Thrombotic characteristics of extracellular vesicles derived from prostate cancer cells

Saleh, Hassan A. Al; Haas‐Neill, Sandor; Al‐Hashimi, Ali; Kapoor, Anil; Shayegan, Bobby; Austin, Richard C.; Al‐Nedawi, Khalid

doi:10.1002/pros.23653

Cited by 19 publications

(15 citation statements)

References 33 publications

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“…9 Also, DU145 overexpressing EGFRvIII are shown to indirectly generate thrombin through release of extracellular vesicles containing tissue factor into the tumor microenvironment. 32 Interestingly, thrombin has also been demonstrated to act on PCa-expressed protease activated receptor (PAR)-1 to increase tumor invasion, cellular migration, angiogenesis, and metastasis. 33,34 Therefore, perhaps it is not a surprise to observe higher level of (pro)thrombin expression among AR-independent cell lines, which have higher invasive potential.…”

Section: Discussionmentioning

confidence: 99%

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

Rudzinski

Govindasamy

Lewis

et al. 2020

Journal of Thrombosis and Haemostasis

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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.

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Section: Discussionmentioning

confidence: 99%

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

Rudzinski

Govindasamy

Lewis

et al. 2020

Journal of Thrombosis and Haemostasis

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“…Circulating cancer cells also release EVs, providing another surface that contributes directly to thrombin generation in cancer. EV-free plasma is not able to generate thrombin [36], and cancer cell-derived EVs directly support thrombin generation, shown by in vitro studies of EVs released from leukaemia cell lines [35,37], prostate cancer cell lines [38] and breast and pancreatic cancer cell lines [39]. Many in vitro studies have linked expression of TF on EVs with their procoagulant potential (as measured by various functional assays such as thrombin generation performed in EV-enriched samples) [35,37,39,40,41].…”

Section: Tumour-specific Factors Contributing To Thrombin Generationmentioning

confidence: 99%

Thrombin Generation and Cancer: Contributors and Consequences

Reddel

Tan

Chen

2019

Cancers

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The high occurrence of cancer-associated thrombosis is associated with elevated thrombin generation. Tumour cells increase the potential for thrombin generation both directly, through the expression and release of procoagulant factors, and indirectly, through signals that activate other cell types (including platelets, leukocytes and erythrocytes). Furthermore, cancer treatments can worsen these effects. Coagulation factors, including tissue factor, and inhibitors of coagulation are altered and extracellular vesicles (EVs), which can promote and support thrombin generation, are released by tumour and other cells. Some phosphatidylserine-expressing platelet subsets and platelet-derived EVs provide the surface required for the assembly of coagulation factors essential for thrombin generation in vivo. This review will explore the causes of increased thrombin production in cancer, and the availability and utility of tests and biomarkers. Increased thrombin production not only increases blood coagulation, but also promotes tumour growth and metastasis and as a consequence, thrombin and its contributors present opportunities for treatment of cancer-associated thrombosis and cancer itself.

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“…The most notable GPCR for prostate cancer is the thrombin receptor PAR-1, which is known to signal to NF-κB [ 144 ], and is also a well-known poor prognostic marker in prostate cancer [ 145 , 146 , 147 , 148 ]. Prostate cancer cells produce thrombotic extracellular vesicles, which can in turn activate the thrombin receptors on prostate cancer cells or surrounding stromal cells [ 149 , 150 ]. Low-dose thrombin inhibition has been suggested as a potential prostate cancer treatment [ 151 ].…”

Section: Nf-κb Signaling Pathways In Prostate Cancersmentioning

confidence: 99%

Inflammation and NF-κB Signaling in Prostate Cancer: Mechanisms and Clinical Implications

Staal

Beyaert

2018

Cells

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Prostate cancer is a highly prevalent form of cancer that is usually slow-developing and benign. Due to its high prevalence, it is, however, still the second most common cause of death by cancer in men in the West. The higher prevalence of prostate cancer in the West might be due to elevated inflammation from metabolic syndrome or associated comorbidities. NF-κB activation and many other signals associated with inflammation are known to contribute to prostate cancer malignancy. Inflammatory signals have also been associated with the development of castration resistance and resistance against other androgen depletion strategies, which is a major therapeutic challenge. Here, we review the role of inflammation and its link with androgen signaling in prostate cancer. We further describe the role of NF-κB in prostate cancer cell survival and proliferation, major NF-κB signaling pathways in prostate cancer, and the crosstalk between NF-κB and androgen receptor signaling. Several NF-κB-induced risk factors in prostate cancer and their potential for therapeutic targeting in the clinic are described. A better understanding of the inflammatory mechanisms that control the development of prostate cancer and resistance to androgen-deprivation therapy will eventually lead to novel treatment options for patients.

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Thrombotic characteristics of extracellular vesicles derived from prostate cancer cells

Cited by 19 publications

References 33 publications

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

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

Thrombin Generation and Cancer: Contributors and Consequences

Inflammation and NF-κB Signaling in Prostate Cancer: Mechanisms and Clinical Implications

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