Mechanisms coupling thrombin to metastasis and tumorigenesis

Remiker, Allison; Palumbo, Joseph S.

doi:10.1016/j.thromres.2017.12.020

Cited by 34 publications

(40 citation statements)

References 73 publications

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“…Several studies have shown a correlation between long‐term anticoagulation and a decreased incidence of multiple types of cancer, including prostate cancer , suggesting that thrombin may play a role in early events that are important in tumorigenesis. Indeed, this conclusion is supported by numerous studies in animal models , including studies showing that thrombin inhibition significantly limits prostate tumor progression in TRAMP mice . However, thrombin has > 12 recognized substrates, and the data presented here suggest that thrombin does not promote tumor progression in TRAMP mice via a mechanism coupled to PAR‐1 activation.…”

Section: Discussionsupporting

confidence: 74%

Protease‐activated receptor‐1 impedes prostate and intestinal tumor progression in mice

Adams

Sharma

Rosenfeldt

et al. 2018

Journal of Thrombosis and Haemostasis

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Essentials Protease activated receptor-1 (PAR-1) has been proposed to drive cancer progression. Surprisingly, PAR-1 deletion accelerated tumor progression in two distinct experimental settings. PAR-1 deletion was shown to limit the apoptosis of transformed epithelial cells. Thrombin- and activated protein C-mediated PAR-1 activation have unique effects on tumor cell biology. SUMMARY: Background Multiple studies have implicated protease-activated receptor-1 (PAR-1), a G-protein-coupled receptor activated by proteolytic cleavage of its N-terminus, as one target coupling thrombin-mediated proteolysis to tumor progression. Objective To analyze the role of PAR-1 in the setting of two distinct spontaneously developing tumor models in mice. Methods We interbred PAR-1-deficient mice with Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, which spontaneously develop prostate tumors, and adenomatous polyposis coli Min (APC ) mice, which spontaneously develop intestinal adenomas. Results Analyses of TRAMP mice with advanced disease (30 weeks) revealed that PAR-1 deficiency resulted in significantly larger and more aggressive prostate tumors. Prostates collected at an earlier time point (12 weeks of age) revealed that PAR-1 promotes apoptosis in transformed epithelia. In vitro analyses of TRAMP-derived cells revealed that activated protein C-mediated PAR-1 cleavage can induce tumor cell apoptosis, suggesting that tumor cell-intrinsic PAR-1 functions can limit tumor progression. Paralleling results in TRAMP mice, PAR-1-deficient APC mice developed three-fold more adenomas than PAR-1-expressing mice, and the adenomas that formed were significantly larger. Moreover, loss of PAR-1 expression was shown to limit apoptosis in transformed intestinal epithelial cells. Conclusions Together, these results demonstrate a previously unrecognized role for PAR-1 in impeding tumor progression in vivo. These results also offer a cautionary note suggesting that long-term PAR-1 inhibition could increase malignancy risk in some contexts.

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Section: Discussionsupporting

confidence: 74%

Protease‐activated receptor‐1 impedes prostate and intestinal tumor progression in mice

Adams

Sharma

Rosenfeldt

et al. 2018

Journal of Thrombosis and Haemostasis

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“…The existence of a relation between pathophysiological pathways of the hemostatic system and cancer development and progression has been confirmed by several preclinical research studies [80]. Hemostatic system activation would favor tumor transformation and progression, throughout angiogenesis, increasing local invasion and remote metastasis dissemination and growth.…”

Section: Anticoagulation In the Absence Of Vte To Improve Survival Inmentioning

confidence: 87%

SEOM clinical guideline of venous thromboembolism (VTE) and cancer (2019)

et al. 2020

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In 2011, the Spanish Society of Medical Oncology (SEOM) first published a clinical guideline of venous thromboembolism (VTE) and cancer. This guideline was updated in 2014, and since then, multiple studies and clinical trials have changed the landscape of the treatment and prophylaxis of VTE in cancer patients. To incorporate the most recent evidence, including data from direct oral anticoagulants (DOACs) randomized clinical trials, SEOM presents a new update of the guideline.

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“…Lastly, TF inhibition leads to reduced thrombin and fibrin generation. Like TF, thrombin triggers clotting and also promotes cellular events through protease-activated receptors (PARs) leading to cancer metastasis (37,38). In our experience, disruption of mTORC2 in H1975 cells or treatment of MDA-MB-231 cells with TF-targeted antibody both inhibited lung metastasis (10,25).…”

Section: Discussionmentioning

confidence: 92%

mTOR Promotes Tissue Factor Expression and Activity in EGFR-Mutant Cancer

Cong

Zhang

et al. 2020

Front. Oncol.

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Mechanistic target of rapamycin (mTOR) signaling pathway mediates the function of oncogenic receptor tyrosine kinases (RTKs). We aimed to elucidate new role of mTOR in EGFR-mutant (EGFR-mut) non-small cell lung cancer (NSCLC) and glioblastoma (GBM) with a focus on tumor microenvironments. Here, we report a novel regulatory link between mTOR complexes (mTORCs) and tissue factor (TF), an initiator of tumorderived thrombosis. TF is elevated in EGFR-mut NSCLC/GBM cell lines and tumors from patients with poor prognosis. Application of mTORC1/2 inhibitors (AZD8055, WYE-125132, MTI-31, and rapamycin) or genetic mTORC-depletion all reduced TF expression, which appeared to be differentially mediated depending on cellular context. In U87MG and HCC827 cells, mTORC1 exerted a dominant role via promoting TF mRNA transcription. In EGFR-TKI-resistant H1975 and PC9 cells, it was mTORC2 that played a major role in specific repression of lysosomal-targeted TF protein degradation. Successful inhibition of TF expression was demonstrated in AZD8055-or MTI-31treated H1975 and U87MG tumors in mice, while a TF-targeted antibody antagonized TF activity without reducing TF protein. Both the mTOR-and TF-targeted therapy induced a multifaceted remodeling of tumor microenvironment reflecting not only a diminished hypercoagulopathy state (fibrin level) but also a reduced stromal fibrosis (collagen distribution), compromised vessel density and/or maturity (CD31 and/or α-SMA) as well as a substantially decreased infiltration of immune-suppressive M2-type tumor-associated macrophages (CD206/F4/80 ratio). Thus, our results have identified TF as a functional biomarker of mTOR. Downregulation of mTOR-TF axis activity likely contributes to the therapeutic mechanism of mTORC1/2-and TF-targeted agents in EGFR-mut advanced NSCLC and GBM.

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Mechanisms coupling thrombin to metastasis and tumorigenesis

Cited by 34 publications

References 73 publications

Protease‐activated receptor‐1 impedes prostate and intestinal tumor progression in mice

Protease‐activated receptor‐1 impedes prostate and intestinal tumor progression in mice

SEOM clinical guideline of venous thromboembolism (VTE) and cancer (2019)

mTOR Promotes Tissue Factor Expression and Activity in EGFR-Mutant Cancer

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