Tumor angiogenesis in the absence of fibronectin or its cognate integrin receptors
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Updated: Apr 15, 2026
Monitoring Functionality and Morphology of Vasculature Recruited by Factors Secreted by Fast-growing Tumor-generating Cells
Published on: November 23, 2014
Patrick A Murphy1, Shahinoor Begum1, Richard O Hynes1
1Howard Hughes Medical Institute, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States of America.
Abstract:
Binding of α5β1 and αvβ3/β5 integrin receptors on the endothelium to their fibronectin substrate in the extracellular matrix has been targeted as a possible means of blocking tumor angiogenesis and tumor growth. However, clinical trials of blocking antibodies and peptides have been disappointing despite promising preclinical results, leading to questions about the mechanism of the inhibitors and the reasons for their failure. Here, using tissue-specific and inducible genetics to delete the α5 and αv receptors in the endothelium or their fibronectin substrate, either in the endothelium or globally, we show that both are dispensable for tumor growth, in transplanted tumors as well as spontaneous and angiogenesis-dependent RIP-Tag-driven pancreatic adenocarcinomas. In the nearly complete absence of fibronectin, no differences in vascular density or the deposition of basement membrane laminins, ColIV, Nid1, Nid2, or the TGFβ binding matrix proteins, fibrillin-1 and -2, could be observed. Our results reveal that fibronectin and the endothelial fibronectin receptor subunits, α5 and αv, are dispensable for tumor angiogenesis, suggesting that the inhibition of angiogenesis induced by antibodies or small molecules may occur through a dominant negative effect, rather than a simple functional block.
Insights
Fibronectin and its endothelial receptors, α5 and αv integrins, are dispensable for tumor growth and angiogenesis. This suggests tumor angiogenesis inhibitors may work via a dominant negative effect, not a simple block.
Area of Science:
- Integrin signaling in cancer biology
- Tumor angiogenesis mechanisms
- Extracellular matrix-receptor interactions
Background:
- Endothelial integrin receptors (α5β1, αvβ3/β5) binding to fibronectin are potential targets for blocking tumor angiogenesis.
- Clinical trials of blocking antibodies and peptides have yielded disappointing results, questioning their mechanism of action.
Purpose of the Study:
- To investigate the necessity of endothelial α5 and αv integrin receptors and their fibronectin substrate for tumor growth and angiogenesis.
- To elucidate the mechanism behind the failure of current anti-angiogenesis therapies targeting these pathways.
Main Methods:
- Utilized tissue-specific and inducible genetic deletion of α5 and αv integrin subunits and fibronectin in endothelial cells and globally.
- Assessed tumor growth in transplanted and spontaneous (RIP-Tag) pancreatic adenocarcinoma models.
- Analyzed vascular density and extracellular matrix component deposition (laminins, ColIV, Nid1, Nid2, fibrillin-1, -2) in fibronectin-deficient conditions.
Main Results:
- Both α5 and αv integrin receptors and fibronectin are dispensable for tumor growth in various models.
- Complete absence of fibronectin did not affect vascular density or basement membrane/matrix protein deposition.
- Tumor angiogenesis and growth proceed effectively without functional fibronectin-ECM interactions.
Conclusions:
- Endothelial fibronectin and its α5 and αv integrin receptors are not essential for tumor angiogenesis or growth.
- The failure of blocking antibodies/peptides may stem from a dominant negative effect rather than a simple functional blockade.
- Re-evaluation of anti-angiogenesis strategies targeting the fibronectin pathway is warranted.
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