat subjective, since various groups score staining intensity by differing protocols and criteria. For mRNA expression studies, ISH has been the most popular method, followed by northern blotting. The problem with both of these techniques is that there is no standard as to what probe is used. Taken together, these issues make it difficult to compare experimental results across studies from different laboratories.

Recently, we attempted to address this issue of standardizing studies by investigating the expression of γ2 chain in a collection of cancer specimens, analyzed by standardized cDNA microarray methods. While in the end only colorectal cancer specimen data were usable, nonetheless we were able to conclude that it is the decreased ratio of β3:γ2 mRNA expression that most closely correlates with progression to metastatic disease (Guess et al., 2009). We submit that the importance of our study is that it provides a standard approach to examine both heterotrimeric and monomeric γ2 chain expression, compatible for comparison across different studies.

7. Conclusions

Clearly, many additional investigations are necessary to clarify the role of Ln-332 and its subunits in carcinoma. In terms of expression, mining the cDNA expression microarray databases can be extremely valuable, as we reported (Guess et al., 2009). However, it will be necessary to complement these studies with protein expression methods, perhaps in tissue microarrays. In this respect, appropriate antibodies, e.g., to various forms of Ln-332 and its distinct subunits and/or cleavage products, would be necessary. Furthermore, standardized ways to score intensity of staining are also desirable.

In terms of mechanism, the key issue remains to distinguish between BM structural and signaling roles of Ln-332 in cancer. This multiplicity of roles complicates analyses, because any changes in ECM caused by the over- or under- expression of Ln-332, will affect cells in several ways: adhesion through hemidesmosomes would be altered, as would crosslinkages with other ECM molecules normally associate with Ln-332; there would be a change of the normal that cell-ECM communication process; the aberrant signaling coupled with the adhesive changes could work to the benefit of the tumor cells and lead to increased invasion and other devastating effects. Deconvolution of these effects would also be exacerbated by any increase in γ2 monomer levels, which results in distinct signaling as well (e.g. EGFR, PI3K activation).

A novel avenue of possible investigation is provided by the recent discovery that human papillomavirus-16 E6 oncogene leads to microRNA (miR) regulation of the LAMB3 gene through miR-218 in cervical cancer (Martinez et al., 2008), underscoring the importance of gene-level regulation of Ln-332 subunits in cancer progression.

In summary, studies at various levels of complexity are necessary to clarify the extent to which Ln-332 is involved in cancer progression mechanisms. Nonetheless, the utility of Ln-332 and its subunits as cancer prognostic indicators should not be difficult to realize.

Acknowledgements

We would like to thank Brandy Weidow for expert editorial assistance and Shanshan Liu for assistance with figure preparation. We would also like to acknowledge grant support given by the National Cancer Institute (Grant #3U54CA11300702S1).

Footnotes

¹The abbreviations used include: EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; EHS, Engelbreth–Holm–Swarm; EMT, epithelial to mesenchymal transition; HPV, human papillomavirus; IHC, immunohistochemistry; ISH, in situ hybridization; JEB, junctional epidermolysis bullosa; MS-PCR, methylation-specific PCR; MMP, metalloproteinase; PI3K, phosphoinositide 3-kinase; RT-PCR, reverse-transcription PCR.

References

Aberdam D, Galliano MF, Vailly J, Pulkkinen L, Bonifas J, Christiano AM, Tryggvason K, Uitto J, Epstein EH, Jr, Ortonne JP, et al. Herlitz's junctional epidermolysis bullosa is linked to mutations in the gene (LAMC2) for the gamma 2 subunit of nicein/kalinin (LAMININ-5) Nat Genet. 1994;6:299–304. [PubMed] [Google Scholar]
Adams JC. Molecular organisation of cell-matrix contacts: essential multiprotein assemblies in cell and tissue function. Expert Rev Mol Med. 2002;4:1–24. [PubMed] [Google Scholar]
Airenne T, Haakana H, Sainio K, Kallunki T, Kallunki P, Sariola H, Tryggvason K. Structure of the human laminin gamma 2 chain gene (LAMC2): alternative splicing with different tissue distribution of two transcripts. Genomics. 1996;32:54–64. [PubMed] [Google Scholar]
Aishima S, Matsuura S, Terashi T, Taguchi K, Shimada M, Maehara Y, Tsuneyoshi M. Aberrant expression of laminin gamma 2 chain and its prognostic significance in intrahepatic cholangiocarcinoma according to growth morphology. Mod Pathol. 2004;17:938–945. [PubMed] [Google Scholar]
Akashi T, Ito E, Eishi Y, Koike M, Nakamura K, Burgeson RE. Reduced expression of laminin alpha 3 and alpha 5 chains in non-small cell lung cancers. Jpn J Cancer Res. 2001;92:293–301. [PMC free article] [PubMed] [Google Scholar]
Akimoto S, Nakanishi Y, Sakamoto M, Kanai Y, Hirohashi S. Laminin 5 beta3 and gamma2 chains are frequently coexpressed in cancer cells. Pathol Int. 2004;54:688–692. [PubMed] [Google Scholar]
Amano S, Scott IC, Takahara K, Koch M, Champliaud MF, Gerecke DR, Keene DR, Hudson DL, Nishiyama T, Lee S, Greenspan DS, Burgeson RE. Bone morphogenetic protein 1 is an extracellular processing enzyme of the laminin 5 gamma 2 chain. J Biol Chem. 2000;275:22728–22735. [PubMed] [Google Scholar]
Anderson TD, Feldman M, Weber RS, Ziober AF, Ziober BL. Tumor deposition of laminin-5 and the relationship with perineural invasion. Laryngoscope. 2001;111:2140–2143. [PubMed] [Google Scholar]
Andersson S, Hellstrom AC, Angstrom T, Stendahl U, Auer G, Wallin KL. The clinicopathologic significance of laminin-5 gamma2 chain expression in cervical squamous carcinoma and adenocarcinoma. Int J Gynecol Cancer. 2005;15:1065–1072. [PubMed] [Google Scholar]
