Malignant cell behavior can arise by several mechanisms but is frequently associated with amplified activities of receptor tyrosine kinases and downstream signaling cascades. These pathways have been linked to anchorage-independent growth, to invasiveness and to multidrug resistance, common properties of malignant cancer cells. Drug resistance is also associated with enhanced drug efflux via ATP-dependent, ABC family transporters, and recent work emphasizes a potential role for cancer progenitor/ """"""""side population"""""""" cells enriched in the ABCG2 transporter in resistance. Close regulatory connections have now been revealed between all of these cellular properties and hyaluronan, a major component of the pericellular matrix surrounding tumor cells in vivo. Emmprin (CD 147), a cell surface glycoprotein enriched in malignant tumor cells, induces hyaluronan synthesis and its effects. Thus the long-term objective of this work is to determine the mechanisms whereby hyaluronan and emmprin regulate these hallmark properties of malignant cells as a basis for designing therapeutic interventions in cancer patients. A central question addressed in this proposal is how hyaluronan signaling becomes activated in malignant cells. Chronic inflammation and associated alterations in the stromal microenvironment of tumors induce or enhance malignant cell properties and tumor progression. In particular, tumor-associated macrophages promote signaling pathways linked to tumor cell survival, invasiveness and multidrug resistance. Both hyaluronan and emmprin are now known to be crucial components of inflammatory processes. The novel hypothesis guiding the proposed work is that mediators produced by cells in the stromal microenvironment, especially macrophages, induce hyaluronan-dependent signaling and consequent malignant outcomes, such as resistance to apoptosis/ drug resistance in tumor cells. The proposed studies address this question in macrophage-tumor co-culture systems, in drug-resistant side population cells and in animal models. These experiments will help illuminate the mechanisms whereby hyaluronan-induced receptor tyrosine kinase signaling is initiated in cancer cells and results in malignant cell properties, especially drug resistance and its relationship to cancer progenitor cells. Consequently, these approaches will help to guide further development of therapeutic interventions in cancer patients, employing antagonists of deregulated HA interactions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082867-10
Application #
7846084
Study Section
Intercellular Interactions (ICI)
Program Officer
Woodhouse, Elizabeth
Project Start
1999-09-01
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
10
Fiscal Year
2010
Total Cost
$251,120
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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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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