Skip to main content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
J Clin Invest. 1997 Mar 15; 99(6): 1390–1398.
doi: 10.1172/JCI119298
PMCID: PMC507955
PMID: 9077549

Insulin-like growth factor receptor cooperates with integrin alpha v beta 5 to promote tumor cell dissemination in vivo.

P C Brooks, R L Klemke, S Schon, J M Lewis, M A Schwartz, and D A Cheresh
Author information Copyright and License information PMC Disclaimer

Abstract

Tumor cell interactions with adhesion proteins and growth factors likely contribute to the metastatic cascade. Evidence is provided that insulin or insulin-like growth factor-mediated signals cooperate with the commonly expressed integrin alpha v beta 5 to promote spontaneous pulmonary metastasis of multiple tumor cell types in both the chick embryo and severe combined immune deficiency mouse/human chimeric models. Expression of alpha v beta 5 in tumor cells promoted their adhesion to vitronectin in vitro. However, cell motility required cytokine stimulation, which caused redistribution of alpha-actinin to membrane-adhesive sites containing alpha v beta 5. Significantly, ligation of alpha v beta 5 and cytokine receptors were both required for spontaneous pulmonary metastasis of multiple tumor types even though it was not necessary for primary tumor growth. Thus, tumor cell metastasis can be regulated by a functional cooperation between cytokine signaling events and the adhesion receptor alpha v beta 5 in a manner independent of tumor cell growth. These findings provide evidence that integrin ligation, in conjunction with cytokine activation, plays an important role in the dissemination of malignant tumor cells.