Aoki S, Nakanishi Y, Akimoto S, Moriya Y, Yoshimura K, Kitajima M, Sakamoto M, Hirohashi S. Prognostic significance of laminin-5 gamma2 chain expression in colorectal carcinoma: immunohistochemical analysis of 103 cases. Dis Colon Rectum. 2002;45:1520–1527. [PubMed] [Google Scholar]
Aumailley M, Smyth N. The role of laminins in basement membrane function. J Anat. 1998;193(Pt 1):1–21. [PMC free article] [PubMed] [Google Scholar]
Aumailley M, Bruckner-Tuderman L, Carter WG, Deutzmann R, Edgar D, Ekblom P, Engel J, Engvall E, Hohenester E, Jones JC, Kleinman HK, Marinkovich MP, Martin GR, Mayer U, Meneguzzi G, Miner JH, Miyazaki K, Patarroyo M, Paulsson M, Quaranta V, Sanes JR, Sasaki T, Sekiguchi K, Sorokin LM, Talts JF, Tryggvason K, Uitto J, Virtanen I, von der Mark K, Wewer UM, Yamada Y, Yurchenco PD. A simplified laminin nomenclature. Matrix Biol. 2005;24:326–332. [PubMed] [Google Scholar]
Aznavoorian S, Murphy AN, Stetler-Stevenson WG, Liotta LA. Molecular aspects of tumor cell invasion and metastasis. Cancer. 1993;71:1368–1383. [PubMed] [Google Scholar]
Baba Y, Iyama K, Honda S, Ishikawa S, Miyanari N, Baba H. Cytoplasmic expression of type VII collagen is related to prognosis in patients with esophageal squamous cell carcinoma. Oncology. 2006;71:221–228. [PubMed] [Google Scholar]
Baba Y, Iyama KI, Hirashima K, Nagai Y, Yoshida N, Hayashi N, Miyanari N, Baba H. Laminin-332 promotes the invasion of oesophageal squamous cell carcinoma via PI3K activation. Br J Cancer. 2008;98:974–980. [PMC free article] [PubMed] [Google Scholar]
Beck K, Hunter I, Engel J. Structure and function of laminin: anatomy of a multidomain glycoprotein. FASEB J. 1990;4:148–160. [PubMed] [Google Scholar]
Beck K, Dixon TW, Engel J, Parry DA. Ionic interactions in the coiled-coil domain of laminin determine the specificity of chain assembly. J Mol Biol. 1993;231:311–323. [PubMed] [Google Scholar]
Berndt A, Borsi L, Hyckel P, Kosmehl H. Fibrillary co-deposition of laminin-5 and large unspliced tenascin-C in the invasive front of oral squamous cell carcinoma in vivo and in vitro. J Cancer Res Clin Oncol. 2001;127:286–292. [PubMed] [Google Scholar]
Borradori L, Sonnenberg A. Structure and function of hemidesmosomes: more than simple adhesion complexes. J Invest Dermatol. 1999;112:411–418. [PubMed] [Google Scholar]
Bracke ME, Van Roy FM, Mareel MM. The E-cadherin/catenin complex in invasion and metastasis. Curr Top Microbiol Immunol. 1996;213(Pt 1):123–161. [PubMed] [Google Scholar]
Briggaman RA, Wheeler CE., Jr The epidermal-dermal junction. J Invest Dermatol. 1975;65:71–84. [PubMed] [Google Scholar]
Burgeson RE, Chiquet M, Deutzmann R, Ekblom P, Engel J, Kleinman H, Martin GR, Meneguzzi G, Paulsson M, Sanes J, et al. A new nomenclature for the laminins. Matrix Biol. 1994;14:209–211. [PubMed] [Google Scholar]
Calaluce R, Bearss DJ, Barrera J, Zhao Y, Han H, Beck SK, McDaniel K, Nagle RB. Laminin-5 beta3A expression in LNCaP human prostate carcinoma cells increases cell migration and tumorigenicity. Neoplasia. 2004;6:468–479. [PMC free article] [PubMed] [Google Scholar]
Carpenter PM, Wang-Rodriguez J, Chan OT, Wilczynski SP. Laminin 5 expression in metaplastic breast carcinomas. Am J Surg Pathol. 2008;32:345–353. [PubMed] [Google Scholar]
Carter WG, Ryan MC, Gahr PJ. Epiligrin, a new cell adhesion ligand for integrin alpha 3 beta 1 in epithelial basement membranes. Cell. 1991;65:599–610. [PubMed] [Google Scholar]
Chambers AF, Matrisian LM. Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst. 1997;89:1260–1270. [PubMed] [Google Scholar]
Chambers AF, Naumov GN, Vantyghem SA, Tuck AB. Molecular biology of breast cancer metastasis. Clinical implications of experimental studies on metastatic inefficiency. Breast Cancer Res. 2000;2:400–407. [PMC free article] [PubMed] [Google Scholar]
Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2:563–572. [PubMed] [Google Scholar]
Champliaud MF, Lunstrum GP, Rousselle P, Nishiyama T, Keene DR, Burgeson RE. Human amnion contains a novel laminin variant, laminin 7, which like laminin 6, covalently associates with laminin 5 to promote stable epithelial-stromal attachment. J Cell Biol. 1996;132:1189–1198. [PMC free article] [PubMed] [Google Scholar]
Chen M, Marinkovich MP, Jones JC, O'Toole EA, Li YY, Woodley DT. NC1 domain of type VII collagen binds to the beta3 chain of laminin 5 via a unique subdomain within the fibronectin-like repeats. J Invest Dermatol. 1999;112:177–183. [PubMed] [Google Scholar]
Colognato H, Yurchenco PD. Form and function: the laminin family of heterotrimers. Dev Dyn. 2000;218:213–234. [PubMed] [Google Scholar]
Couzin J. Medicine. Tracing the steps of metastasis, cancer's menacing ballet. Science. 2003;299:1002–1006. [PubMed] [Google Scholar]
Decline F, Rousselle P. Keratinocyte migration requires alpha2beta1 integrin-mediated interaction with the laminin 5 gamma2 chain. J Cell Sci. 2001;114:811–823. [PubMed] [Google Scholar]
Domloge-Hultsch N, Gammon WR, Briggaman RA, Gil SG, Carter WG, Yancey KB. Epiligrin, the major human keratinocyte integrin ligand, is a target in both an acquired autoimmune and an inherited subepidermal blistering skin disease. J Clin Invest. 1992;90:1628–1633. [PMC free article] [PubMed] [Google Scholar]
Driemel O, Dahse R, Hakim SG, Tsioutsias T, Pistner H, Reichert TE, Kosmehl H. Laminin-5 immunocytochemistry: a new tool for identifying dysplastic cells in oral brush biopsies. Cytopathology. 2007;18:348–355. [PubMed] [Google Scholar]
Eguchi T, Inoue T, Fujii K, Yamaguchi H, Nishiyama K, Yonemasu H, Yao T, Tanaka M, Tsuneyoshi M. Laminin-5 (gamma2 chain) is a marker of invading cancer cells in human gallbladder carcinoma: special emphasis on extension of carcinoma in situ along Rokitansky-Aschoff sinuses. Oncol Rep. 2008;20:33–39. [PubMed] [Google Scholar]
Ewing J. Neoplastic diseases. 6th edn. Philadelphia: WB Saunders; 1928. [Google Scholar]
