Invasion and metastasis are the most lethal characteristics of cancer and the leading causes of cancer-related death. TGF-beta normally suppresses these processes by inhibiting the proliferation of epithelial, endothelial, and hematopoietic cells. In contrast, cancer cells are commonly resistant to TGF-beta-mediated growth arrest, transforming the cellular response of this cytokine from a suppressor of tumor formation to a promoter of tumor growth, invasion, and metastasis. How TGF-beta stimulates both tumor suppression and promotion is not entirely clear. We suspect that TGF-beta mediates these opposing reactions by regulating cell microenvironments, particularly the expression of cytokines, growth factors, and extracellular matrix proteins. These secretory proteins likely collaborate with TGF-beta to regulate target cell activities in a context-specific manner. Identifying these secretory proteins and determining their function will greatly advance our understanding of the molecular mechanisms underlying both the biology and pathology of TGF-beta. We identified Fibulin-5 (FBLN5) as a novel TGF-beta-inducible secretory protein. Recent findings in our laboratory indicate that FBLN-5 both positively and negatively regulates tumorigenesis in a context-specific manner. For instance, FBLN-5 (i) stimulates and inhibits proliferation in a context-specific manner; (ii) is expressed aberrantly in metastatic human malignancies; and (iii) enhances the malignancy of a human fibrosarcoma. We therefore hypothesize that the inappropriate absence or presence of FBLN-5 in cell microenvironments leads to enhanced growth, motility, and invasion of cancer cells. Retroviral vectors will be used to manipulate FBLN-5 expression in normal cell lines, which then will be subjected to contemporary techniques in molecular biology and biochemistry to identify the signaling molecules stimulated by FBLN-5. We will similarly manipulate FBLN-5 expression in cancer cell lines to study its impact on cancer cell growth, motility, and invasion using in vitro and in vivo models of tumor growth and motility.
Our specific aims are to (i) define the function of integrins during stimulation of FBLN-5 signaling systems; (ii) determine the mechanisms whereby FBLN-5 effects the activities of normal and cancer cells; and (iii) define the function of FBLN-5 in the biology and pathology of TGF-?. These studies will provide valuable new information on how TGF-beta accelerates the growth and spread of cancers, and on how FBLN-5 participates in these processes. They may also aid in the development of novel therapeutics designed to abrogate the oncogenic effects of TGF-beta.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA095519-01A1
Application #
6614402
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Ault, Grace S
Project Start
2003-05-01
Project End
2008-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
1
Fiscal Year
2003
Total Cost
$265,007
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Albig, Allan R; Becenti, Darryl J; Roy, Thessa G et al. (2008) Microfibril-associate glycoprotein-2 (MAGP-2) promotes angiogenic cell sprouting by blocking notch signaling in endothelial cells. Microvasc Res 76:7-14
Neil, Jason R; Johnson, Kyle M; Nemenoff, Raphael A et al. (2008) Cox-2 inactivates Smad signaling and enhances EMT stimulated by TGF-beta through a PGE2-dependent mechanisms. Carcinogenesis 29:2227-35
Lee, Yong-Hun; Albig, Allan R; Regner, MaryAnn et al. (2008) Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and enhances EMT induced by TGF-beta in mammary epithelial cells via a MMP-dependent mechanism. Carcinogenesis 29:2243-51
Neil, Jason R; Schiemann, William P (2008) Altered TAB1:I kappaB kinase interaction promotes transforming growth factor beta-mediated nuclear factor-kappaB activation during breast cancer progression. Cancer Res 68:1462-70
Galliher-Beckley, Amy J; Schiemann, William P (2008) Grb2 binding to Tyr284 in TbetaR-II is essential for mammary tumor growth and metastasis stimulated by TGF-beta. Carcinogenesis 29:244-51
Albig, Allan R; Roy, Thessa G; Becenti, Darryl J et al. (2007) Transcriptome analysis of endothelial cell gene expression induced by growth on matrigel matrices: identification and characterization of MAGP-2 and lumican as novel regulators of angiogenesis. Angiogenesis 10:197-216
Schiemann, William P (2007) Targeted TGF-beta chemotherapies: friend or foe in treating human malignancies? Expert Rev Anticancer Ther 7:609-11
Galliher, Amy J; Schiemann, William P (2007) Src phosphorylates Tyr284 in TGF-beta type II receptor and regulates TGF-beta stimulation of p38 MAPK during breast cancer cell proliferation and invasion. Cancer Res 67:3752-8
Galliher, Amy J; Neil, Jason R; Schiemann, William P (2006) Role of transforming growth factor-beta in cancer progression. Future Oncol 2:743-63
Albig, Allan R; Neil, Jason R; Schiemann, William P (2006) Fibulins 3 and 5 antagonize tumor angiogenesis in vivo. Cancer Res 66:2621-9

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