Hyaluronan-cell interactions have been implicated in growth, invasion and metastasis of several types of tumors. However, the manner in which hyaluronan is involved is complex and poorly understood. Perturbation of endogenous hyaluronan-tumor cell interactions by small oligomers of hyaluronan inhibits tumor growth in vivo and reverses several malignant characteristics of tumor cells in vitro. Thus further investigation of these phenomena will lead to increased understanding of the way in which endogenous tumor cell hyaluronan promotes malignancy and the mechanism by which hyaluronan oligomers reverse its effects. The influence of hyaluronan oligomers and of increased endogenous hyaluronan on tumor cell survival and apoptotic pathways will be studied, especially with relation to the phosphatidylinositol-3-kinase/ Akt and Erk pathways. Upstream events that are known to regulate these pathways and that are potential candidates for perturbation by the hyaluronan oligomers are the major focus of the proposed studies. In particular, the influence of these oligomers on the following will be examined: a) ErbB2 activity and interactions of CD44 with ErbB2, ezrin, phosphatidylinositol-3-kinase and cdc37; b) complex formation between cdc37 (a co-chaperone with hsp90) and """"""""nascent"""""""" hyaluronan, and its potential role in production, targeting and cellular function of hyaluronan. Finally, the effects of hyaluronan oligomers in vivo on tumor cell apoptosis and growth arrest, tumor angiogenesis, mutagen-induced tumor initiation, and suppression of growth of spontaneous mammary tumors will be assessed. Increased knowledge of the role of hyaluronan in tumor progression and understanding the reversal of its effects by hyaluronan oligomers should lead to innovative therapeutic interventions for human cancer patients. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073839-08
Application #
7079428
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Forry, Suzanne L
Project Start
1997-07-01
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
8
Fiscal Year
2006
Total Cost
$256,624
Indirect Cost
Name
Medical University of South Carolina
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Grass, G Daniel; Toole, Bryan P (2015) How, with whom and when: an overview of CD147-mediated regulatory networks influencing matrix metalloproteinase activity. Biosci Rep 36:e00283
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Grass, G Daniel; Bratoeva, Momka; Toole, Bryan P (2012) Regulation of invadopodia formation and activity by CD147. J Cell Sci 125:777-88
Qin, Z; Dai, L; Bratoeva, M et al. (2011) Cooperative roles for emmprin and LYVE-1 in the regulation of chemoresistance for primary effusion lymphoma. Leukemia 25:1598-609
Misra, Suniti; Hascall, Vincent C; De Giovanni, Carla et al. (2009) Delivery of CD44 shRNA/nanoparticles within cancer cells: perturbation of hyaluronan/CD44v6 interactions and reduction in adenoma growth in Apc Min/+ MICE. J Biol Chem 284:12432-46
Toole, Bryan P (2009) Hyaluronan-CD44 Interactions in Cancer: Paradoxes and Possibilities. Clin Cancer Res 15:7462-7468
Slomiany, Mark G; Dai, Lu; Bomar, Paul A et al. (2009) Abrogating drug resistance in malignant peripheral nerve sheath tumors by disrupting hyaluronan-CD44 interactions with small hyaluronan oligosaccharides. Cancer Res 69:4992-8
Slomiany, Mark G; Dai, Lu; Tolliver, Lauren B et al. (2009) Inhibition of Functional Hyaluronan-CD44 Interactions in CD133-positive Primary Human Ovarian Carcinoma Cells by Small Hyaluronan Oligosaccharides. Clin Cancer Res 15:7593-7601

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