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Review
. 2024 Feb 16;16(4):805.
doi: 10.3390/cancers16040805.

Tissue-Based Diagnostic Biomarkers of Aggressive Variant Prostate Cancer: A Narrative Review

Olga Kouroukli  1 , Vasiliki Bravou  2 , Konstantinos Giannitsas  3 , Vasiliki Tzelepi  4
Affiliations
Review

Tissue-Based Diagnostic Biomarkers of Aggressive Variant Prostate Cancer: A Narrative Review

Olga Kouroukli et al. Cancers (Basel). .

Abstract

Prostate cancer (PC) is a common malignancy among elderly men, characterized by great heterogeneity in its clinical course, ranging from an indolent to a highly aggressive disease. The aggressive variant of prostate cancer (AVPC) clinically shows an atypical pattern of disease progression, similar to that of small cell PC (SCPC), and also shares the chemo-responsiveness of SCPC. The term AVPC does not describe a specific histologic subtype of PC but rather the group of tumors that, irrespective of morphology, show an aggressive clinical course, dictated by androgen receptor (AR) indifference. AR indifference represents an adaptive response to androgen deprivation therapy (ADT), driven by epithelial plasticity, an inherent ability of tumor cells to adapt to their environment by changing their phenotypic characteristics in a bi-directional way. The molecular profile of AVPC entails combined alterations in the tumor suppressor genes retinoblastoma protein 1 (RB1), tumor protein 53 (TP53), and phosphatase and tensin homolog (PTEN). The understanding of the biologic heterogeneity of castration-resistant PC (CRPC) and the need to identify the subset of patients that would potentially benefit from specific therapies necessitate the development of prognostic and predictive biomarkers. This review aims to discuss the possible pathophysiologic mechanisms of AVPC development and the potential use of emerging tissue-based biomarkers in clinical practice.

Keywords: ADT; AVPC; DDR; NEPC; biomarkers; epigenetic regulation; transdifferentiation; tumor suppressors.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Representative histologic images from two AVPC cases (a,b) with mixed adenocarcinoma and small cell carcinoma. (a) The two components are admixed. AR is expressed in the adenocarcinoma component, and chromogranin A is expressed in the small cell carcinoma; (b) The two components are separate within the tumor, as demonstrated by the intense expression of the neuroendocrine marker CD56 only in the small cell carcinoma. Their distinctive morphology and immunohistochemical profiles are depicted in the right panel, yet both show intense p53 expression, consistent with TP53 mutation. [AR = Androgen receptor, AVPC = Aggressive variant prostate cancer, TP53 = Tumor protein 53].
Figure 2
Figure 2
Schematic representation of the transition of PCA to NEPC with the accompanying molecular and phenotypic changes. During transition to NEPC, PCA under the effect of AR blockage (abiraterone/enzalutamide) switches from an AR-dependent to an AR-independent state. An intermediate phase of double negativity for AR and NE markers (DNPC) indicates transient reversal to an undifferentiated, stem-cell-like state. The acquisition of a mesenchymal program marks EMT. The state of DNPC is flexible and can probably be reversed. On the molecular level, combined alterations of tumor suppressors and the recruitment of pioneer epigenetic regulators initiate AVPC emergence. Additional epigenetic events potentiate NE differentiation with the expression of late proneural TFs and NE markers. The reliance of NEPC emergence on epigenetic modifications indicates a probably reversable process. [AR = Androgen receptor, ASCL1 = Achaete-scute homolog 1, AVPC = Aggressive variant prostate cancer, BRN2 (POU3F2) = POU domain class 3 transcription factor 2, DNPC = Double negative prostate cancer, EMT = Epithelial-to-mesenchymal transition, NE = Neuroendocrine (markers), NEPC = Neuroendocrine prostate cancer, PCA = Prostate adenocarcinoma, PTEN = Phosphatase and tensin homolog, SOX2 = SRY-Box transcription factor 2, RB1 = Retinoblastoma protein 1, TP53 = Tumor protein 53].
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