The pleiotropic fibroblast growth factors (FGF) control a broad spectrum of cellular processes, including prostate development, function, and homeostasis, by activating the four highly homologous FGF receptor (FGFR) transmembrane tyrosine kinases. Aberrant expression and activation of the FGF signaling axis are often found associated with prostatic tumor development and progression. FRS2? is an adaptor protein linking the FGFR kinases to downstream signaling targets, which is differentially phosphorylated by the FGFR1 and FGFR2 kinases in prostate epithelial cells. FRS2? is dynamically expressed in developing prostates, which is associated with prostatic branching morphogenesis, androgen-induced regeneration, and tumorigenesis. The project is to test the hypothesis that FGFR isoform-specific activation of FRS2?-mediated signals play important roles in regulating proliferation and differentiation of precursor cells for prostatic epithelial cells during development and regeneration, and aberrant activation of FRS2?-mediated signaling contributes to prostatic tumorigenesis, which was formulated based on our recent findings. Efforts will be focused on using genetically engineered mouse as well as molecular biological, cell biological, and biochemical technologies to understand how aberrant cell signaling contributes to prostate tumor initiation and progression.
The specific aims are to characterize the structural domain of FRS2? that are important for mediating FGFR signals;to characterize the role of FRS2 in prostatic development and tissue homeostasis;and to investigate how aberrant signals mediated by FRS2? contribute to prostatic tumorigenesis and tumor progression. The objective is to understand how FGFR elicits receptor specific signals at the substrate level and the roles of FRS2?-mediated signals in prostatic development, tissue homeostasis, and tumorigenesis. Understanding the role of FGFR signals in prostatic development and tumorigenesis will shed new light on designing new strategies for prevention and interception of prostate cancer initiation and progression in the future. Animal models developed in the project will provide a useful tool not only for further studying FGFR signals in prostate cancer initiation and progression, but also for assessing the role of nutrition and active dietary components on prevention, intervention, and interruption on prostate tumor progression.

Public Health Relevance

Prostate cancer is the most diagnostic cancer and the second leading cause of cancer death in American males. Like normal prostates, prostate cancer at early stages is androgen dependent. Yet, at late stages, prostate cancer frequently progresses to androgen independent and becomes malignant. Aberrant cell signaling, including signals mediated by FRS2?, often found accompanying the progression to malignancy, which confers autonomous growth and invasion capability to tumor cells. This project is to use genetically engineered mouse models and in vitro biochemical and molecular biological methods to study the roles of FRS2?-mediated signals in prostate development and tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096824-08
Application #
8015334
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Ault, Grace S
Project Start
2002-07-01
Project End
2012-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
8
Fiscal Year
2011
Total Cost
$247,036
Indirect Cost
Name
Texas A&M University
Department
Biology
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
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Wang, Cong; Ke, Yuepeng; Liu, Shaoyou et al. (2018) Ectopic fibroblast growth factor receptor 1 promotes inflammation by promoting nuclear factor-?B signaling in prostate cancer cells. J Biol Chem 293:14839-14849
Li, Xiaokun; Wang, Cong; Xiao, Jian et al. (2016) Fibroblast growth factors, old kids on the new block. Semin Cell Dev Biol 53:155-67
Liu, J; You, P; Chen, G et al. (2016) Hyperactivated FRS2?-mediated signaling in prostate cancer cells promotes tumor angiogenesis and predicts poor clinical outcome of patients. Oncogene 35:1750-9
Huang, Yanqing; Hamana, Tomoaki; Liu, Junchen et al. (2015) Prostate Sphere-forming Stem Cells Are Derived from the P63-expressing Basal Compartment. J Biol Chem 290:17745-52
Huang, Yanqing; Jin, Chengliu; Hamana, Tomoaki et al. (2015) Overexpression of FGF9 in prostate epithelial cells augments reactive stroma formation and promotes prostate cancer progression. Int J Biol Sci 11:948-60
Huang, Yanqing; Hamana, Tomoaki; Liu, Junchen et al. (2015) Type 2 Fibroblast Growth Factor Receptor Signaling Preserves Stemness and Prevents Differentiation of Prostate Stem Cells from the Basal Compartment. J Biol Chem 290:17753-61
Fang, Zanxi; Tang, Jing; Bai, Yongying et al. (2015) Plasma levels of microRNA-24, microRNA-320a, and microRNA-423-5p are potential biomarkers for colorectal carcinoma. J Exp Clin Cancer Res 34:86
Wan, Xinhai; Corn, Paul G; Yang, Jun et al. (2014) Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases. Sci Transl Med 6:252ra122
Wang, Cong; Yang, Chaofeng; Chang, Julia Yf et al. (2014) Hepatocyte FRS2? is essential for the endocrine fibroblast growth factor to limit the amplitude of bile acid production induced by prandial activity. Curr Mol Med 14:703-711

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