Ferrigno O, Virolle T, Galliano MF, Chauvin N, Ortonne JP, Meneguzzi G, Aberdam D. Murine laminin alpha3A and alpha3B isoform chains are generated by usage of two promoters and alternative splicing. J Biol Chem. 1997;272:20502–20507. [PubMed] [Google Scholar]
Fidler IJ. Critical determinants of metastasis. Semin Cancer Biol. 2002;12:89–96. [PubMed] [Google Scholar]
Fokas E, Engenhart-Cabillic R, Daniilidis K, Rose F, An HX. Metastasis: the seed and soil theory gains identity. Cancer Metastasis Rev. 2007;26:705–715. [PubMed] [Google Scholar]
Friedl P, Brocker EB. The biology of cell locomotion within three-dimensional extracellular matrix. Cell Mol Life Sci. 2000;57:41–64. [PMC free article] [PubMed] [Google Scholar]
Fukai Y, Masuda N, Kato H, Fukuchi M, Miyazaki T, Nakajima M, Sohda M, Kuwano H, Nakajima T. Correlation between laminin-5 gamma2 chain and epidermal growth factor receptor expression in esophageal squamous cell carcinomas. Oncology. 2005;69:71–80. [PubMed] [Google Scholar]
Fukushima Y, Ohnishi T, Arita N, Hayakawa T, Sekiguchi K. Integrin alpha3beta1-mediated interaction with laminin-5 stimulates adhesion, migration and invasion of malignant glioma cells. Int J Cancer. 1998;76:63–72. [PubMed] [Google Scholar]
Fukushima N, Sakamoto M, Hirohashi S. Expression of laminin-5-gamma-2 chain in intraductal papillary-mucinous and invasive ductal tumors of the pancreas. Mod Pathol. 2001;14:404–409. [PubMed] [Google Scholar]
Gagnoux-Palacios L, Allegra M, Spirito F, Pommeret O, Romero C, Ortonne JP, Meneguzzi G. The short arm of the laminin gamma2 chain plays a pivotal role in the incorporation of laminin 5 into the extracellular matrix and in cell adhesion. J Cell Biol. 2001;153:835–850. [PMC free article] [PubMed] [Google Scholar]
Gasparoni A, Della Casa M, Milillo L, Lorenzini G, Rubini C, Urso R, Lo Muzio L. Prognostic value of differential expression of Laminin-5 gamma2 in oral squamous cell carcinomas: correlation with survival. Oncol Rep. 2007;18:793–800. [PubMed] [Google Scholar]
Gerecke DR, Wagman DW, Champliaud MF, Burgeson RE. The complete primary structure for a novel laminin chain, the laminin B1k chain. J Biol Chem. 1994;269:11073–11080. [PubMed] [Google Scholar]
Giannelli G, Falk-Marzillier J, Schiraldi O, Stetler-Stevenson WG, Quaranta V. Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science. 1997;277:225–228. [PubMed] [Google Scholar]
Giannelli G, Pozzi A, Stetler-Stevenson WG, Gardner HA, Quaranta V. Expression of matrix metalloprotease-2-cleaved laminin-5 in breast remodeling stimulated by sex steroids. Am J Pathol. 1999;154:1193–1201. [PMC free article] [PubMed] [Google Scholar]
Giannelli G, Bergamini C, Fransvea E, Marinosci F, Quaranta V, Antonaci S. Human hepatocellular carcinoma (HCC) cells require both alpha3beta1 integrin and matrix metalloproteinases activity for migration and invasion. Lab Invest. 2001;81:613–627. [PubMed] [Google Scholar]
Giannelli G, Fransvea E, Bergamini C, Marinosci F, Antonaci S. Laminin-5 chains are expressed differentially in metastatic and nonmetastatic hepatocellular carcinoma. Clin Cancer Res. 2003;9:3684–3691. [PubMed] [Google Scholar]
Giannelli G, Bergamini C, Fransvea E, Sgarra C, Antonaci S. Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular. 2005 [PubMed] [Google Scholar]
Gilles C, Polette M, Coraux C, Tournier JM, Meneguzzi G, Munaut C, Volders L, Rousselle P, Birembaut P, Foidart JM. Contribution of MT1-MMP and of human laminin-5 gamma2 chain degradation to mammary epithelial cell migration. J Cell Sci. 2001;114:2967–2976. [PMC free article] [PubMed] [Google Scholar]
Guess CM, LaFleur BJ, Weidow BL, Quaranta V. A decreased ratio of Laminin-332 Beta3 to Gamma2 subunit mRNA is associated with poor prognosis in colon cancer. CEBP. 2009;18(5):1584–1590. [PMC free article] [PubMed] [Google Scholar]
Habermann J, Lenander C, Roblick UJ, Kruger S, Ludwig D, Alaiya A, Freitag S, Dumbgen L, Bruch HP, Stange E, Salo S, Tryggvason K, Auer G, Schimmelpenning H. Ulcerative colitis and colorectal carcinoma: DNA-profile, laminin-5 gamma2 chain and cyclin A expression as early markers for risk assessment. Scand J Gastroenterol. 2001;36:751–758. [PubMed] [Google Scholar]
Hagedorn HG, Sauer U, Schleicher ED, Nerlich AG. Divergence in distribution and prognostic significance of major basement components in laryngeal carcinomas. Int J Oncol. 2001;18:1045–1051. [PubMed] [Google Scholar]
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70. [PubMed] [Google Scholar]
Hao J, Yang Y, McDaniel KM, Dalkin BL, Cress AE, Nagle RB. Differential expression of laminin 5 (alpha 3 beta 3 gamma 2) by human malignant and normal prostate. Am J Pathol. 1996;149:1341–1349. [PMC free article] [PubMed] [Google Scholar]
Hao J, Jackson L, Calaluce R, McDaniel K, Dalkin BL, Nagle RB. Investigation into the mechanism of the loss of laminin 5 (alpha3beta3gamma2) expression in prostate cancer. Am J Pathol. 2001;158:1129–1135. [PMC free article] [PubMed] [Google Scholar]
Hao J, McDaniel K, Weyer C, Barrera J, Nagle RB. Cell line-specific translation of two laminin 5 beta3 chain isoforms. Gene. 2002;283:237–244. [PubMed] [Google Scholar]
Heinonen S, Mannikko M, Klement JF, Whitaker-Menezes D, Murphy GF, Uitto J. Targeted inactivation of the type VII collagen gene (Col7a1) in mice results in severe blistering phenotype: a model for recessive dystrophic epidermolysis bullosa. J Cell Sci. 1999;112(Pt 21):3641–3648. [PubMed] [Google Scholar]
Hellman K, Hellstrom AC, Silfversward C, Salo S, Aspenblad U, Nilsson B, Frankendal B, Tryggvasson K, Auer G. Cancer of the vagina: Laminin-5gamma2 chain expression and prognosis. Int J Gynecol Cancer. 2000;10:391–396. [PubMed] [Google Scholar]
Hendrix MJC, Seftor EA, Hess AR, Seftor REB. Vasculogenic mimicry and tumour-cell plasticity: Lessons from melanoma. Nat Rev Cancer. 2003;3(6):411–421. [PubMed] [Google Scholar]
Hintermann E, Quaranta V. Epithelial cell motility on laminin-5: regulation by matrix assembly, proteolysis, integrins and erbB receptors. Matrix Biol. 2004;23:75–85. [PubMed] [Google Scholar]
