The Role of the Androgen Receptor in Prostate Cancer-induced Platelet Aggregation and Platelet-induced Invasion.

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 (TCIPA), 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.

To characterize the role of androgen receptor in prostate cancer-induced platelet aggregation and platelet-induced invasion.

TCIPA 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.

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.

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.

Journal of thrombosis and haemostasis : JTH. 2020 Jul 21 [Epub ahead of print]

Jan K Rudzinski, Natasha P Govindasamy, John D Lewis, Paul Jurasz

Division of Urology, Department of Surgery, University of Alberta, Edmonton, Canada., Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada., Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.