The desmoplastic response to tumor invasion is an important though poorly understood collagenous host reaction responsible for the hard lump appearance of many cancers. In human breast carcinoma, approximately 80% of cases are associated with intense desmoplasia, a response which promotes early clinical detection. Both the mechanism of this response and its effect on tumor invasion and metastasis are not known, but previous studies have indicated that the desmoplastic reaction is composed of numerous host myofibroblasts and a unique collagen profile with relatively high amounts of Type V collagen.
The aims of this research project are three-fold.
The first aim i s to characterize and purify a myofibroblast growth factor elaborated by invasive tumor cells. Human breast carcinoma tissue of the desmoplastic variety and cell lines such as MCF-7 and MDA-MB-134-VI will be studied for the presence of such factors by chemotaxis, mitogenesis, and myofibroblast-differentiating assays. Non-desmoplastic human breast carcinoms (medullary type) and cell lines derived from them will serve as controls.
The second aim i s to further characterize the desmoplastic response biochemically, specifically identifying inhibitors to tumor proteases such as Type IV collagenase, cathepsins, and plasminogen activator, all of which have been implicated in the invasive process. Human breast carcinoma tissue of the desmoplastic variety again will serve as source from which to extract these inhibitors to invasion. The demonstration of high amounts of protease inhibitors within desmoplastic tissue would suggest that one purpose of the response is to limit the local spread of tumor.
The final aim of this study is to examine the effect of the desmoplastic response on distant metastasis. To achieve this, a new quantitative model of desmoplasia has been developed in the C57 BL/6 mouse, utilizing the syngeneic transplantable tumor, BL6 melanoma, and ?14?C proline instilled intraperitoneally. Host collagen synthesis is measured at the primary site and perturbated with blockers of collagen synthesis. The effect on pulmonary metastases will be determined. The long-term purpose then is insight into the mechanism and meaning of desmoplasia. (A)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA040225-01
Application #
3179895
Study Section
Pathology B Study Section (PTHB)
Project Start
1985-07-01
Project End
1988-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Mahooti, Sepi; Porter, Kyle; Alpaugh, Mary L et al. (2010) Breast carcinomatous tumoral emboli can result from encircling lymphovasculogenesis rather than lymphovascular invasion. Oncotarget 1:131-47
Barsky, Sanford H; Karlin, Nina J (2006) Mechanisms of disease: breast tumor pathogenesis and the role of the myoepithelial cell. Nat Clin Pract Oncol 3:138-51
Barsky, Sanford H; Karlin, Nina J (2005) Myoepithelial cells: autocrine and paracrine suppressors of breast cancer progression. J Mammary Gland Biol Neoplasia 10:249-60
Barsky, Sanford H (2003) Myoepithelial mRNA expression profiling reveals a common tumor-suppressor phenotype. Exp Mol Pathol 74:113-22
Shao, Z M; Nguyen, M; Barsky, S H (2000) Human breast carcinoma desmoplasia is PDGF initiated. Oncogene 19:4337-45
Shao, Z M; Shen, Z Z; Fontana, J A et al. (2000) Genistein's ""ER-dependent and independent"" actions are mediated through ER pathways in ER-positive breast carcinoma cell lines. Anticancer Res 20:2409-16
Shao, Z M; Alpaugh, M L; Fontana, J A et al. (1998) Genistein inhibits proliferation similarly in estrogen receptor-positive and negative human breast carcinoma cell lines characterized by P21WAF1/CIP1 induction, G2/M arrest, and apoptosis. J Cell Biochem 69:44-54
Shao, Z M; Wu, J; Shen, Z Z et al. (1998) Genistein inhibits both constitutive and EGF-stimulated invasion in ER-negative human breast carcinoma cell lines. Anticancer Res 18:1435-9
Shao, Z M; Nguyen, M; Alpaugh, M L et al. (1998) The human myoepithelial cell exerts antiproliferative effects on breast carcinoma cells characterized by p21WAF1/CIP1 induction, G2/M arrest, and apoptosis. Exp Cell Res 241:394-403
Shao, Z M; Wu, J; Shen, Z Z et al. (1998) Genistein exerts multiple suppressive effects on human breast carcinoma cells. Cancer Res 58:4851-7

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