Circulating Fibronectin Controls Tumor Growth

Abstract

Fibronectin is ubiquitously expressed in the extracellular matrix, and experimental evidence has shown that it modulates blood vessel formation. The relative contribution of local and circulating fibronectin to blood vessel formation in vivo remains unknown despite evidence for unexpected roles of circulating fibronectin in various diseases. Using transgenic mouse models, we established that circulating fibronectin facilitates the growth of bone metastases by enhancing blood vessel formation and maturation. This effect is more relevant than that of fibronectin produced by endothelial cells and pericytes, which only exert a small additive effect on vessel maturation. Circulating fibronectin enhances its local production in tumors through a positive feedback loop and increases the amount of vascular endothelial growth factor (VEGF) retained in the matrix. Both fibronectin and VEGF then cooperate to stimulate blood vessel formation. Fibronectin content in the tumor correlates with the number of blood vessels and tumor growth in the mouse models. Consistent with these results, examination of three separate arrays from patients with breast and prostate cancers revealed that a high staining intensity for fibronectin in tumors is associated with increased mortality. These results establish that circulating fibronectin modulates blood vessel formation and tumor growth by modifying the amount of and the response to VEGF. Furthermore, determination of the fibronectin content can serve as a prognostic biomarker for breast and prostate cancers and possibly other cancers.

Inhibition of fibronectin deposition improves experimental liver fibrosis

“…Fibronectin also binds to growth factors, including TGF-b [13,14]. In conditional knockout mice, unable to produce fibronectin in the liver, the decrease in fibronectin production is associated with an increase in available active-TGF-b, and hence an increase in the activation of HSCs, collagen production and matrix accumulation [15].…”

Protein-crystal interface mediates cell adhesion and proangiogenic secretion

“…Tumor cells promote angiogenesis essentially by up-regulating proangiogenic factors such as VEGF [65]. High Fn levels detected in tumors have been associated with increased mortality among patients with breast and prostate cancers, and circulating plasma Fn was reported to enhance blood vessel formation and facilitate tumor growth by increasing soluble VEGF contents and enhancing subsequent VEGF-mediated signaling [66]. To assess secretion per cell, all our data (VEGF and IL-8 levels) were normalized by the number of live cells for each sample.…”

Selective Reversible Inhibition of Autophagy in Hypoxic Breast Cancer Cells Promotes Pulmonary Metastasis

“…Thus, the source of fibronectin may be due to a reduction in autophagic degradation or an increase in secretion of fibronectin protein. Fibronectin is a key component of the extracellular matrix (ECM) that is expressed by both cancer-associated fibroblasts (CAFs) and cancer cells, and drives metastasis via mechanotransduction(35–37). Importantly, fibronectin engages integrin receptors leading to the activation of intracellular GTPases for cytoskeletal remodeling and cell motility(35,38).…”