The direct oral anticoagulants rivaroxaban and dabigatran do not inhibit orthotopic growth and metastasis of human breast cancer in mice

Factor Xa‐targeting DOACs were recently found to reduce recurrentVTE efficiently in cancer patients when compared to the standard treatment withlow‐molecular‐weight heparins (LMWHs). While the anticancer effects of LMWHshave been extensively studied in preclinical cancer models, the effects of FXa‐targetingDOACs on cancer progression remain to be studied.We investigated whether the FXa‐targeting DOAC rivaroxaban and thethrombin‐targeting DOAC dabigatran etexilate (DE) affected human breast cancergrowth and metastasis in orthotopic xenograft models.Mice that were put on a custom‐made chow diet supplementedwith rivaroxaban (0.4 or 1.0 mg/g diet) or dabigatran etexilate (DE) (10 mg/g diet)showed prolonged ex vivo coagulation times (prothrombin time [PT] and activatedpartial thromboplastin time [aPTT] assay, respectively). However, rivaroxabanand DE did not inhibit MDA‐MB‐231 tumor growth and metastasis formationin lungs or livers of 7‐week‐old fully immunodeficient NOD/SCID/ƴC−/− (NSG) mice.Comparable data were obtained for rivaroxaban‐treated mice when using NOD‐SCIDmice. Rivaroxaban and DE treatment also did not significantly inhibit tumor growthand metastasis formation when using another human triple negative breast cancer(TNBC) cell line (HCC1806) in NOD‐SCID mice. The FXa and thrombin‐induced geneexpression of the downstream target CXCL8 in both cell lines, but FXa and thrombin,did not significantly stimulate migration, proliferation, or stemness in vitro.Although effectively inhibiting coagulation, the DOACs rivaroxaban andDE did not inhibit orthotopic growth and metastasis of human TNBC. It remains to beinvestigated whether DOACs exert antitumorigenic effects in other types of cancer.Toxicolog

Role of Tissue Factor in Tumor Progression and Cancer-Associated Thrombosis

It has been long-established that cancer and thrombosis are linked, but the exact underlying pathological mechanism remains to be unraveled. As the initiator of the coagulation cascade, the transmembrane glycoprotein tissue factor (TF) has been intensely investigated for its role in cancer-associated thrombosis and cancer progression. TF expression is regulated by both specific oncogenes and environmental factors, and it is shown to regulate primary growth and metastasis formation in a variety of cancer models. In clinical studies, TF has been shown to be overexpressed in most cancer types and is strongly associated with disease progression. While TF clearly associates with cancer progression, a prominent role for TF in the development of cancer-associated thrombosis is less clear. The current concept is that cancer-associated thrombosis is associated with the secretion of tumor-derived TF-positive extracellular vesicles in certain tumor types. To date, many therapeutic strategies to target TF-both in preclinical and clinical phase-are being pursued, including targeting TF or the TF:FVIIa complex by itself or by exploiting TF as a docking molecule to deliver cytotoxic compounds to the tumor. In this review, the authors summarize the current understanding of the role of TF in both cancer progression and cancer-associated thrombosis, and discuss novel insights on TF as a therapeutic target as well as a biomarker for cancer progression and VTE.Thrombosis and Hemostasi

Vaginal and anal human papillomavirus infection and seropositivity among female sex workers in amsterdam, the Netherlands: prevalence, concordance and risk factors

We studied prevalence, risk factors and concordance of vaginal and anal HPV infection and L1 seropositivity among female sex workers (FSW) in Amsterdam. In 2016, FSW aged ≥18 years having a sexually transmitted infections (STI) consultation were invited to participate. Participation entailed taking vaginal and anal self-swabs. Demographics and sexual behaviour data were collected. HPV DNA was analysed using the SPF10-PCR-DEIA-LiPA25-system-v1. Serum was tested for HPV L1 antibodies using multiplex serology assays. Determinants of vaginal and anal high-risk HPV (hrHPV) infection and L1 seropositivity were assessed with logistic regression analyses. We included 304 FSW; median age was 29 years (IQR 25-37). Vaginal and anal hrHPV prevalence were 46% and 55%, respectively. HrHPV L1 seropositivity was 37%. Vaginal-anal hrHPV concordance was strong, but no significant association between vaginal or anal hrHPV infection and seropositivity was found. Having had anal sexual contact was not associated with anal hrHPV infection (P=0.119). Vaginal and anal hrHPV prevalence is high among FSW in Amsterdam, the Netherlands. Promotion of HPV vaccination, preferably at the beginning of the sex (work) career, may be a useful prevention method against hrHPV infection and diseas

Direct oral anticoagulants do not inhibit growth and metastasis of human triple negative breast cancer in immunodeficient mice

