The long term objective of these studies has been to use transgenic mice to test the hypothesis that keratinocyte growth factor (KGF; FGF-7) and members of the fibroblast growth factor receptor (FGFR) family regulate the growth and metastasis of prostatic cancer in vivo. The rational for these studies was based on the implication that KGF acts as an andromedin to influence prostate epithelial development, growth, and differentiation. Now, based on transgenic and cell line data obtained during the initial period of this project, it is clear that epithelial KGF expression disrupts epithelial-mesenchymal signaling and causes a hyperplastic prostatic epithelium and is probably an early event during the initiation and progression of prostate cancer. Furthermore, based on data from transgenic mice expressing the rat probasin (rPB)-directed dominant-negative form of FGFR2iiib receptor, it is clear that abrogation of KGF signaling in the prostate leads to poorly differentiated and disorganized epithelium and stroma. In fact, abrogated KGF signaling was associated with apoptotic epithelial cell death and impaired smooth muscle differentiation in the prostate. The proposed studies exploit the investigators' autochthonous TRAMP model, derivative TRAMP-C cell lines and the novel rPB-KGF(PKS) and rPB-dnmFGFR2iiib(KDNR) transgenic mice to determine 1) whether epithelial expression of KGF facilitates the progression of prostate cancer to a state that is ultimately metastatic and independent of stroma and androgens; 2) whether ablation of andromedin signals inhibit the initiation, progression and metastasis of prostate cancer; and 3) whether novel FGFR splice forms identified in the TRAMP model influence the proliferation and malignant transformation of prostate epithelial cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA064851-06
Application #
2895174
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Mohla, Suresh
Project Start
1994-08-15
Project End
2003-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Huss, Wendy J; Gray, Danny R; Tavakoli, Keyvan et al. (2007) Origin of androgen-insensitive poorly differentiated tumors in the transgenic adenocarcinoma of mouse prostate model. Neoplasia 9:938-50
Winter, S F; Acevedo, V D; Gangula, R D et al. (2007) Conditional activation of FGFR1 in the prostate epithelium induces angiogenesis with concomitant differential regulation of Ang-1 and Ang-2. Oncogene 26:4897-907
Huss, Wendy J; Gray, Danny R; Greenberg, Norman M et al. (2005) Breast cancer resistance protein-mediated efflux of androgen in putative benign and malignant prostate stem cells. Cancer Res 65:6640-50
Huss, Wendy J; Lai, Lihua; Barrios, Roberto J et al. (2004) Retinoic acid slows progression and promotes apoptosis of spontaneous prostate cancer. Prostate 61:142-52
Jin, Chengliu; McKeehan, Kerstin; Guo, Wei et al. (2003) Cooperation between ectopic FGFR1 and depression of FGFR2 in induction of prostatic intraepithelial neoplasia in the mouse prostate. Cancer Res 63:8784-90
Hernandez, Inmaculada; Maddison, Lisette A; Wei, Yongli et al. (2003) Prostate-specific expression of p53(R172L) differentially regulates p21, Bax, and mdm2 to inhibit prostate cancer progression and prolong survival. Mol Cancer Res 1:1036-47
Huss, Wendy J; Barrios, Roberto J; Greenberg, Norman M (2003) SU5416 selectively impairs angiogenesis to induce prostate cancer-specific apoptosis. Mol Cancer Ther 2:611-6
Huss, Wendy J; Barrios, Roberto J; Foster, Barbara A et al. (2003) Differential expression of specific FGF ligand and receptor isoforms during angiogenesis associated with prostate cancer progression. Prostate 54:8-16
Kazansky, Alexander V; Spencer, David M; Greenberg, Norman M (2003) Activation of signal transducer and activator of transcription 5 is required for progression of autochthonous prostate cancer: evidence from the transgenic adenocarcinoma of the mouse prostate system. Cancer Res 63:8757-62
Uzgare, Aarti R; Kaplan, Paula J; Greenberg, Norman M (2003) Differential expression and/or activation of P38MAPK, erk1/2, and jnk during the initiation and progression of prostate cancer. Prostate 55:128-39

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