Full Text

The Full Text of this article is available as a PDF (11M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  • Blood CH, Zetter BR. Tumor interactions with the vasculature: angiogenesis and tumor metastasis. Biochim Biophys Acta. 1990 Jun 1;1032(1):89–118. [PubMed] [Google Scholar]
  • Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell. 1991 Jan 25;64(2):327–336. [PubMed] [Google Scholar]
  • Herlyn M, Malkowicz SB. Regulatory pathways in tumor growth and invasion. Lab Invest. 1991 Sep;65(3):262–271. [PubMed] [Google Scholar]
  • Matsumoto K, Matsumoto K, Nakamura T, Kramer RH. Hepatocyte growth factor/scatter factor induces tyrosine phosphorylation of focal adhesion kinase (p125FAK) and promotes migration and invasion by oral squamous cell carcinoma cells. J Biol Chem. 1994 Dec 16;269(50):31807–31813. [PubMed] [Google Scholar]
  • Chan BM, Matsuura N, Takada Y, Zetter BR, Hemler ME. In vitro and in vivo consequences of VLA-2 expression on rhabdomyosarcoma cells. Science. 1991 Mar 29;251(5001):1600–1602. [PubMed] [Google Scholar]
  • Nip J, Shibata H, Loskutoff DJ, Cheresh DA, Brodt P. Human melanoma cells derived from lymphatic metastases use integrin alpha v beta 3 to adhere to lymph node vitronectin. J Clin Invest. 1992 Oct;90(4):1406–1413. [PMC free article] [PubMed] [Google Scholar]
  • Nip J, Brodt P. The role of the integrin vitronectin receptor, alpha v beta 3 in melanoma metastasis. Cancer Metastasis Rev. 1995 Sep;14(3):241–252. [PubMed] [Google Scholar]
  • Seftor RE, Seftor EA, Gehlsen KR, Stetler-Stevenson WG, Brown PD, Ruoslahti E, Hendrix MJ. Role of the alpha v beta 3 integrin in human melanoma cell invasion. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1557–1561. [PMC free article] [PubMed] [Google Scholar]
  • Akiyama SK, Olden K, Yamada KM. Fibronectin and integrins in invasion and metastasis. Cancer Metastasis Rev. 1995 Sep;14(3):173–189. [PubMed] [Google Scholar]
  • Wayner EA, Orlando RA, Cheresh DA. Integrins alpha v beta 3 and alpha v beta 5 contribute to cell attachment to vitronectin but differentially distribute on the cell surface. J Cell Biol. 1991 May;113(4):919–929. [PMC free article] [PubMed] [Google Scholar]
  • Felding-Habermann B, Mueller BM, Romerdahl CA, Cheresh DA. Involvement of integrin alpha V gene expression in human melanoma tumorigenicity. J Clin Invest. 1992 Jun;89(6):2018–2022. [PMC free article] [PubMed] [Google Scholar]
  • Luna EJ, Hitt AL. Cytoskeleton--plasma membrane interactions. Science. 1992 Nov 6;258(5084):955–964. [PubMed] [Google Scholar]
  • Haimovich B, Lipfert L, Brugge JS, Shattil SJ. Tyrosine phosphorylation and cytoskeletal reorganization in platelets are triggered by interaction of integrin receptors with their immobilized ligands. J Biol Chem. 1993 Jul 25;268(21):15868–15877. [PubMed] [Google Scholar]
  • Plopper GE, McNamee HP, Dike LE, Bojanowski K, Ingber DE. Convergence of integrin and growth factor receptor signaling pathways within the focal adhesion complex. Mol Biol Cell. 1995 Oct;6(10):1349–1365. [PMC free article] [PubMed] [Google Scholar]
  • Miyamoto S, Teramoto H, Coso OA, Gutkind JS, Burbelo PD, Akiyama SK, Yamada KM. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. J Cell Biol. 1995 Nov;131(3):791–805. [PMC free article] [PubMed] [Google Scholar]
  • Klemke RL, Yebra M, Bayna EM, Cheresh DA. Receptor tyrosine kinase signaling required for integrin alpha v beta 5-directed cell motility but not adhesion on vitronectin. J Cell Biol. 1994 Nov;127(3):859–866. [PMC free article] [PubMed] [Google Scholar]
  • Filardo EJ, Brooks PC, Deming SL, Damsky C, Cheresh DA. Requirement of the NPXY motif in the integrin beta 3 subunit cytoplasmic tail for melanoma cell migration in vitro and in vivo. J Cell Biol. 1995 Jul;130(2):441–450. [PMC free article] [PubMed] [Google Scholar]
  • Stracke ML, Kohn EC, Aznavoorian SA, Wilson LL, Salomon D, Krutzsch HC, Liotta LA, Schiffmann E. Insulin-like growth factors stimulate chemotaxis in human melanoma cells. Biochem Biophys Res Commun. 1988 Jun 30;153(3):1076–1083. [PubMed] [Google Scholar]
  • Stracke ML, Engel JD, Wilson LW, Rechler MM, Liotta LA, Schiffmann E. The type I insulin-like growth factor receptor is a motility receptor in human melanoma cells. J Biol Chem. 1989 Dec 25;264(36):21544–21549. [PubMed] [Google Scholar]
  • Rodeck U, Melber K, Kath R, Menssen HD, Varello M, Atkinson B, Herlyn M. Constitutive expression of multiple growth factor genes by melanoma cells but not normal melanocytes. J Invest Dermatol. 1991 Jul;97(1):20–26. [PubMed] [Google Scholar]
  • Rodeck U, Herlyn M. Growth factors in melanoma. Cancer Metastasis Rev. 1991 Jun;10(2):89–101. [PubMed] [Google Scholar]
  • Matsumoto K, Ziober BL, Yao CC, Kramer RH. Growth factor regulation of integrin-mediated cell motility. Cancer Metastasis Rev. 1995 Sep;14(3):205–217. [PubMed] [Google Scholar]
  • Kalebic T, Tsokos M, Helman LJ. In vivo treatment with antibody against IGF-1 receptor suppresses growth of human rhabdomyosarcoma and down-regulates p34cdc2. Cancer Res. 1994 Nov 1;54(21):5531–5534. [PubMed] [Google Scholar]
  • Cheresh DA, Smith JW, Cooper HM, Quaranta V. A novel vitronectin receptor integrin (alpha v beta x) is responsible for distinct adhesive properties of carcinoma cells. Cell. 1989 Apr 7;57(1):59–69. [PubMed] [Google Scholar]
  • Yatohgo T, Izumi M, Kashiwagi H, Hayashi M. Novel purification of vitronectin from human plasma by heparin affinity chromatography. Cell Struct Funct. 1988 Aug;13(4):281–292. [PubMed] [Google Scholar]