Hlubek F, Jung A, Kotzor N, Kirchner T, Brabletz T. Expression of the invasion factor laminin gamma2 in colorectal carcinomas is regulated by beta-catenin. Cancer Res. 2001;61:8089–8093. [PubMed] [Google Scholar]
Hojima Y, van der Rest M, Prockop DJ. Type I procollagen carboxyl-terminal proteinase from chick embryo tendons. Purification and characterization. J Biol Chem. 1985;260:15996–16003. [PubMed] [Google Scholar]
Hulmes DJ. The collagen superfamily–diverse structures and assemblies. Essays Biochem. 1992;27:49–67. [PubMed] [Google Scholar]
Iozzo RV. Matrix proteoglycans: from molecular design to cellular function. Annu Rev Biochem. 1998;67:609–652. [PubMed] [Google Scholar]
Kagesato Y, Mizushima H, Koshikawa N, Kitamura H, Hayashi H, Ogawa N, Tsukuda M, Miyazaki K. Sole expression of laminin gamma 2 chain in invading tumor cells and its association with stromal fibrosis in lung adenocarcinomas. Jpn J Cancer Res. 2001;92:184–192. [PMC free article] [PubMed] [Google Scholar]
Kainulainen T, Autio-Harmainen H, Oikarinen A, Salo S, Tryggvason K, Salo T. Altered distribution and synthesis of laminin-5 (kalinin) in oral lichen planus, epithelial dysplasias and squamous cell carcinomas. Br J Dermatol. 1997;136:331–336. [PubMed] [Google Scholar]
Kariya Y, Yasuda C, Nakashima Y, Ishida K, Tsubota Y, Miyazaki K. Characterization of laminin 5B and NH2-terminal proteolytic fragment of its alpha3B chain: promotion of cellular adhesion, migration, and proliferation. J Biol Chem. 2004;279:24774–24784. [PubMed] [Google Scholar]
Katayama M, Sekiguchi K. Laminin-5 in epithelial tumour invasion. J Mol Histol. 2004;35:277–286. [PubMed] [Google Scholar]
Katayama M, Funakoshi A, Sumii T, Sanzen N, Sekiguchi K. Laminin γ2-chain fragment circulating level increases in patients with metastatic pancreatic ductal cell adenocarcinomas. Cancer Lett. 2005;225:167–176. [PubMed] [Google Scholar]
Kato N, Sasou S, Teshima S, Motoyama T. Overexpression of laminin-5 gamma2 chain in clear cell carcinoma of the ovary. Virchows Arch. 2007;450:273–278. [PubMed] [Google Scholar]
Katoh K, Nakanishi Y, Akimoto S, Yoshimura K, Takagi M, Sakamoto M, Hirohashi S. Correlation between laminin-5 gamma2 chain expression and epidermal growth factor receptor expression and its clinicopathological significance in squamous cell carcinoma of the tongue. Oncology. 2002;62:318–326. [PubMed] [Google Scholar]
Keene DR, Sakai LY, Lunstrum GP, Morris NP, Burgeson RE. Type VII collagen forms an extended network of anchoring fibrils. J Cell Biol. 1987;104:611–621. [PMC free article] [PubMed] [Google Scholar]
Kivirikko S, McGrath JA, Pulkkinen L, Uitto J, Christiano AM. Mutational hotspots in the LAMB3 gene in the lethal (Herlitz) type of junctional epidermolysis bullosa. Hum Mol Genet. 1996;5:231–237. [PubMed] [Google Scholar]
Kiyoshima K, Oda Y, Kinukawa N, Naito S, Tsuneyoshi M. Overexpression of laminin-5 gamma2 chain and its prognostic significance in urothelial carcinoma of urinary bladder: association with expression of cyclooxygenase 2, epidermal growth factor receptor and human epidermal growth factor receptor [corrected] 2. Hum Pathol. 2005;36:522–530. [PubMed] [Google Scholar]
Kohlberger P, Muller-Klingspor V, Heinzl H, Obermair A, Breitenecker G, Leodolter S. Prognostic value of laminin-5 in serous adenocarcinomas of the ovary. Anticancer Res. 2002;22:3541–3544. [PubMed] [Google Scholar]
Komoriya A, Green LJ, Mervic M, Yamada SS, Yamada KM, Humphries MJ. The minimal essential sequence for a major cell type-specific adhesion site (CS1) within the alternatively spliced type III connecting segment domain of fibronectin is leucine-aspartic acid-valine. J Biol Chem. 1991;266:15075–15079. [PubMed] [Google Scholar]
Korpi JT, Kervinen V, Maklin H, Vaananen A, Lahtinen M, Laara E, Ristimaki A, Thomas G, Ylipalosaari M, Astrom P, Lopez-Otin C, Sorsa T, Kantola S, Pirila E, Salo T. Collagenase-2 (matrix metalloproteinase-8) plays a protective role in tongue cancer. Br J Cancer. 2008;98:766–775. [PMC free article] [PubMed] [Google Scholar]
Koshikawa N, Moriyama K, Takamura H, Mizushima H, Nagashima Y, Yanoma S, Miyazaki K. Overexpression of laminin gamma2 chain monomer in invading gastric carcinoma cells. Cancer Res. 1999;59:5596–5601. [PubMed] [Google Scholar]
Koshikawa N, Giannelli G, Cirulli V, Miyazaki K, Quaranta V. Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5. J Cell Biol. 2000;148:615–624. [PMC free article] [PubMed] [Google Scholar]
Koshikawa N, Schenk S, Moeckel G, Sharabi A, Miyazaki K, Gardner H, Zent R, Quaranta V. Proteolytic processing of laminin-5 by MT1-MMP in tissues and its effects on epithelial cell morphology. FASEB J. 2004;18:364–366. [PubMed] [Google Scholar]
Koshikawa N, Minegishi T, Sharabi A, Quaranta V, Seiki M. Membrane-type matrix metalloproteinase-1 (MT1-MMP) is a processing enzyme for human laminin gamma 2 chain. J Biol Chem. 2005;280:88–93. [PubMed] [Google Scholar]
Koshikawa N, Minegishi T, Nabeshima K, Seiki M. Development of a new tracking tool for the human monomeric laminin-gamma 2 chain in vitro and in vivo. Cancer Res. 2008;68:530–536. [PubMed] [Google Scholar]
Kosmehl H, Berndt A, Strassburger S, Borsi L, Rousselle P, Mandel U, Hyckel P, Zardi L, Katenkamp D. Distribution of laminin and fibronectin isoforms in oral mucosa and oral squamous cell carcinoma. Br J Cancer. 1999;81:1071–1079. [PMC free article] [PubMed] [Google Scholar]
Kuang W, Xu H, Vachon PH, Liu L, Loechel F, Wewer UM, Engvall E. Merosin-deficient congenital muscular dystrophy. Partial genetic correction in two mouse models. J Clin Invest. 1998;102:844–852. [PMC free article] [PubMed] [Google Scholar]
Lander AD, Selleck SB. The elusive functions of proteoglycans: in vivo veritas. J Cell Biol. 2000;148:227–232. [PMC free article] [PubMed] [Google Scholar]
LeBleu VS, Macdonald B, Kalluri R. Structure and function of basement membranes. Exp Biol Med (Maywood) 2007;232:1121–1129. [PubMed] [Google Scholar]
