title: 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.
authors.affiliation: Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: von Au
authors.forename: Matthaeus
authors.initials: M
authors.lastname: Vasel
authors.forename: Sabrina
authors.initials: S
authors.lastname: Kraft
authors.forename: Carla
authors.initials: C
authors.lastname: Sens
authors.forename: Norman
authors.initials: N
authors.lastname: Hackl
authors.forename: Alexander
authors.initials: A
authors.lastname: Marx
authors.forename: Philipp
authors.initials: P
authors.lastname: Stroebel
authors.forename: Jörg
authors.initials: J
authors.lastname: Hennenlotter
authors.forename: Tilman
authors.initials: T
authors.lastname: Todenhöfer
authors.forename: Arnulf
authors.initials: A
authors.lastname: Stenzl
authors.forename: Sarah
authors.initials: S
authors.lastname: Schott
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Sinn
authors.forename: Antoinette
authors.initials: A
authors.lastname: Wetterwald
authors.forename: Justo Lorenzo
authors.initials: JL
authors.lastname: Bermejo
authors.forename: Marco G
authors.initials: MG
authors.lastname: Cecchini
authors.forename: Inaam A
authors.initials: IA
authors.lastname: Nakchbandi
mesh_terms: D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000097:blood / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000097:blood* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000097:blood* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000097:blood / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D046888:Tissue Array Analysis; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D005353:Fibronectins; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2
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