  • Wickham TJ, Filardo EJ, Cheresh DA, Nemerow GR. Integrin alpha v beta 5 selectively promotes adenovirus mediated cell membrane permeabilization. J Cell Biol. 1994 Oct;127(1):257–264. [PMC free article] [PubMed] [Google Scholar]
  • Brooks PC, Strömblad S, Klemke R, Visscher D, Sarkar FH, Cheresh DA. Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest. 1995 Oct;96(4):1815–1822. [PMC free article] [PubMed] [Google Scholar]
  • Lewis JM, Schwartz MA. Mapping in vivo associations of cytoplasmic proteins with integrin beta 1 cytoplasmic domain mutants. Mol Biol Cell. 1995 Feb;6(2):151–160. [PMC free article] [PubMed] [Google Scholar]
  • Brooks PC, Lin JM, French DL, Quigley JP. Subtractive immunization yields monoclonal antibodies that specifically inhibit metastasis. J Cell Biol. 1993 Sep;122(6):1351–1359. [PMC free article] [PubMed] [Google Scholar]
  • Yan HC, Juhasz I, Pilewski J, Murphy GF, Herlyn M, Albelda SM. Human/severe combined immunodeficient mouse chimeras. An experimental in vivo model system to study the regulation of human endothelial cell-leukocyte adhesion molecules. J Clin Invest. 1993 Mar;91(3):986–996. [PMC free article] [PubMed] [Google Scholar]
  • Brooks PC, Montgomery AM, Rosenfeld M, Reisfeld RA, Hu T, Klier G, Cheresh DA. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell. 1994 Dec 30;79(7):1157–1164. [PubMed] [Google Scholar]
  • Doerr ME, Jones JI. The roles of integrins and extracellular matrix proteins in the insulin-like growth factor I-stimulated chemotaxis of human breast cancer cells. J Biol Chem. 1996 Feb 2;271(5):2443–2447. [PubMed] [Google Scholar]
  • Morton DM, Tchao R. Regulation of motility and cytoskeletal organization of rat bladder carcinoma cells by cyclic AMP. Cell Motil Cytoskeleton. 1994;29(4):375–382. [PubMed] [Google Scholar]
  • Juliano R. Signal transduction by integrins and its role in the regulation of tumor growth. Cancer Metastasis Rev. 1994 Mar;13(1):25–30. [PubMed] [Google Scholar]
  • Dedhar S. Integrin mediated signal transduction in oncogenesis: an overview. Cancer Metastasis Rev. 1995 Sep;14(3):165–172. [PubMed] [Google Scholar]
  • Lester BR, McCarthy JB. Tumor cell adhesion to the extracellular matrix and signal transduction mechanisms implicated in tumor cell motility, invasion and metastasis. Cancer Metastasis Rev. 1992 Mar;11(1):31–44. [PubMed] [Google Scholar]
  • Pedersen PH, Ness GO, Engebraaten O, Bjerkvig R, Lillehaug JR, Laerum OD. Heterogeneous response to the growth factors [EGF, PDGF (bb), TGF-alpha, bFGF, IL-2] on glioma spheroid growth, migration and invasion. Int J Cancer. 1994 Jan 15;56(2):255–261. [PubMed] [Google Scholar]
  • Brooks PC, Strömblad S, Sanders LC, von Schalscha TL, Aimes RT, Stetler-Stevenson WG, Quigley JP, Cheresh DA. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell. 1996 May 31;85(5):683–693. [PubMed] [Google Scholar]
  • Albelda SM. Role of integrins and other cell adhesion molecules in tumor progression and metastasis. Lab Invest. 1993 Jan;68(1):4–17. [PubMed] [Google Scholar]
  • Boukerche H, Benchaibi M, Berthier-Vergnes O, Lizard G, Bailly M, Bailly M, McGregor JL. Two human melanoma cell-line variants with enhanced in vivo tumor growth and metastatic capacity do not express the beta 3 integrin subunit. Eur J Biochem. 1994 Mar 1;220(2):485–491. [PubMed] [Google Scholar]
  • Lewis JM, Cheresh DA, Schwartz MA. Protein kinase C regulates alpha v beta 5-dependent cytoskeletal associations and focal adhesion kinase phosphorylation. J Cell Biol. 1996 Sep;134(5):1323–1332. [PMC free article] [PubMed] [Google Scholar]
  • Pasqualini R, Bodorova J, Ye S, Hemler ME. A study of the structure, function and distribution of beta 5 integrins using novel anti-beta 5 monoclonal antibodies. J Cell Sci. 1993 May;105(Pt 1):101–111. [PubMed] [Google Scholar]
  • Resnicoff M, Ambrose D, Coppola D, Rubin R. Insulin-like growth factor-1 and its receptor mediate the autocrine proliferation of human ovarian carcinoma cell lines. Lab Invest. 1993 Dec;69(6):756–760. [PubMed] [Google Scholar]
  • Ambrose D, Resnicoff M, Coppola D, Sell C, Miura M, Jameson S, Baserga R, Rubin R. Growth regulation of human glioblastoma T98G cells by insulin-like growth factor-1 and its receptor. J Cell Physiol. 1994 Apr;159(1):92–100. [PubMed] [Google Scholar]
  • Otey CA, Vasquez GB, Burridge K, Erickson BW. Mapping of the alpha-actinin binding site within the beta 1 integrin cytoplasmic domain. J Biol Chem. 1993 Oct 5;268(28):21193–21197. [PubMed] [Google Scholar]
  • Sastry SK, Horwitz AF. Integrin cytoplasmic domains: mediators of cytoskeletal linkages and extra- and intracellular initiated transmembrane signaling. Curr Opin Cell Biol. 1993 Oct;5(5):819–831. [PubMed] [Google Scholar]
  • Stossel TP. On the crawling of animal cells. Science. 1993 May 21;260(5111):1086–1094. [PubMed] [Google Scholar]
  • Albelda SM, Mette SA, Elder DE, Stewart R, Damjanovich L, Herlyn M, Buck CA. Integrin distribution in malignant melanoma: association of the beta 3 subunit with tumor progression. Cancer Res. 1990 Oct 15;50(20):6757–6764. [PubMed] [Google Scholar]
  • Chambers AF, Tuck AB. Ras-responsive genes and tumor metastasis. Crit Rev Oncog. 1993;4(2):95–114. [PubMed] [Google Scholar]
  • Rong S, Segal S, Anver M, Resau JH, Vande Woude GF. Invasiveness and metastasis of NIH 3T3 cells induced by Met-hepatocyte growth factor/scatter factor autocrine stimulation. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4731–4735. [PMC free article] [PubMed] [Google Scholar]
  • Felding-Habermann B, Cheresh DA. Vitronectin and its receptors. Curr Opin Cell Biol. 1993 Oct;5(5):864–868. [PubMed] [Google Scholar]
Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation
-