Lenander C, Habermann JK, Ost A, Nilsson B, Schimmelpenning H, Tryggvason K, Auer G. Laminin-5 gamma 2 chain expression correlates with unfavorable prognosis in colon carcinomas. Anal Cell Pathol. 2001;22:201–209. [PMC free article] [PubMed] [Google Scholar]
Lenander C, Roblick UJ, Habermann JK, Ost A, Tryggvason K, Auer G. Laminin 5 gamma 2 chain expression, a marker of early invasiveness in colorectal adenomas. Mol Pathol. 2003;56:342–346. [PMC free article] [PubMed] [Google Scholar]
Li S, Edgar D, Fassler R, Wadsworth W, Yurchenco PD. The role of laminin in embryonic cell polarization and tissue organization. Dev Cell. 2003;4:613–624. [PubMed] [Google Scholar]
Lim SC, Zhang S, Ishii G, Endoh Y, Kodama K, Miyamoto S, Hayashi R, Ebihara S, Cho JS, Ochiai A. Predictive markers for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral tongue. Clin Cancer Res. 2004;10:166–172. [PubMed] [Google Scholar]
Liotta LA, Stetler-Stevenson WG. Tumor invasion and metastasis: an imbalance of positive and negative regulation. Cancer Res. 1991;51 5054s-5059s. [PubMed] [Google Scholar]
Lloyd JM, McIver CM, Stephenson SA, Hewett PJ, Rieger N, Hardingham JE. Identification of early-stage colorectal cancer patients at risk of relapse post-resection by immunobead reverse transcription-PCR analysis of peritoneal lavage fluid for malignant cells. Clin Cancer Res. 2006;12:417–423. [PubMed] [Google Scholar]
Lohi J, Tani T, Leivo I, Linnala A, Kangas L, Burgeson RE, Lehto VP, Virtanen I. Expression of laminin in renal-cell carcinomas, renal-cell carcinoma cell lines and xenografts in nude mice. Int J Cancer. 1996;68:364–371. [PubMed] [Google Scholar]
Lohi J, Leivo I, Owaribe K, Burgeson RE, Franssila K, Virtanen I. Neoexpression of the epithelial adhesion complex antigens in thyroid tumours is associated with proliferation and squamous differentiation markers. J Pathol. 1998;184:191–196. [PubMed] [Google Scholar]
Lohi J, Oivula J, Kivilaakso E, Kiviluoto T, Frojdman K, Yamada Y, Burgeson RE, Leivo I, Virtanen I. Basement membrane laminin-5 is deposited in colorectal adenomas and carcinomas and serves as a ligand for alpha3beta1 integrin. APMIS. 2000;108:161–172. [PubMed] [Google Scholar]
Maatta M, Soini Y, Paakko P, Salo S, Tryggvason K, Autio-Harmainen H. Expression of the laminin gamma2 chain in different histological types of lung carcinoma. A study by immunohistochemistry and in situ hybridization. J Pathol. 1999;188:361–368. [PubMed] [Google Scholar]
Marinkovich MP. Laminin 332 in squamous-cell carcinoma. Nature Reviews Cancer. 2007;7(5):370–380. [PubMed] [Google Scholar]
Marinkovich MP, Verrando P, Keene DR, Meneguzzi G, Lunstrum GP, Ortonne JP, Burgeson RE. Basement membrane proteins kalinin and nicein are structurally and immunologically identical. Lab Invest. 1993;69:295–299. [PubMed] [Google Scholar]
Martinez I, Gardiner AS, Board KF, Monzon FA, Edwards RP, Khan SA. Human papillomavirus type 16 reduces the expression of microRNA-218 in cervical carcinoma cells. Oncogene. 2008;27:2575–2582. [PMC free article] [PubMed] [Google Scholar]
Masaki T, Matsuoka H, Sugiyama M, Abe N, Izumisato Y, Sakamoto A, Atomi Y. Laminin-5 gamma2 chain expression as a possible determinant of tumor aggressiveness in T1 colorectal carcinomas. Dig Dis Sci. 2003;48:272–278. [PubMed] [Google Scholar]
Meneguzzi G, Marinkovich MP, Aberdam D, Pisani A, Burgeson R, Ortonne JP. Kalinin is abnormally expressed in epithelial basement membranes of Herlitz's junctional epidermolysis bullosa patients. Exp Dermatol. 1992;1:221–229. [PubMed] [Google Scholar]
Mercurio AM, Bachelder RE, Rabinovitz I, O'Connor KL, Tani T, Shaw LM. The metastatic odyssey: the integrin connection. Surg Oncol Clin N Am. 2001;10:313–328. viii–ix. [PubMed] [Google Scholar]
Miner JH, Yurchenco PD. Laminin functions in tissue morphogenesis. Annu Rev Cell Dev Biol. 2004;20:255–284. [PubMed] [Google Scholar]
Miner JH, Cunningham J, Sanes JR. Roles for laminin in embryogenesis: exencephaly, syndactyly, and placentopathy in mice lacking the laminin alpha5 chain. J Cell Biol. 1998;143:1713–1723. [PMC free article] [PubMed] [Google Scholar]
Miyagoe Y, Hanaoka K, Nonaka I, Hayasaka M, Nabeshima Y, Arahata K, Takeda S. Laminin alpha2 chain-null mutant mice by targeted disruption of the Lama2 gene: a new model of merosin (laminin 2)-deficient congenital muscular dystrophy. FEBS Lett. 1997;415:33–39. [PubMed] [Google Scholar]
Miyazaki K, Kikkawa Y, Nakamura A, Yasumitsu H, Umeda M. A large cell-adhesive scatter factor secreted by human gastric carcinoma cells. Proc Natl Acad Sci U S A. 1993;90:11767–11771. [PMC free article] [PubMed] [Google Scholar]
Mizushima H, Miyagi Y, Kikkawa Y, Yamanaka N, Yasumitsu H, Misugi K, Miyazaki K. Differential expression of laminin-5/ladsin subunits in human tissues and cancer cell lines and their induction by tumor promoter and growth factors. J Biochem. 1996;120:1196–1202. [PubMed] [Google Scholar]
Mizushima H, Koshikawa N, Moriyama K, Takamura H, Nagashima Y, Hirahara F, Miyazaki K. Wide distribution of laminin-5 gamma 2 chain in basement membranes of various human tissues. Horm Res. 1998;50 Suppl 2:7–14. [PubMed] [Google Scholar]
Moriya Y, Niki T, Yamada T, Matsuno Y, Kondo H, Hirohashi S. Increased expression of laminin-5 and its prognostic significance in lung adenocarcinomas of small size. An immunohistochemical analysis of 102 cases. Cancer. 2001;91:1129–1141. [PubMed] [Google Scholar]
Nakashima Y, Kariya Y, Yasuda C, Miyazaki K. Regulation of cell adhesion and type VII collagen binding by the beta3 chain short arm of laminin-5: effect of its proteolytic cleavage. J Biochem. 2005;138:539–552. [PubMed] [Google Scholar]
Nakayama M, Sato Y, Okamoto M, Hirohashi S. Increased expression of laminin-5 and its prognostic significance in hypopharyngeal cancer. Laryngoscope. 2004;114:1259–1263. [PubMed] [Google Scholar]
Negri G, Romano F, Vittadello F, Kasal A, Mazzoleni G, Colombetti V, Egarter-Vigl E. Laminin-5 gamma2 chain immunohistochemistry facilitates the assessment of invasiveness and improves the diagnostic reproducibility of glandular lesions of the cervix uteri. Hum Pathol. 2006;37:704–710. [PubMed] [Google Scholar]
