The long-term objective of this competing grant is to understand the biology of perlecan, a multifunctional heparan sulfate proteoglycan with wide tissue distribution and functional activities, and to discern its precise role in tumorigenesis. The central hypothesis is that the aberrant expression of perlecan contributes to tumor promotion and invasion, a working theory based on several key observations: [a] Perlecan expression is elevated in the pericellular matrix of human colon cancer and melanomas, [b] Abundant deposition of this gene product occurs in and around the newly-formed tumor blood vessels, [c] Transformed cells with a high proliferative index overproduce perlecan, [d] Perlecan is directly involved in the storing of angiogenic growth factors, [e] Perlecan protein core binds FGF7 and modulates its mitogenic activity, and [f] Perlecan protein core interacts with FGF- binding protein (FGF-BP), a protein that is also implicated in tumor formation and angiogenesis. The last two discoveries were made in the P.I.'s laboratory under the auspices of this grant and indicate that various modules of perlecan may act synergistically with biologically active proteins in modulating tumor growth. Over the next five years we plan to: (1) Investigate the role of perlecan in tumorigenesis by testing the behavior of cancer cells with abrogated or induced expression of perlecan in syngeneic hosts, (2) Investigate in depth the interaction between perlecan and FGF-BP, and (3) Identify cell surface proteins interacting with perlecan using expression cloning and the yeast two hybrid system. These concerted research lines will provide information, not only on the functional roles of mammalian perlecan in tumorigenesis, but will also identify novel biological partners that could directly affect perlecan's functions. The expected results could lead to future approaches of cancer prevention and treatment directed at hindering the expression of this proteoglycan thereby depriving the tumor cells of an essential macromolecule.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA047282-15S1
Application #
7277496
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Woodhouse, Elizabeth
Project Start
1990-08-06
Project End
2007-09-27
Budget Start
2005-07-01
Budget End
2007-09-27
Support Year
15
Fiscal Year
2006
Total Cost
$64,584
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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 :
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
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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