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R. Vilar et al.
nificantly increase thrombosis risk (Online Supplementary Table S1) can have a family history of CVD, and experi- ence thrombotic events at a young age.37 Interestingly, four out of seven mutations result in an amino acid change to cysteine, which may bind to albumin, resulting in struc- turally abnormal clots.66 Polymorphisms in the fibrinogen genes67 have also been linked to CVD: for example, Aα p.Thr331Ala, which alters factor XIII-mediated cross-link- ing, results in fibrin clots prone to undergo embolization.68 Post-translational modifications of fibrinogen (e.g., oxida- tion, phosphorylation, glycosylation and sialyation), might also have a role in CVD by affecting clot architec- ture, the rate and form of fibrin networks or the interac- tion with platelets and fibrinolysis.67 In accordance with this, dysfibrinogenemic variants that result in the over-sia- lylation of fibrinogen, aberrant fibrin polymerization or hypofibrinolysis were identified with relatively high prevalence in patients with chronic thromboembolic pul- monary hypertension.69 Fibrinolytic resistance and high proportions of monosialyted Bβ chains were linked to angiogenesis and growth of fibroblasts and endothelial cells, resulting in chronic inflammation and remodeling of pulmonary cells.70
Other known cardiovascular risk factors, including body mass index, smoking, and diabetes mellitus, can also affect the fibrin network and CVD risk.71
Cancer
Coagulation factors have been linked with malignancy for over a 100 years and high plasma fibrinogen levels, in particular, have been associated with cancer development and progression. Fibrinogen can be produced by some non-hepatocyte-derived cancer cells and present in the surroundings of tumors, such as in breast cancer.72
A meta-analysis examining the prognostic effect of cir- culating fibrinogen in solid tumors showed a positive cor- relation between pretreatment fibrinogen levels and poor- er survival (hazard ratio=1.51).73 Conflicting results came from studies on hematologic cancers,74-76 but overall patients with elevated baseline plasma fibrinogen levels had a significantly poorer clinical outcome.
Fibrinogen-deficient mice (Fga-/-) were protected against hematogenous pulmonary metastasis, but not tumor growth after intravenous injection of lung carcinoma and melanoma cell lines. Hirudin, a thrombin inhibitor, further reduced the metastatic potential of circulating cancer cells in Fga-/- mice, while plasmin depletion had no effect.77 In a colon cancer model, the thrombin-fibrinogen axis was shown to mediate primary tumor development, as it was diminished in Fga-/- mice.78
The aforementioned associations between fibrinogen and cancer do, however, still require investigation as they do not prove causality. Several hypotheses can be made for the molecular mechanisms implicating fibrinogen in the initiation and development of neoplasms (Figure 2). First, fibrinogen binds growth factors, including vascular endothelial growth factor and fibroblast growth factor.13 Thus, extracellular matrix-residing fibrinogen may serve as a reservoir, controlling growth factor bioavailability and accessibility, and influencing cancer cell proliferation, inhi- bition of apoptosis, angiogenesis and metastases.72 For example, fibrinogen produced by epithelial cancer cells promotes lung and prostate cancer cell growth through an
Figure 2. Schematic diagram of pro-tumorigenic mechanisms involving fibrin(ogen). Fibrin(ogen) binds and surrounds cancer cells, forming a structure that protects tumors from immune cells, in a process that may be enhanced by attracted platelets. By interacting with endothelial cells via intercellular adhesion molecule-1, among other receptors, fibrin(ogen) contributes to the extravasation, cell migration and establishment of secondary tumors, while the link with leuko- cytes via αMβ2 results in the production of pro-inflammatory cytokines (e.g., inter- leukin-1β) rendering an inflammatory microenvironment that potentially favors tumor progression. The presence of fibrin(ogen) surrounding the tumor, in addi- tion to its protective role, may generate thrombotic events which could prompt a worse clinical outcome. Finally, fibrinogen’s ability to bind different growth fac- tors further contributes to tumor maintenance. This figure was adapted from Simpson-Haidaris et al.72 and prepared using BioRender.com. BM: basement membrane; ECM: extracellular matrix; ICAM-1: intercellular adhesion molecule 1.
interaction with fibroblast growth factor 2.79 Second, fib- rinogen binds to several cell types. Fibrinogen-mediated cellular bridging may provide traction for cancer cell adhe- sion, shape changes, motility, and invasive potential.72 An example is fibrin(ogen) binding to endothelial intercellular adhesion molecule-1, facilitating the lodging of circulating tumor cells.80 Finally, the fibrinogen interaction with platelets via β3-integrins facilitates the protection of tumor cells from natural killer-cell cytotoxicity, permitting escape from host immune surveillance.81 Furthermore, interaction with integrin receptor αMβ2 has been suggested to modulate the inflammatory response by inducing leukocyte adhesion to endothelial cells and production of pro-inflammatory cytokines in peripheral blood mononu- clear cells.82 Thus, fibrinogen influences an inflammatory tumor microenvironment to favor tumor progression.
These studies suggest that modulating fibrinogen levels in cancer patients may have therapeutic potential. Lowering plasma fibrinogen, either via drug therapy or
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haematologica | 2020; 105(2)