Expression of coagulation factors and their receptors in tumor tissue and coagulation factor upregulation in peripheral blood of patients with cerebral carcinoma metastases

Walter, Jan; Handel, Linn L.; Brodhun, Michael; Rossum, Denise van; Hanisch, Uwe‐Karsten; Liebmann, Lutz; Heppner, Frank L.; Goldbrunner, Roland; Koch, Arend; Kuhn, Susanne

doi:10.1007/s00432-011-1078-x

Cited by 9 publications

(10 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…reported that PAR‐4 protein was overexpressed in the majority of stage IB NSCLC tissues (65% of all cases and 87% of adenocarcinoma cases) and overexpression of PAR‐4 was associated with significantly shorter 3‐year survival . PAR‐4 expression was also detected in intracerebral metastases of small cell lung carcinoma in a recent study . However, Jiang et al .…”

Section: Discussionmentioning

confidence: 90%

“…The F2RL3 gene codes for the thrombin PAR‐4, which is expressed in a number of human tissues, including blood leukocytes and lung tissue . The function of PAR‐4 is not fully clear yet but there is emerging evidence that it might be involved in the pathophysiology of several malignant tumors and metastasis, including lung cancer . Ghio et al .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

F2RL3 methylation, lung cancer incidence and mortality

Zhang

Schöttker

Ordóñez‐Mena

et al. 2015

Intl Journal of Cancer

View full text Add to dashboard Cite

Smoking accounts for a large share of lung cancer. F2RL3 methylation was recently identified as a biomarker closely reflecting both current and past smoking exposure. We aimed to assess the associations of F2RL3 methylation with lung cancer incidence and mortality. In a large population-based cohort study, F2RL3 methylation was measured in baseline blood samples of 4,987 participants by MassARRAY. Associations of F2RL3 methylation and smoking with lung cancer incidence/mortality during a median follow-up of 10.9 years were assessed by Cox regression, controlling for potential confounders. The ability of F2RL3 methylation to predict lung cancer was examined by Harrell's C statistics. Hypomethylation at F2RL3 was strongly associated with both lung cancer incidence and mortality, with age-and sex-adjusted hazard ratios (HR; 95% CI) of 9.99 (5.61-17.79) and 16.86 (8.53-33.34), respectively, for participants whose methylation intensity were 0.54 compared with whose methylation intensity were 0.75. Strongly elevated HRs of 2.88 (1.42-5.84) and 5.17 (2.28-11.70) persisted even after controlling for multiple covariates including smoking status and pack-years. With fully adjusted HRs of 9.92 (2.88-34.12) and 16.48 (4.10-66.15), the associations between methylation and the two outcomes were particularly strong among participants 65 years. Combination of F2RL3 methylation and pack-years predicted lung cancer incidence with high accuracy (optimism-corrected Harrell's C statistics 5 0.86 for participants 65 years). These findings suggested that F2RL3 methylation is a very strong predictor of lung cancer risk and mortality, particularly at older age. The potential implications of F2RL3 methylation for early detection, risk stratification and prevention of lung cancer warrant further exploration.With 1.8 million new cases and 1.6 million deaths per year, lung cancer is the most common form of cancer and cause of cancer-related death worldwide. 1 Cigarette smoking is a well-known major risk factor for lung cancer. It is estimated that 80-90% of lung cancer cases and 71% of lung cancer deaths are attributable to smoking. 2,3 Exposure to multiple carcinogens during inhalation of tobacco smoke results in formation of DNA adducts and further induces mutations/ deletions in oncogenes or tumor suppressor genes, such as KRAS, TP53 and P16, which are considered to be involved in the key pathways of lung carcinogenesis. 4,5 Over the last decade, increasing evidence has emerged that epigenetic modifications, in particular aberrant DNA methylation, also play a role in lung tumor initiation and progression, 6,7 primarily

show abstract

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

F2RL3 methylation, lung cancer incidence and mortality

Zhang

Schöttker

Ordóñez‐Mena

et al. 2015

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Nonetheless, coagulation factors were found to be expressed in brain metastases of human clear cell renal cancer and small cell lung carcinoma. 138 TFPI was found to be elevated in plasma of patients with several PBTs and SBTs, and further studies of a possible link between coagulopathy and brain metastasis would be of great interest.…”

