Differential expression of αVβ3 and αVβ6 integrins in prostate cancer progression

PLoS One. 2021 Jan 22;16(1):e0244985. doi: 10.1371/journal.pone.0244985. eCollection 2021.

Abstract

Neuroendocrine prostate cancer (NEPrCa) arises de novo or after accumulation of genomic alterations in pre-existing adenocarcinoma tumors in response to androgen deprivation therapies. We have provided evidence that small extracellular vesicles released by PrCa cells and containing the αVβ3 integrin promote neuroendocrine differentiation of PrCa in vivo and in vitro. Here, we examined αVβ3 integrin expression in three murine models carrying a deletion of PTEN (SKO), PTEN and RB1 (DKO), or PTEN, RB1 and TRP53 (TKO) genes in the prostatic epithelium; of these three models, the DKO and TKO tumors develop NEPrCa with a gene signature comparable to those of human NEPrCa. Immunostaining analysis of SKO, DKO and TKO tumors shows that αVβ3 integrin expression is increased in DKO and TKO primary tumors and metastatic lesions, but absent in SKO primary tumors. On the other hand, SKO tumors show higher levels of a different αV integrin, αVβ6, as compared to DKO and TKO tumors. These results are confirmed by RNA-sequencing analysis. Moreover, TRAMP mice, which carry NEPrCa and adenocarcinoma of the prostate, also have increased levels of αVβ3 in their NEPrCa primary tumors. In contrast, the αVβ6 integrin is only detectable in the adenocarcinoma areas. Finally, analysis of 42 LuCaP patient-derived xenografts and primary adenocarcinoma samples shows a positive correlation between αVβ3, but not αVβ6, and the neuronal marker synaptophysin; it also demonstrates that αVβ3 is absent in prostatic adenocarcinomas. In summary, we demonstrate that αVβ3 integrin is upregulated in NEPrCa primary and metastatic lesions; in contrast, the αVβ6 integrin is confined to adenocarcinoma of the prostate. Our findings suggest that the αVβ3 integrin, but not αVβ6, may promote a shift in lineage plasticity towards a NE phenotype and might serve as an informative biomarker for the early detection of NE differentiation in prostate cancer.

Grant support

This study was supported by the National Cancer Institute in the form of grants awarded to LRL (R01-CA224769, P01-CA140043), DWG (R01-CA207757), and KEK (R01-CA176401) and Philadelphia Prostate Cancer Biome Project in the form of funds awarded to WKK (6/01/19- 5/31/23). This project was also funded, in part, under a Commonwealth University Research Enhancement Program grant with the Pennsylvania Department of Health (H.R.) awarded to LRL (SAP 4100072566). The Department specifically disclaims responsibility for any analyses, interpretations, or conclusions. The establishment and characterization of the LuCaP PDXs was supported by the Pacific Northwest Prostate Cancer SPORE in the form of a grant awarded to EC (P50CA97186), the Department of Defense Prostate Cancer Biorepository Network in the form of a grant awarded to EC (W81XWH-14-2-0183), and National Cancer Institute (NCI) in the form of a grant awarded to EC (P01 CA163227). The research reported in this publication utilized the shared flow cytometry, histopathology, and bioimaging facilities at the Sidney Kimmel Cancer Center (Thomas Jefferson University, Philadelphia, PA) that are supported by the National Cancer Institute of the National Institutes of Health in the form of a grant awarded to KEK (P30CA056036). NIH grants partially support the salaries of FQ, SRK, YW, DWG, AM, KEK, EC, LRL. Biogen Inc. provided support in the form of a salary for PW. The specific roles of this author are articulated in the ‘author contributions’ section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.