thromboplastin and Bone-Neoplasms

Coagulation activation is associated with cancer progression and morbidity. Recently, mechanisms through which coagulation proteases drive the tumor microenvironment (TME) have been elucidated. This review aims to develop a new strategy dependent on the coagulation system for treating osteosarcoma (OS). We focused on tissue factor (TF), the main initiator of the extrinsic coagulant pathway, as a target for OS treatment. It was found that cell surface-TF, TF-positive extracellular vesicles, and TF-positive circulating tumor cells could drive progression, metastasis, and TME in carcinomas, including OS. Thus, targeting tumor-associated coagulation by focusing on TF, the principle catalyst of the extrinsic pathway, TF is a promising target for OS.

Topics: Blood Coagulation; Bone Neoplasms; Humans; Osteosarcoma; Thromboplastin; Tumor Microenvironment

Osteosarcoma is the most common primary malignant bone tumour. Patients often develop lung metastasis and have a poor prognosis despite extensive chemotherapy and surgical resections. Tissue Factor is associated with poor clinical outcome in a wide range of cancer types, and promotes angiogenesis and metastasis. The role of Tissue Factor in OS tumourigenesis is unknown. Fifty-three osteosarcoma pre-treatment biopsies and four osteosarcoma cell lines were evaluated for Tissue Factor expression, and a possible association with clinical parameters was investigated. Tissue Factor function was inhibited in an osteosarcoma cell line (143B) by shRNA knockdown or specific antibodies, and pro-tumourigenic gene expression, proliferation, matrigel invasion and transwell migration was examined. 143B cells were implanted in mice in the presence of Tissue Factor-blocking antibodies, and tumour volume, micro-vessel density and metastases in the lung were evaluated. Tissue Factor was highly expressed in 73.6 % of osteosarcoma biopsies, and expression associated significantly with disease-free survival. Tissue Factor was expressed in all four investigated cell lines. Tissue Factor was knocked down in 143B cells, which led to reduced expression of IL-8, CXCL-1, SNAIL and MMP2, but not MMP9. Tissue Factor knockdown or inhibition with antibodies reduced matrigel invasion. Tissue Factor antibodies limited 143B tumour growth in vivo, and resulted in decreased intra-tumoural micro-vessel density. Furthermore, lung metastasis from the primary tumour was significantly reduced. Thus, Tissue Factor expression in osteosarcoma reduces metastasis-free survival in patients, and increases pro-tumourigenic behaviour both in vitro and in vivo.

Topics: Adolescent; Animals; Bone Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Child; Disease-Free Survival; Female; Gene Expression; Gene Knockdown Techniques; Humans; Male; Mice, Inbred NOD; Mice, SCID; Neoplasm Invasiveness; Osteosarcoma; RNA, Messenger; RNA, Neoplasm; Thromboplastin; Young Adult

Breast cancer has the potential to metastasize to bone, causing debilitating symptoms. Although many tumor cells have thrombin-generating systems originating from tissue factor (TF), therapy in terms of the coagulation system is not well established. To elucidate the efficacy of the thrombin inhibitor, argatroban, on bone metastasis, we investigated TF activation and vascular endothelial growth factor (VEGF) secretion on treatment with thrombin and argatroban.. MDA-231 breast cancer cells were treated with thrombin in presence or absence of argatroban, and TF activity was measured in the form of activated factor X. Enzyme-linked immunosorbent assay (ELISA) was used to measure VEGF concentrations in the medium. MDA-231 cells were injected into the left heart ventricle of mice, and then argatroban or saline was administered intraperitoneally for 28 days. After 28 days, incidence of bone metastasis was evaluated in the limbs by radiography.. TF activity and VEGF secretion were upregulated by thrombin. Argatroban inhibited the enhancement of TF activity and VEGF secretion induced by thrombin. In vivo analysis revealed that the number of metastasized limbs in the argatroban group was significantly lower compared with the saline group (P < 0.05).. Thrombin not only enhances VEGF secretion but also has a positive feedback mechanism to reexpress TF. These results indicate that inhibition of thrombin is of great value in suppression of tumor metastasis. Argatroban is a noteworthy and useful thrombin inhibitor because it has already been used in the clinical setting and has antimetastatic effects in vivo.

Topics: Animals; Antithrombins; Arginine; Body Weight; Bone Neoplasms; Breast Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Humans; Mice; Pipecolic Acids; Sulfonamides; Thrombin; Thromboplastin; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

To assess immunohistochemically the pattern of tissue factor (TF) expression in patients with metastatic prostate cancer, because TF is aberrantly expressed in human cancer. TF is the primary initiator of the coagulation cascade.. Seventy-three patients with untreated metastatic prostate cancer who received hormonal therapy were included in the present study. Biopsy specimens were stained with anti-human TF antibody. We evaluated the histologic grade, extent of bony metastasis, clinical response to hormonal therapy, and patient prognosis.. TF was detected in 75.3% of the tumors of the patients with metastatic prostate cancer. TF expression showed no association with histologic grade, extent of bony metastasis, or clinical response to hormonal therapy. Patients with TF-positive tumors had a poorer cause-specific survival than those with TF-negative tumors. Multivariate analysis showed that TF expression, clinical response to hormonal therapy, and extent of bony metastasis were significant prognostic factors.. The TF content measured using immunohistochemical staining was a useful prognostic factor for patients with metastatic prostate cancer treated with androgen withdrawal therapy.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Bone Neoplasms; Chlormadinone Acetate; Diethylstilbestrol; Gene Expression Regulation, Neoplastic; Humans; Life Tables; Male; Middle Aged; Neoplasm Proteins; Orchiectomy; Prognosis; Proportional Hazards Models; Prostatic Neoplasms; Survival Analysis; Thromboplastin

Coagulation activation is a recognized complication of cancer in which increased tissue factor (TF) is implicated. TF can be detected in urine (uTF). This study assesses uTF levels in benign and malignant urological disease and correlates the results with conventional markers of tumour progression.. Using a simple and reproducible kinetic chromogenic assay, we determined uTF levels in controls (normal volunteers (n = 57) and patients with renal stones (n = 30)), benign and malignant bladder (n = 75) or prostate (n = 106) disease and in patients with or without recurrent bladder cancer (n=30). Each benign disease group was stratified as inflammatory (cystitis or prostatitis) or non-inflammatory (negative cystoscopy following haematuria or benign prostatic hypertrophy).. The controls and the benign non-inflammatory results were indistinguishable. The malignant and inflammatory groups showed raised uTF levels over controls (P<0.001 bladder and P<0.01 prostate). The difference between malignant and benign inflammatory disease was only significant for the bladder group. uTF levels were significantly related to histological tumour grading, prostate serum specific antigen, static bone scan images and recurrence status.. uTF levels can distinguish, statistically but not without overlap, patients with malignancy from normal controls and benign non-inflammatory conditions. Discrimination between inflammatory and malignant disease has only been demonstrated in the bladder. uTF levels showed a significant association with markers of tumour progression or metastasis and may be useful in predicting bladder tumour recurrence.

Topics: Adult; Aged; Biomarkers, Tumor; Bone Neoplasms; Case-Control Studies; Cystitis; Disease Progression; Humans; Kidney Calculi; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Hyperplasia; Prostatic Neoplasms; Prostatitis; Thromboplastin; Urinary Bladder Neoplasms