The long term objectives of this proposal are to elucidate the role of TPF (for Tumor Promoting Factor), a recently identified secretory molecule which is overexpressed in a wide range of human tumors, in the pathological process of tumorigenesis. Although significant progress has been made in recent years in studies of molecular events associated with tumor progression, much more needs to be done to further our understanding of the molecular mechanisms underlying specific pathological processes, such as angiogenesis, tumor migration and metastasis. It is important to identify and investigate the functions of novel factors associated with these processes. In this context, the investigator's preliminary results strongly suggest that TPF possesses the functional and structural characteristics as such a factor, as non-metastatic tumor cells engineered to overexpress the molecule grow aggressively and form dramatically enlarged tumors in an animal model system. Furthermore, TPF appears to have a significant effect on the survival of microvascular endothelial cells under serum-starved condition. To firmly establish a specific role for TPF in the multistep process of carcinogenesis the investigator will focus studies on two Specific Aims.
For Aim 1, he will define the molecular nature of functional mechanism for TPF under both in vitro and in vivo conditions. He will test if TPF acts to affect the functions of microvascular endothelial cells using established systems assaying for angiogenesis. He will also test the effect of TPF overexpression on tumor progression in a recently established model system using human epithelial cells and nude mice.
For Aim 2, he will identify and isolate the receptor or binding target of TPF using several established approaches and lay the ground work for future studies on the mechanism by which TPF potentiates tumor progression and metastasis. Tumorigenesis is a complex multistep process. To significantly advance the knowledge of molecular events underlying tumor progression and metastasis, novel factors involved in this pathological process need to be identified and characterized. Thus, the accomplishment of these proposed studies will provide further understanding of the molecular mechanism by which TPF promotes tumor progression and contribute to the development of novel therapeutics for the treatment of human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA083770-02
Application #
6377556
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mohla, Suresh
Project Start
2000-07-01
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$277,200
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Ali, Ambereen; Zhang, Ji; Bao, Shideng et al. (2004) Requirement of protein phosphatase 5 in DNA-damage-induced ATM activation. Genes Dev 18:249-54
Waddell, David S; Liberati, Nicole T; Guo, Xing et al. (2004) Casein kinase Iepsilon plays a functional role in the transforming growth factor-beta signaling pathway. J Biol Chem 279:29236-46
Shao, Rong; Bao, Shideng; Bai, Xuefang et al. (2004) Acquired expression of periostin by human breast cancers promotes tumor angiogenesis through up-regulation of vascular endothelial growth factor receptor 2 expression. Mol Cell Biol 24:3992-4003
Frederick, Joshua P; Liberati, Nicole T; Waddell, David S et al. (2004) Transforming growth factor beta-mediated transcriptional repression of c-myc is dependent on direct binding of Smad3 to a novel repressive Smad binding element. Mol Cell Biol 24:2546-59
Bao, Shideng; Ouyang, Gaoliang; Bai, Xuefang et al. (2004) Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway. Cancer Cell 5:329-39
Rich, Jeremy N; Shi, Qing; Hjelmeland, Mark et al. (2003) Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model. J Biol Chem 278:15951-7
Rich, J N; Guo, C; McLendon, R E et al. (2001) A genetically tractable model of human glioma formation. Cancer Res 61:3556-60