Anti-angiogenic therapy is based on a simple, elegant theory: eradicate tumors by depriving them of their blood supply. An emerging concept in the field of matrix biology is that several heparan sulfate proteoglycans such as perlecan act not only as structural constituents during development and in tissue homeostasis, but also as key signaling molecules in tumor angiogenesis. We have discovered that the C-terminal fragment of perlecan protein core, named """"""""endorepellin"""""""" to signify its anti-endothelial activity, is a powerful angiogenesis inhibitor. We have further discovered the functional receptor for endorepellin, namely the a2?1 integrin, and shown that recombinant endorepellin blocks endothelial cell migration, collagen-induced capillary morphogenesis, and growth of blood vessels in Matrigel in vitro and in vivo. More recent results have demonstrated that endorepellin targets tumor vasculature in vivo and reduces the growth of orthotopic tumor xenografts and syngeneic tumors in mice. In spite of this accumulating evidence, the precise mode of action of endorepellin is not fully established. Our long-term objectives are to expand our initial observations and investigate in more depth the mechanism of action of endorepellin, identify novel genes affected by the action of this powerful protein, and systematically test its in vivo anti-angiogenic activity. Specifically, we plan to: [1] Decipher the precise mechanism of binding of endorepellin on the I domain of the a2?1 integrin and its structural requirements, [2] Determine the precise mechanism of internalization, intracellular fate and downstream signaling of endorepellin in endothelial cells, and [3] Establish its in vivo anti-angiogenic activity by utilizing animal tumor models possessing or lacking the endorepellin functional receptor. Collectively, the expected results should generate a coherent and unified mode of action for endorepellin, identify new target proteins involved in its signaling pathway which could be potential novel targets for anti-angiogenesis therapy, and establish its in vivo role as an anti-angiogenic factor using unambiguous loss-of-function experiments through gene targeting. A better understanding of the biology of endorepellin would benefit research not only in cancer but also in other fields where angiogenesis plays a key role. The anti-angiogenic approach to controlling cancer can eventually succeed only if we deepen our understanding of angiogenesis and discover new compounds that modulate this key biological process. This proposal is focused on understanding the precise mechanism of action of a newly-discovered anti-angiogenic protein named endorepellin. Targeting the established tumor vasculature represents an alternate and potentially important therapeutic modality against cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA047282-19
Application #
7906715
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Woodhouse, Elizabeth
Project Start
1990-08-06
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
19
Fiscal Year
2010
Total Cost
$368,855
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Neill, Thomas; Andreuzzi, Eva; Wang, Zi-Xuan et al. (2018) Endorepellin remodels the endothelial transcriptome toward a pro-autophagic and pro-mitophagic gene signature. J Biol Chem 293:12137-12148
Iozzo, Renato V; Gubbiotti, Maria A (2018) Extracellular matrix: The driving force of mammalian diseases. Matrix Biol 71-72:1-9
Gubbiotti, Maria A; Seifert, Erin; Rodeck, Ulrich et al. (2018) Metabolic reprogramming of murine cardiomyocytes during autophagy requires the extracellular nutrient sensor decorin. J Biol Chem 293:16940-16950
Karamanos, Nikos K; Theocharis, Achilleas D; Neill, Thomas et al. (2018) Matrix modeling and remodeling: A biological interplay regulating tissue homeostasis and diseases. Matrix Biol :
Schaefer, Liliana; Tredup, Claudia; Gubbiotti, Maria A et al. (2017) Proteoglycan neofunctions: regulation of inflammation and autophagy in cancer biology. FEBS J 284:10-26
Buraschi, Simone; Neill, Thomas; Iozzo, Renato V (2017) Decorin is a devouring proteoglycan: Remodeling of intracellular catabolism via autophagy and mitophagy. Matrix Biol :
Torres, Annabel; Gubbiotti, Maria A; Iozzo, Renato V (2017) Decorin-inducible Peg3 Evokes Beclin 1-mediated Autophagy and Thrombospondin 1-mediated Angiostasis. J Biol Chem 292:5055-5069
Gubbiotti, Maria A; Neill, Thomas; Iozzo, Renato V (2017) A current view of perlecan in physiology and pathology: A mosaic of functions. Matrix Biol 57-58:285-298
Neill, Thomas; Sharpe, Catherine; Owens, Rick T et al. (2017) Decorin-evoked paternally expressed gene 3 (PEG3) is an upstream regulator of the transcription factor EB (TFEB) in endothelial cell autophagy. J Biol Chem 292:16211-16220
Pozzi, Ambra; Yurchenco, Peter D; Iozzo, Renato V (2017) The nature and biology of basement membranes. Matrix Biol 57-58:1-11

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