It has been well-established that cancer results in a hypercoagulable state and an increased risk for venous thromboembolism (VTE). More recently, it has been suggested that coagulation may also affect cancer progression and metastasis. Cancer patients with VTE are currently treated with the anticoagulant low molecular weight heparins (LMWHs). Preclinical studies have shown that LMWHs can inhibit metastasis formation in several types of cancer, but beneficial effects of LMWHs on survival have not been consistently found in clinical trials. Recently, a new class of anticoagulants are available for treatment of VTE, the so-called direct oral anticoagulant (DOACs), which include dabigatran and rivaroxaban, a direct thrombin and FXa inhibitor, respectively. However, the effects of DOACs on cancer are currently under studied.Toxicolog

Targeting development of incretin-producing cells increases insulin secretion

Nephrolog

L-Cell Differentiation Is Induced by Bile Acids Through GPBAR1 and Paracrine GLP-1 and Serotonin Signaling

Glucagon-like peptide 1 (GLP-1) mimetics are effective drugs for treatment of type 2 diabetes, and there is consequently extensive interest in increasing endogenous GLP-1 secretion and L-cell abundance. Here we identify G-protein-coupled bile acid receptor 1 (GPBAR1) as a selective regulator of intestinal L-cell differentiation. Lithocholic acid and the synthetic GPBAR1 agonist, L3740, selectively increased L-cell density in mouse and human intestinal organoids and elevated GLP-1 secretory capacity. L3740 induced expression of Gcg and transcription factors Ngn3 and NeuroD1. L3740 also increased the L-cell number and GLP-1 levels and improved glucose tolerance in vivo. Further mechanistic examination revealed that the effect of L3740 on L cells required intact GLP-1 receptor and serotonin 5-hydroxytryptamine receptor 4 (5-HT4) signaling. Importantly, serotonin signaling through 5-HT4 mimicked the effects of L3740, acting downstream of GLP-1. Thus, GPBAR1 agonists and other powerful GLP-1 secretagogues facilitate L-cell differentiation through a paracrine GLP-1-dependent and serotonin-mediated mechanism.Diabetes mellitus: pathophysiological changes and therap

LIM-only protein FHL2 attenuates vascular tissue factor activity, inhibits thrombus formation in mice and <i>FHL2</i> genetic variation associates with human venous thrombosis

Bleeding disorders and thrombotic complications are major causes of morbidity and mortality with many cases being unexplained. Thrombus formation involves aberrant expression and activation of tissue factor (TF) in vascular endothelial and smooth muscle cells. Here, we sought to identify factors that modulate IT gene expression and activity in these vascular cells. The LIM-only protein FHL2 is a scaffolding protein that modulates signal transduction pathways with crucial functions in endothelial and smooth muscle cells. However, the role of FHL2 in TF regulation and thrombosis remains unexplored. Using a murine model of venous thrombosis in mesenteric vessels, we demonstrated that FHL2 deficiency results in exacerbated thrombus formation. Gain- and loss-of-function experiments revealed that FHL2 represses TF expression in endothelial and smooth muscle cells through inhibition of the transcription factors nuclear factor kappa B and activating protein-1. Furthermore, we observed that FHL2 interacts with the cytoplasmic tail of TF. In line with our in vivo observations, FHL2 decreases TF activity in endothelial and smooth muscle cells whereas FHL2 knockdown or deficiency results in enhanced TF activity. Finally, the FHL2 single nucleotide polymorphism rs4851770 was associated with the risk of venous thrombosis in a large population of venous thrombosis cases and control subjects from 12 studies (INVENT consortium). Altogether, our results highlight functional involvement of FHL2 in TF-mediated coagulation and identify FHL2 as a novel gene associated with venous thrombosis in humans.Thrombosis and Hemostasi

Tumor-expressed factor VII is associated with survival and regulates tumor progression in breast cancer

Cancer enhances the risk of venous thromboembolism, but a hypercoagulant microenvironment also promotes cancer progression. Although anticoagulants have been suggested as a potential anticancer treatment, clinical studies on the effect of such modalities on cancer progression have not yet been successful for unknown reasons. In normal physiology, complex formation between the subendothelial-expressed tissue factor (TF) and the blood-borne liver-derived factor VII (FVII) results in induction of the extrinsic coagulation cascade and intracellular signaling via protease-activated receptors (PARs). In cancer, TF is overexpressed and linked to poor prognosis. Here, we report that increased levels of FVII are also observed in breast cancer specimens and are associated with tumor progression and metastasis to the liver. In breast cancer cell lines, tumor-expressed FVII drives changes reminiscent of epithelial-to-mesenchymal transition (EMT), tumor cell invasion, and expression of the prometastatic genes, SNAI2 and SOX9. In vivo, tumorexpressed FVII enhanced tumor growth and liver metastasis. Surprisingly, liver-derived FVII appeared to inhibit metastasis. Finally, tumor-expressed FVII-induced prometastatic gene expression independent of TF but required a functional endothelial protein C receptor, whereas recombinant activated FVII acting via the canonical TF:PAR2 pathway inhibited prometastatic gene expression. Here, we propose that tumor-expressed FVII and liverderived FVII have opposing effects on EMT and metastasis.Surgical oncolog