Nievers MG, Schaapveld RQ, Sonnenberg A. Biology and function of hemidesmosomes. Matrix Biol. 1999;18:5–17. [PubMed] [Google Scholar]
Nilsson PJ, Rubio C, Lenander C, Auer G, Glimelius B. Tumour budding detected by laminin-5 {gamma}2-chain immunohistochemistry is of prognostic value in epidermoid anal cancer. Ann Oncol. 2005;16:893–898. [PubMed] [Google Scholar]
Noakes PG, Miner JH, Gautam M, Cunningham JM, Sanes JR, Merlie JP. The renal glomerulus of mice lacking s-laminin/laminin beta 2: nephrosis despite molecular compensation by laminin beta 1. Nat Genet. 1995;10:400–406. [PubMed] [Google Scholar]
Noel JC, Fernandez-Aguilar S, Fayt I, Buxant F, Ansion MH, Simon P, Anaf V. Laminin-5 gamma 2 chain expression in cervical intraepithelial neoplasia and invasive cervical carcinoma. Acta Obstet Gynecol Scand. 2005;84:1119–1123. [PubMed] [Google Scholar]
Nordemar S, Kronenwett U, Auer G, Hogmo A, Lindholm J, Edstrom S, Tryggvasson K, Linder S, Munck-Wikland E. Laminin-5 as a predictor of invasiveness in cancer in situ lesions of the larynx. Anticancer Res. 2001;21:509–512. [PubMed] [Google Scholar]
Nordemar S, Hogmo A, Lindholm J, Auer G, Munck-Wikland E. Laminin-5 gamma 2: a marker to identify oral mucosal lesions at risk for tumor development? Anticancer Res. 2003;23:4985–4989. [PubMed] [Google Scholar]
Nordstrom B, Einhorn N, Silfversward C, Sjovall K, Tryggvason K, Auer G. Laminin-5 gamma 2 chain as an invasivity marker for uni- and multifocal lesions in the lower anogenital tract. Int J Gynecol Cancer. 2002;12:105–109. [PubMed] [Google Scholar]
Oku N, Sasabe E, Ueta E, Yamamoto T, Osaki T. Tight junction protein claudin-1 enhances the invasive activity of oral squamous cell carcinoma cells by promoting cleavage of laminin-5 gamma2 chain via matrix metalloproteinase (MMP)-2 and membrane-type MMP-1. Cancer Res. 2006;66:5251–5257. [PubMed] [Google Scholar]
Ono Y, Nakanishi Y, Ino Y, Niki T, Yamada T, Yoshimura K, Saikawa M, Nakajima T, Hirohashi S. Clinocopathologic significance of laminin-5 gamma2 chain expression in squamous cell carcinoma of the tongue: immunohistochemical analysis of 67 lesions. Cancer. 1999;85:2315–2321. [PubMed] [Google Scholar]
Ono Y, Nakanishi Y, Gotoh M, Sakamoto M, Hirohashi S. Epidermal growth factor receptor gene amplification is correlated with laminin-5 gamma2 chain expression in oral squamous cell carcinoma cell lines. Cancer Lett. 2002;175:197–204. [PubMed] [Google Scholar]
Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 1989;8:98–101. [PubMed] [Google Scholar]
Park SY, Choe G, Lee HS, Jung SY, Park JG, Kim WH. Tumor budding as an indicator of isolated tumor cells in lymph nodes from patients with node-negative colorectal cancer. Dis Colon Rectum. 2005;48:292–302. [PubMed] [Google Scholar]
Pierschbacher MD, Ruoslahti E. Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule. Nature. 1984;309:30–33. [PubMed] [Google Scholar]
Pirila E, Sharabi A, Salo T, Quaranta V, Tu H, Heljasvaara R, Koshikawa N, Sorsa T, Maisi P. Matrix metalloproteinases process the laminin-5 gamma 2-chain and regulate epithelial cell migration. Biochem Biophys Res Commun. 2003;303:1012–1017. [PubMed] [Google Scholar]
Pulkkinen L, Uitto J. Mutation analysis and molecular genetics of epidermolysis bullosa. Matrix Biol. 1999;18:29–42. [PubMed] [Google Scholar]
Pulkkinen L, Christiano AM, Airenne T, Haakana H, Tryggvason K, Uitto J. Mutations in the gamma 2 chain gene (LAMC2) of kalinin/laminin 5 in the junctional forms of epidermolysis bullosa. Nat Genet. 1994a;6:293–297. [PubMed] [Google Scholar]
Pulkkinen L, Christiano AM, Gerecke D, Wagman DW, Burgeson RE, Pittelkow MR, Uitto J. A homozygous nonsense mutation in the beta 3 chain gene of laminin 5 (LAMB3) in Herlitz junctional epidermolysis bullosa. Genomics. 1994b;24:357–360. [PubMed] [Google Scholar]
Pulkkinenm L, Gerecke DR, Christiano AM, Wagman DW, Burgeson RE, Uitto J. Cloning of the beta 3 chain gene (LAMB3) of human laminin 5, a candidate gene in junctional epidermolysis bullosa. Genomics. 1995a;25:192–198. [PubMed] [Google Scholar]
Pulkkinen L, McGrath JA, Christiano AM, Uitto J. Detection of sequence variants in the gene encoding the beta 3 chain of laminin 5 (LAMB3) Hum Mutat. 1995b;6:77–84. [PubMed] [Google Scholar]
Pyke C, Romer J, Kallunki P, Lund LR, Ralfkiaer E, Dano K, Tryggvason K. The gamma 2 chain of kalinin/laminin 5 is preferentially expressed in invading malignant cells in human cancers. Am J Pathol. 1994;145:782–791. [PMC free article] [PubMed] [Google Scholar]
Pyke C, Salo S, Ralfkiaer E, Romer J, Dano K, Tryggvason K. Laminin-5 is a marker of invading cancer cells in some human carcinomas and is coexpressed with the receptor for urokinase plasminogen activator in budding cancer cells in colon adenocarcinomas. Cancer Res. 1995;55:4132–4139. [PubMed] [Google Scholar]
Richter P, Bohmer FD, Hindermann W, Borsi L, Hyckel P, Schleier P, Katenkamp D, Kosmehl H, Berndt A. Analysis of activated EGFR signalling pathways and their relation to laminin-5 gamma2 chain expression in oral squamous cell carcinoma (OSCC) Histochem Cell Biol. 2005;124:151–160. [PubMed] [Google Scholar]
Robbins PB, Lin Q, Goodnough JB, Tian H, Chen X, Khavari PA. In vivo restoration of laminin 5 beta 3 expression and function in junctional epidermolysis bullosa. Proc Natl Acad Sci U S A. 2001;98:5193–5198. [PMC free article] [PubMed] [Google Scholar]
Rousselle P, Lunstrum GP, Keene DR, Burgeson RE. Kalinin: an epithelium-specific basement membrane adhesion molecule that is a component of anchoring filaments. J Cell Biol. 1991;114:567–576. [PMC free article] [PubMed] [Google Scholar]
Rousselle P, Golbik R, van der Rest M, Aumailley M. Structural requirement for cell adhesion to kalinin (laminin-5) J Biol Chem. 1995;270:13766–13770. [PubMed] [Google Scholar]
Rousselle P, Keene DR, Ruggiero F, Champliaud MF, Rest M, Burgeson RE. Laminin 5 binds the NC-1 domain of type VII collagen. J Cell Biol. 1997;138:719–728. [PMC free article] [PubMed] [Google Scholar]
