Differential Expression Of Alpha V Beta 3 And Alpha V Beta 6 Integrins In Prostate Cancer Progression

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 alpha V beta 3 integrin promote neuroendocrine differentiation of PrCa in vivo and in vitro. Here, we examined alpha V beta 3 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 alpha V beta 3 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 alpha V integrin, alpha V beta 6, 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 alpha V beta 3 in their NEPrCa primary tumors. In contrast, the alpha V beta 6 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 alpha V beta 3, but not alpha V beta 6, and the neuronal marker synaptophysin; it also demonstrates that alpha V beta 3 is absent in prostatic adenocarcinomas. In summary, we demonstrate that alpha V beta 3 integrin is upregulated in NEPrCa primary and metastatic lesions; in contrast, the alpha(V)beta 6 integrin is confined to adenocarcinoma of the prostate. Our findings suggest that the alpha V beta 3 integrin, but not alpha V beta 6, 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.