Plasma Fibronectin Promotes Lung Metastasis by Contributions to Fibrin Clots and Tumor Cell Invasion

Abstract

The attachment of circulating tumor cells to the blood vessels of distant organs is an important step in metastasis. We show here that experimental lung metastasis by two cell lines, B16F1 melanoma and 3LL lung carcinoma, is greatly reduced in transgenic mice that lack plasma fibronectin. This multifunctional adhesive glycoprotein becomes cross-linked to fibrin during clotting. Here, we report that eliminating plasma fibronectin from the blood circulation reverses the prometastatic effects of blood clotting and tumor cell integrin αvβ3. In vitro studies showed that fibrin-fibronectin complexes, but not purified fibrin, supported tumor cell attachment and invasion. These functions correlate with the ability of fibrin-fibronectin complexes to induce the activation of integrin αvβ3. Our findings reveal an important contribution of plasma fibronectin in lung metastasis. Furthermore, they suggest that the previously noted effects of blood clotting on lung metastasis might be mediated in part by a fibronectin-αvβ3 integrin axis, in which plasma fibronectin has to be incorporated into the blood clot. Cancer Res; 70(11); 4327-34. ©2010 AACR.

Liver Metastasis Is Facilitated by the Adherence of Circulating Tumor Cells to Vascular Fibronectin Deposits

“…Indeed, recent evidence has shown that fibronectin upregulation is important for liver premetastatic niche formation induced by pancreatic cancer-derived exosomes (12). Furthermore, studies in lung cancer suggest that plasma fibronectin could confer a prometastatic ability to cancer cells by activating a V b3 integrins (33). These observations suggest that fibronectin could play a role in premetastatic organ conditioning.…”

Recombinant Human Erythropoietin in Combination with Chemotherapy Increases Breast Cancer Metastasis in Preclinical Mouse Models

“…Importantly, these parameters are not usually monitored clinically after rHuEPO is given (31), although studies have shown that activation of these processes can also enhance metastasis (52). In the case of thrombosis, an increase in the formation of microthrombi may increase the metastatic burden (53) and could account for the results seen in this study, although this was not investigated because of technical challenges associated with accurately assessing coagulation parameters in mice (53). Interestingly, multiple rHuEPO trials have reported increases in thrombotic events in the EPO arm (6,8,11,54), and taken together with our preclinical data showing effects on metastasis without any observed direct effects on cancer cells, it is possible that this may be a factor leading to disease progression and decreased patient survival.…”

Platelet Regulation of Angiogenesis, Tumor Growth and Metastasis

“…The difference in metastatic burden was suggested to depend on increased survival of the metastatic tumor cells in the lungs during the first 24 hours. Fibronectin, another extracellular matrix-protein involved in platelet aggregation and stored in platelet -granules, seem to have pro-metastatic effects, reverting the metastasis-preventing effects of clot formation (Malik et al, 2010). Fibronectin binds to v3 integrin and forms complex w i t h f i b r i n d u r i n g c l o t f o r m a t i o n .…”