Ryan MC, Tizard R, VanDevanter DR, Carter WG. Cloning of the LamA3 gene encoding the alpha 3 chain of the adhesive ligand epiligrin. Expression in wound repair. J Biol Chem. 1994;269:22779–22787. [PubMed] [Google Scholar]
Ryan MC, Lee K, Miyashita Y, Carter WG. Targeted disruption of the LAMA3 gene in mice reveals abnormalities in survival and late stage differentiation of epithelial cells. J Cell Biol. 1999;145:1309–1323. [PMC free article] [PubMed] [Google Scholar]
Sadowski T, Dietrich S, Koschinsky F, Ludwig A, Proksch E, Titz B, Sedlacek R. Matrix metalloproteinase 19 processes the laminin 5 gamma 2 chain and induces epithelial cell migration. Cell Mol Life Sci. 2005;62:870–880. [PubMed] [Google Scholar]
Sakai LY, Keene DR, Morris NP, Burgeson RE. Type VII collagen is a major structural component of anchoring fibrils. J Cell Biol. 1986;103:1577–1586. [PMC free article] [PubMed] [Google Scholar]
Sasaki T, Gohring W, Mann K, Brakebusch C, Yamada Y, Fassler R, Timpl R. Short arm region of laminin-5 gamma2 chain: structure, mechanism of processing and binding to heparin and proteins. J Mol Biol. 2001;314:751–763. [PubMed] [Google Scholar]
Sathyanarayana UG, Padar A, Huang CX, Suzuki M, Shigematsu H, Bekele BN, Gazdar AF. Aberrant promoter methylation and silencing of laminin-5-encoding genes in breast carcinoma. Clin Cancer Res. 2003a;9:6389–6394. [PubMed] [Google Scholar]
Sathyanarayana UG, Padar A, Suzuki M, Maruyama R, Shigematsu H, Hsieh JT, Frenkel EP, Gazdar AF. Aberrant promoter methylation of laminin-5-encoding genes in prostate cancers and its relationship to clinicopathological features. Clin Cancer Res. 2003b;9:6395–6400. [PubMed] [Google Scholar]
Sathyanarayana UG, Maruyama R, Padar A, Suzuki M, Bondaruk J, Sagalowsky A, Minna JD, Frenkel EP, Grossman HB, Czerniak B, Gazdar AF. Molecular detection of noninvasive and invasive bladder tumor tissues and exfoliated cells by aberrant promoter methylation of laminin-5 encoding genes. Cancer Res. 2004;64:1425–1430. [PubMed] [Google Scholar]
Schenk S, Quaranta V. Tales from the crypt[ic] sites of the extracellular matrix. Trends Cell Biol. 2003;13:366–375. [PubMed] [Google Scholar]
Schenk S, Hintermann E, Bilban M, Koshikawa N, Hojilla C, Khokha R, Quaranta V. Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution. J Cell Biol. 2003;161:197–209. [PMC free article] [PubMed] [Google Scholar]
Schneider H, Muhle C, Pacho F. Biological function of laminin-5 and pathogenic impact of its deficiency. Eur J Cell Biol. 2007;86:701–717. [PubMed] [Google Scholar]
Schofield O, Kist D, Lucas A, Wayner E, Carter W, Zachary C. Abnormal expression of epiligrin and alpha 6 beta 4 integrin in basal cell carcinoma. Dermatol Surg. 1998;24:555–559. [PubMed] [Google Scholar]
Seftor RE, Seftor EA, Koshikawa N, Meltzer PS, Gardner LM, Bilban M, Stetler-Stevenson WG, Quaranta V, Hendrix MJ. Cooperative interactions of laminin 5 gamma 2 chain, matrix mettaloproteinase-2, and membrane type-1-matrix/ metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma [PubMed] [Google Scholar]
Shang M, Koshikawa N, Schenk S, Quaranta V. The LG3 module of laminin-5 harbors a binding site for integrin alpha3beta1 that promotes cell adhesion, spreading, and migration. J Biol Chem. 2001;276:33045–33053. [PubMed] [Google Scholar]
Shen XM, Wu YP, Feng YB, Luo ML, Du XL, Zhang Y, Cai Y, Xu X, Han YL, Zhang X, Zhan QM, Wang MR. Interaction of MT1-MMP and laminin-5gamma2 chain correlates with metastasis and invasiveness in human esophageal squamous cell carcinoma. Clin Exp Metastasis. 2007;24:541–550. [PubMed] [Google Scholar]
Shinto E, Tsuda H, Ueno H, Hashiguchi Y, Hase K, Tamai S, Mochizuki H, Inazawa J, Matsubara O. Prognostic implication of laminin-5 gamma 2 chain expression in the invasive front of colorectal cancers, disclosed by area-specific four-point tissue microarrays. Lab Invest. 2005;85:257–266. [PubMed] [Google Scholar]
Skyldberg B, Salo S, Eriksson E, Aspenblad U, Moberger B, Tryggvason K, Auer G. Laminin-5 as a marker of invasiveness in cervical lesions. J Natl Cancer Inst. 1999;91:1882–1887. [PubMed] [Google Scholar]
Smyth N, Vatansever HS, Murray P, Meyer M, Frie C, Paulsson M, Edgar D. Absence of basement membranes after targeting the LAMC1 gene results in embryonic lethality due to failure of endoderm differentiation. J Cell Biol. 1999;144:151–160. [PMC free article] [PubMed] [Google Scholar]
Soini Y, Maatta M, Salo S, Tryggvason K, Autio-Harmainen H. Expression of the laminin gamma 2 chain in pancreatic adenocarcinoma. J Pathol. 1996;180:290–294. [PubMed] [Google Scholar]
Sordat I, Bosman FT, Dorta G, Rousselle P, Aberdam D, Blum AL, Sordat B. Differential expression of laminin-5 subunits and integrin receptors in human colorectal neoplasia. J Pathol. 1998;185:44–52. [PubMed] [Google Scholar]
Sordat I, Rousselle P, Chaubert P, Petermann O, Aberdam D, Bosman FT, Sordat B. Tumor cell budding and laminin-5 expression in colorectal carcinoma can be modulated by the tissue micro-environment. Int J Cancer. 2000;88:708–717. [PubMed] [Google Scholar]
Takahashi S, Hasebe T, Oda T, Sasaki S, Kinoshita T, Konishi M, Ochiai T, Ochiai A. Cytoplasmic expression of laminin gamma2 chain correlates with postoperative hepatic metastasis and poor prognosis in patients with pancreatic ductal adenocarcinoma. Cancer. 2002;94:1894–1901. [PubMed] [Google Scholar]
Tani T, Karttunen T, Kiviluoto T, Kivilaakso E, Burgeson RE, Sipponen P, Virtanen I. Alpha 6 beta 4 integrin and newly deposited laminin-1 and laminin-5 form the adhesion mechanism of gastric carcinoma. Continuous expression of laminins but not that of collagen VII is preserved in invasive parts of the carcinoma: Implications for acquisition of the invading phenotype. Am J Pathol. 1996 Sep.149(3):781–793. [PMC free article] [PubMed] [Google Scholar]
