Hyaluronan and its cell surface receptors, CD44 and RHAMM, are involved in the cascade of events that lead to growth and metastasis of several tumor types. Transfection of tumor cells with soluble, hyaluronan-binding forms of CD44 or treatment with hyaluronan oligomers inhibits murine mammary carcinoma or melanoma growth in vivo, as well as formation of metastatic nodules in the lung after dissemination from the vasculature. Thus hyaluronan interactions are an essential contributor to progression of at least some tumor types and introduction of reagents that perturb hyaluronan interactions is likely to be therapeutically effective. Thus the major objective of this proposal is to design recombinant adenoviruses driving efficient production of hyaluronan-binding polypeptides that effectively inhibit tumor progression, but are engineered to have minimal side effects by removing non-hyaluronan-binding domains to whatever extent is possible without losing efficacy. The relative efficacy of recombinant adenoviral constructs encoding hyaluronan-binding polypeptides composed only of hyaluronan-binding domains (i.e., link modules), or of hyaluronan-binding motifs within a neutral background, will be compared to constructs encoding soluble CD44's that contain more extensive extracellular domains, in the murine mammary carcinoma system used previously. Successful constructs will then be tested in vivo for their ability to inhibit rat gliomal invasion and to allay human breast and ovarian carcinomas, grown in nude mice, at different stages of progression. Such constructs could be used widely for experimental manipulations in numerous systems and may ultimately lead to useful strategies for gene therapy in cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082867-03
Application #
6377441
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Woodhouse, Elizabeth
Project Start
1999-09-01
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
3
Fiscal Year
2001
Total Cost
$273,731
Indirect Cost
Name
Tufts University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
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
Dai, Lu; Chen, Yihan; Bonstaff, Karlie et al. (2015) Induction of hyaluronan production by oncogenic KSHV and the contribution to viral pathogenesis in AIDS patients. Cancer Lett 362:158-66
Spaeth, Erika L; Labaff, Adam M; Toole, Bryan P et al. (2013) Mesenchymal CD44 expression contributes to the acquisition of an activated fibroblast phenotype via TWIST activation in the tumor microenvironment. Cancer Res 73:5347-59
Dai, Lu; Bai, Lihua; Lu, Ying et al. (2013) Emmprin and KSHV: new partners in viral cancer pathogenesis. Cancer Lett 337:161-6
Grass, G Daniel; Tolliver, Lauren B; Bratoeva, Momka et al. (2013) CD147, CD44, and the epidermal growth factor receptor (EGFR) signaling pathway cooperate to regulate breast epithelial cell invasiveness. J Biol Chem 288:26089-104
Dai, Lu; Guinea, Maria C; Slomiany, Mark G et al. (2013) CD147-dependent heterogeneity in malignant and chemoresistant properties of cancer cells. Am J Pathol 182:577-85
Dai, Lu; Qin, Zhiqiang; Defee, Michael et al. (2012) Kaposi sarcoma-associated herpesvirus (KSHV) induces a functional tumor-associated phenotype for oral fibroblasts. Cancer Lett 318:214-20
Dai, Lu; Bratoeva, Momka; Toole, Bryan P et al. (2012) KSHV activation of VEGF secretion and invasion for endothelial cells is mediated through viral upregulation of emmprin-induced signal transduction. Int J Cancer 131:834-43
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

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