Cancer‐associated thrombosis: The search for the holy grail continues

Abstract

Cancer patients have an increased risk of developing venous thromboembolism (VTE), a condition that is associated with increased morbidity and mortality. Although risk assessment tools have been developed, it is still very challenging to predict which cancer patients will suffer from VTE. The scope of this review is to summarize and discuss studies focusing on the link between genetic alterations and risk of cancer‐associated thrombosis (CAT). Thus far, classical risk factors that contribute to VTE have been tried as risk factors of CAT, with low success. In support, hypercoagulant plasma profiles in patients with CAT differ from those with only VTE, indicating other risk factors that contribute to VTE in cancer. As germline mutations do not significantly contribute to elevated risk of VTE, somatic mutations in tumors may significantly associate with and contribute to CAT. As it is very time‐consuming to investigate each and every mutation, an unbiased approach is warranted. In this light we discuss our own recent unbiased proof‐of‐principle study using RNA sequencing in isolated colorectal cancer cells. Our work has uncovered candidate genes that associate with VTE in colorectal cancer, and these gene profiles associated with VTE more significantly than classical parameters such as platelet counts, D‐dimer, and P‐selectin levels. Genes associated with VTE could be linked to pathways being involved in coagulation, inflammation and methionine degradation. We conclude that tumor cell‐specific gene expression profiles and/or mutational status has superior potential as predictors of VTE in cancer patients.

EMT-Associated Heterogeneity in Circulating Tumor Cells: Sticky Friends on the Road to Metastasis

“…If TF displays coagulation-independent pro-tumoral signaling functions, it is essentially known as the major cell-associated activator of the coagulation cascade. Its expression by tumor cells, triggering coagulant properties, has been demonstrated to be determinant for CTC survival and seeding [194,195,206,226]. This has been exemplified in numerous animal studies using tumor cells modified for TF expression or TF blocking antibodies, demonstrating that tumor-cell expressed TF is associated with increased abilities to form micrometastases [227][228][229][230].…”

“…The activation of the coagulation system is today recognized as a crucial process facilitating early metastasis. Hypercoagulability is actually a long-known correlate of malignancy (Trousseau's syndrome), and venous thromboembolism (VTE) has been associated with worse prognosis [193][194][195]. Accordingly, the CTC count has been associated with hypercoagulability, increased risk of venous thrombosis and dismal prognosis [196][197][198][199][200].…”

Detection and Investigation of Extracellular Vesicles in Serum and Urine Supernatant of Prostate Cancer Patients

“…Then, regarding the antigens detected in the serum, these are potentially derived from EVs related to endothelial cells and platelets. Since endothelial cells and platelets could have a key role in tumor growth, metastasis, and cancer-associated thrombosis, the detection of EVs presenting these antigens could a have a possible use, e.g., in revealing and monitoring cancer-related venous thromboembolism, a circumstance associated with increased morbidity and mortality [ 30 , 31 ]. Indeed, the role and involvement of EVs in cancer-related hypercoagulation is worthy of being investigated deeply, as already suggested [ 32 ].…”

Circulating ensembles of tumor‐associated cells: A redoubtable new systemic hallmark of cancer

“…C-ETACs are a further potent danger because it has been shown that they have a very high metastatic potential 1,9,10,21 besides posing the imminent threat of thromboembolic complications. 22,23 Though C-ETACs have received due attention in recent years, their composite detection, harvest and culture has remained difficult and sporadic, with only few anecdotal successes. 3 The limited successes of prior efforts may be attributable to the processes relying on devices and methods originally designed for detection/capture of single CTC.…”