Tani T, Lumme A, Linnala A, Kivilaakso E, Kiviluoto T, Burgeson RE, Kangas L, Leivo I, Virtanen I. Pancreatic carcinomas deposit laminin-5, preferably adhere to laminin-5, and migrate on the newly deposited basement membrane. Am J Pathol. 1997;151:1289–1302. [PMC free article] [PubMed] [Google Scholar]
Teti A. Regulation of cellular functions by extracellular matrix. J Am Soc Nephrol. 1992;2:S83–S87. [PubMed] [Google Scholar]
Thorup AK, Reibel J, Schiodt M, Stenersen TC, Therkildsen MH, Carter WG, Dabelsteen E. Can alterations in integrin and laminin-5 expression be used as markers of malignancy? APMIS. 1998;106:1170–1180. [PubMed] [Google Scholar]
Timpl R, Rohde H, Robey PG, Rennard SI, Foidart JM, Martin GR. Laminin–a glycoprotein from basement membranes. J Biol Chem. 1979;254:9933–9937. [PubMed] [Google Scholar]
Tran M, Rousselle P, Nokelainen P, Tallapragada S, Nguyen NT, Fincher EF, Marinkovich MP. Targeting a tumor-specific laminin domain critical for human carcinogenesis. Cancer Res. 2008;68:2885–2894. [PubMed] [Google Scholar]
Tringler B, Grimm C, Dudek G, Horvat R, Zeillinger R, Hefler LA, Kohlberger P. The lack of laminin-5 as a prognostic marker in low-grade cervical squamous intraepithelial lesions: correlation with clinical follow-up data. Int J Gynecol Pathol. 2007;26:89–94. [PubMed] [Google Scholar]
Tripathi M, Nandana S, Yamashita H, Ganesan R, Kirchhofer D, Quaranta V. Laminin-332 is a substrate for hepsin, a protease associated with prostate cancer progression. J Biol Chem. 2008;283:30576–30584. [PMC free article] [PubMed] [Google Scholar]
Tunggal L, Ravaux J, Pesch M, Smola H, Krieg T, Gaill F, Sasaki T, Timpl R, Mauch C, Aumailley M. Defective laminin 5 processing in cylindroma cells. Am J Pathol. 2002;160:459–468. [PMC free article] [PubMed] [Google Scholar]
Udayakumar TS, Chen ML, Bair EL, Von Bredow DC, Cress AE, Nagle RB, Bowden GT. Membrane type-1-matrix metalloproteinase expressed by prostate carcinoma cells cleaves human laminin-5 beta3 chain and induces cell migration. Cancer Res. 2003;63:2292–2299. [PubMed] [Google Scholar]
Vailly J, Verrando P, Champliaud MF, Gerecke D, Wagman DW, Baudoin C, Aberdam D, Burgeson R, Bauer E, Ortonne JP. The 100-kDa chain of nicein/kalinin is a laminin B2 chain variant. Eur J Biochem. 1994;219:209–218. [PubMed] [Google Scholar]
van der Neut R, Krimpenfort P, Calafat J, Niessen CM, Sonnenberg A. Epithelial detachment due to absence of hemidesmosomes in integrin beta 4 null mice. Nat Genet. 1996;13:366–369. [PubMed] [Google Scholar]
Veitch DP, Nokelainen P, McGowan KA, Nguyen TT, Nguyen NE, Stephenson R, Pappano WN, Keene DR, Spong SM, Greenspan DS, Findell PR, Marinkovich MP. Mammalian tolloid metalloproteinase, and not matrix metalloprotease 2 or membrane type 1 metalloprotease, processes laminin-5 in keratinocytes and skin. J Biol Chem. 2003;278:15661–15668. [PubMed] [Google Scholar]
Verrando P, His BL, Yeh CJ, Pisani A, Serieys N, Ortonne JP. Monoclonal antibody GB3, a new probe for the study of human basement membranes and hemidesmosomes. Exp Cell Res. 1987;170:116–128. [PubMed] [Google Scholar]
Verrando P, Pisani A, Ortonne JP. The new basement membrane antigen recognized by the monoclonal antibody GB3 is a large size glycoprotein: modulation of its expression by retinoic acid. Biochim Biophys Acta. 1988;942:45–56. [PubMed] [Google Scholar]
Vidal F, Baudoin C, Miquel C, Galliano MF, Christiano AM, Uitto J, Ortonne JP, Meneguzzi G. Cloning of the laminin alpha 3 chain gene (LAMA3) and identification of a homozygous deletion in a patient with Herlitz junctional epidermolysis bullosa. Genomics. 1995;30:273–280. [PubMed] [Google Scholar]
Vivinus-Nebot M, Rousselle P, Breittmayer JP, Cenciarini C, Berrih-Aknin S, Spong S, Nokelainen P, Cottrez F, Marinkovich MP, Bernard A. Mature human thymocytes migrate on laminin-5 with activation of metalloproteinase-14 and cleavage of CD44. J Immunol. 2004;172:1397–1406. [PubMed] [Google Scholar]
Wang JL, Andersson S, Li X, Hellstrom AC, Auer G, Angstrom T, Lindstrom MS, Wallin KL. p16INK4a and laminin-5gamma2 chain expression during the progression of cervical neoplasia. Acta Oncol. 2006;45:676–684. [PubMed] [Google Scholar]
Waterman EA, Sakai N, Nguyen NT, Horst BA, Veitch DP, Dey CN, Ortiz-Urda S, Khavari PA, Marinkovich MP. A laminin-collagen complex drives human epidermal carcinogenesis through phosphoinositol-3-kinase activation. Cancer Res. 2007;67:4264–4270. [PubMed] [Google Scholar]
Watt FM, Hotchin NA. Kalinin, epiligrin and GB3 antigen: kalinepiligrinin-3? Curr Biol. 1992;2:106–107. [PubMed] [Google Scholar]
Wayner EA, Garcia-Pardo A, Humphries MJ, McDonald JA, Carter WG. Identification and characterization of the T lymphocyte adhesion receptor for an alternative cell attachment domain (CS-1) in plasma fibronectin. J Cell Biol. 1989;109:1321–1330. [PMC free article] [PubMed] [Google Scholar]
Weaver AM. Invadopodia: specialized cell structures for cancer invasion. Clin Exp Metastasis. 2006;23 97-10. [PubMed] [Google Scholar]
Wittekind C, Neid M. Cancer invasion and metastasis. Oncology. 2005;69 Suppl 1:14–16. [PubMed] [Google Scholar]
Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA. Novel regulators of bone formation : molecular clones and activities. Science. 1988;242:1528–1534. [PubMed] [Google Scholar]
Yamamoto H, Itoh F, Iku S, Hosokawa M, Imai K. Expression of the gamma(2) chain of laminin-5 at the invasive front is associated with recurrence and poor prognosis in human esophageal squamous cell carcinoma. Clin Cancer Res. 2001;7:896–900. [PubMed] [Google Scholar]
Yan HH, Cheng CY. Laminin alpha 3 forms a complex with beta3 and gamma3 chains that serves as the ligand for alpha 6beta1-integrin at the apical ectoplasmic specialization in adult rat testes. J Biol Chem. 2006;281:17286–17303. [PubMed] [Google Scholar]
Ye H, Yu T, Temam S, Ziober BL, Wang J, Schwartz JL, Mao L, Wong DT, Zhou X. Transcriptomic dissection of tongue squamous cell carcinoma. BMC Genomics. 2008;9:69. [PMC free article] [PubMed] [Google Scholar]
Yurchenco PD, Schittny JC. Molecular architecture of basement membranes. FASEB J. 1990;4:1577–1590. [PubMed] [Google Scholar]