Section: Coagulation System and The Natural History Of Brain Tumorsmentioning

confidence: 94%

“…92,100 TF upregulation was also observed in the case of ligand dependent activation of the MET receptor in MB cells (DAOY), 97 and these properties were mitigated by the expression of the oncogenic miR-520 g. 137 Although TF is among the most frequently studied molecular paradigms of procoagulant conversion in cancer, the expression of other coagulation factors has also been reported in various tumor types, including FVII, 124 prothrombin, 125,126 FX, PAR-1, and other factors. 128,138 This is of note as some of these proteins are normally produced exclusively in the liver and under control of vitamin K-dependent mechanisms, which is the principle behind using vitamin K antagonists (warfarin) to control cancer coagulopathy. 139 To examine whether the ectopic (extrahepatic) production of coagulation factors could be a result of oncogenic transformation, two human glioma cell lines (U87 and U373) were engineered to express mutant EGFRvIII and tested for levels of elements of the TF-related coagulation pathway at both messenger RNA (mRNA) and protein levels.…”

Section: Genetic Determinants Of Brain Tumor Coagulomementioning

confidence: 99%

Brain Neoplasms and Coagulation

Magnus

D’Asti

Garnier

et al. 2013

Semin Thromb Hemost

View full text Add to dashboard Cite

Brain vasculature is uniquely programmed to protect central nervous system tissues and respond to their metabolic demands. These functions are subverted during the development of primary and metastatic brain tumors, resulting in vascular perturbations that are thought to contribute to progression and comorbidities of the underlying disease, including thrombosis and hemorrhage. Chronic activation of the coagulation system is particularly obvious in glioblastoma multiforme (GBM), where intratumoral vasoocclusive thrombosis may contribute to hypoxia, pseudopalisading necrosis, and angiogenesis. GBM is also associated with spontaneous or iatrogenic bleeding, and the emission of circulating procoagulants implicated in the unusually high risk of peripheral venous thromboembolism. Tissue factor (TF) expression is elevated in several types of brain tumors, including adult and pediatric GBM, as is the production of TF-containing microparticles (TF-MPs). Both TF expression and its vesicular emission are regulated by tumor microenvironment (e.g., hypoxia), in concert with activated oncogenic and growth factor pathways (RAS, EGFR, MET), as well as the loss of tumor suppressor gene activity (PTEN). Discovery of distinct oncogenic networks led to recognition of unique molecular subtypes within brain tumors, of which GBM (proneural, neural, classical, and mesenchymal), and medulloblastoma (SHH, WNT, group 3, and group 4) exhibit subtype-specific composition of the tumor coagulome. It remains to be established whether mechanisms of thrombosis and biological effects of coagulation in brain tumors are also subtype specific. In this regard, TF pathway represents a paradigm, and its impact on tumor dormancy, inflammation, angiogenesis, formation of cancer stem cell niches, and dissemination is a subject of considerable interest. However, establishing the extent to which TF and TF-MPs contribute to pathogenesis and thromboembolic disease in the context of primary and secondary brain tumors may require molecular stratification of patient populations. We suggest that a better understanding of these molecular linkages may pave the way to a more effective (targeted) therapy, prophylaxis, adjunctive use of anticoagulants, and other agents able to modulate interactions between brain tumors and the coagulation system.

show abstract

“…The drugs used in this study were RS67333, a potent and highly selective 5-HT4 partial agonist [10], and RS23597, a high affinity and selective competitive antagonist at 5-HT4 receptors [40], from (TOCRIS bioscience. USA) and MK801 (NMDA receptor antagonist, Sigma, Poole, Dorset, UK).…”

Section: Drugsmentioning

confidence: 99%