The role of the androgen receptor in prostate cancer‐induced platelet aggregation and platelet‐induced invasion

Abstract

Background: Metastatic prostate cancer progresses from a hormone sensitive androgen receptor expressing phenotype to a hormone insensitive androgen receptor-independent subtype with low overall survival. Human platelets contribute to metastasis via tumor cell-induced platelet aggregation, which in part enhances cancer cell invasion. Given the more aggressive nature of hormone insensitive prostate cancer, we hypothesized that androgen receptor-negative prostate cancer cells exhibit higher platelet aggregation potency and invasive response compared to cells with androgen receptor. Objective: To characterize the role of androgen receptors in prostate cancer-induced platelet aggregation and platelet-induced invasion. Methods: Tumor cell-induced platelet aggregation experiments were performed with platelets from healthy human donors and benign prostate (RWPE-1) and prostate cancer cell lines positive (LNCaP) and negative for androgen receptor (DU145 and PC3). Immunoblot measured prostate cancer prothrombin. Modified Boyden chamber invasion assays and zymography were performed to assess the effects of platelets on prostate cancer cell invasion and matrix metalloproteinase (MMP) expression, respectively. Results: Androgen receptor-positive prostate cancer cell lines failed to induce platelet aggregation. However, androgen receptor-inhibited and-negative cell lines all induced platelet aggregation, which was abolished by dabigatran. Androgen receptor-inhibited and-negative cell lines demonstrated greater expression of prothrombin than androgen receptor-positive cells. Platelets enhanced invasion and MMP-2 and-9 expression by androgen receptor-inhibited and negative prostate cancer cells, but not that of the androgen receptor-positive cells. Conclusions: Androgen receptor loss within prostate cancer results in increased thrombogenicity due to upregulation of prothrombin expression. Reciprocally, platelets enhance invasion of androgen receptor-negative prostate cancer cells via increased MMP expression. | 2977 RUDZINSKI et al.

The induction of a mesenchymal phenotype by platelet cloaking of cancer cells is a universal phenomenon

“…This might be explained by a higher propensity to cloak with other cell types like macrophages or neutrophils. A recent study has shown that prostate cell line models can vary in their ability to induce platelet aggregation which is linked to their androgen receptor expression and this may also explain the reciprocal trends observed between the PC-3 and LNCaP [36] that represent androgen independent and dependent models respectively.…”

Platelet-Cancer Interplay: Molecular Mechanisms and New Therapeutic Avenues

“…Conclusively, the loss of androgen receptors in cancer cells accounted for the increased thrombogenicity, due to the enhanced expression of prothrombin. In sharp contrast, androgen receptor-positive prostate cancer cells cannot induce TCIPA ( 40 ). Mitrugno et al.…”

“…The thrombogenic lesions also increase the risk of TCIPA after surgical intervention ( 39 ). Interestingly, deficiency or inhibition of androgen receptor function in prostate cancer cells could induce TCIPA in vitro ( 40 ). Conclusively, the loss of androgen receptors in cancer cells accounted for the increased thrombogenicity, due to the enhanced expression of prothrombin.…”

Novel Strategy of Proxalutamide for the Treatment of Prostate Cancer through Coordinated Blockade of Lipogenesis and Androgen Receptor Axis

“…The 22RV1 cell line was derived from a xenograft that was serially propagated in mice after castrationinduced regression and relapse of a human prostatic carcinoma xenograft, and its growth is androgen-independent [66]. PC3 and DU145 are human metastatic PCa cells [67,68] without AR expression, and their growth is androgen-independent [69][70][71].…”