Circulating Fibronectin Controls Tumor Growth

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2013-08, Vol.15 (8), p.925-IN24
• Main Authors: von Au, Anja, Vasel, Matthaeus, Kraft, Sabrina, Sens, Carla, Hackl, Norman, Marx, Alexander, Stroebel, Philipp, Hennenlotter, Jörg, Todenhöfer, Tilman, Stenzl, Arnulf, Schott, Sarah, Sinn, Hans-Peter, Wetterwald, Antoinette, Bermejo, Justo Lorenzo, Cecchini, Marco G, Nakchbandi, Inaam A
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Breast Neoplasms - blood; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation; Endothelial Cells - metabolism; Female; Fibronectins - blood; Fibronectins - genetics; Fibronectins - metabolism; Gene Expression Regulation, Neoplastic; Humans; Male; Mammary Neoplasms, Experimental - blood; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Mice; Mice, Knockout; Mice, Transgenic; Middle Aged; Neovascularization, Pathologic - blood; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Oncology; Prostatic Neoplasms - blood; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Reverse Transcriptase Polymerase Chain Reaction; Survival Analysis; Tissue Array Analysis; Transplantation, Heterologous; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.13762

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.