Genetic pathways linking hemostasis and cancer.
Oncogenic events impact interactions of cancer cells with their surroundings. Amongst the most consequential, in this regard, is the influence on angiogenesis, inflammation and hemostasis. Indeed, mutant oncogenes (EGFR, HER2, RAS, MET, PML-RARα) are known to alter the expression of angiogenic and pro-inflammatory factors, as well as change the cancer cell coagulome, including the levels of tissue factor (TF) and other mediators (PAI-1, COX2). Accompanying losses of tumour suppressor genes (PTEN, p53), and changes in microRNA (miR-19b, miR-520) facilitate these effects. Transforming genes may also trigger ectopic production of coagulation factors (e.g. FVII) by cancer cells and their release and properties of procoagulant microparticles (MPs). By deregulating protease activated receptors (PAR1/2) oncogenes may also change tumour cell responses to coagulation factor signalling. These changes act in concert with microenvironmental factors (hypoxia), stress responses (therapy) and differentiation programs, including epithelial-to-mesechymal transitions (EMT) and through tumour initiating cell (TIC) compartment. In so doing, the coagulation system influences early (initiation, angiogenesis), intermediate (growth, invasion) and late stages (metastasis, relapse) of cancer progression. In fact, TF may act as a molecular switch that controls the transition between dormant, latent and progressive/metastatic disease. TIC-like cells may play a role in these effects, as they express TF and PAR-1/2, and respond to stimulation with their agonists. As major human malignancies (e.g. glioblastoma) are increasingly recognized to consist of a spectrum of molecularly distinct disease subtypes driven by specific genetic pathways, so too may their patterns of interaction differ with the coagulation system. A better understanding of these linkages may be a source of new diagnostic, prognostic and therapeutic opportunities.
Montreal Children's Hospital, McGill University, QC, Canada.
Delphine
D
Garnier
Nathalie
N
Magnus
Esterina
E
D'Asti
Maryam
M
Hashemi
Brian
B
Meehan
Chloe
C
Milsom
Janusz
J
Rak
D000818:Animals; D001779:Blood Coagulation Factors / Q000235:genetics* / Q000276:immunology*; D006487:Hemostasis / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology*
D001779:Blood Coagulation Factors