Prostate cancer is a disease typified by a reactive stroma response, which is likely tumor promoting. The reactive stroma is composed of myofibroblasts and fibroblasts, activated to remodel extracellular matrix and induce angiogenesis. This response is similar to generic wound repair responses. In the previous project period, we have defined reactive stroma in human prostate cancer progression and have developed new models to address mechanisms of reactive stroma biology. These studies have shown the induction of reactive stroma during prostatic intraepithelial neoplasia (PIN) and evolution with cancer progression. Elevated expression of TGF-beta1 by PIN epithelium was correlated with induction of adjacent reactive stroma. To address reactive stroma mechanisms, we developed the differential reactive stroma (DRS) model. The DRS model permits transgene gene expression in both the stromal and epithelial compartments of a human xenograft tumor in host mice. Our recent studies show that tumor incidence, angiogenesis, and tumor growth are dependent on reactive stroma. Different human prostate stromal cell lines produced differential tumorigenesis. Differential expression of connective tissue growth factor (CTGF) in stromal cells was associated with tumorigenesis. CTGF is a downstream mediator of TGF-beta1 action in stroma and a stimulator of angiogenesis. Inhibition of TGF-beta1 action in DRS tumors inhibited angiogenesis and tumor growth. Furthermore, FGF-2 action regulates reactive stroma, particularly in a TGF-beta1 microenvironment. It is our hypothesis that TGF-beta31 induced reactive stroma is a critical regulator of angiogenesis in early prostate cancer, and that both CTGF and FGF-2 are key co-regulatory factors of TFG-beta1 paracrine actions in reactive stroma. We propose three Specific Aims to address this hypothesis in detail: 1.) To test the hypothesis that the paracrine action of epithelial expressed TGF-beta1 is a key inducer of prostate reactive stroma and that TGF-beta1 induced reactive stroma drives angiogenesis and tumor progression; 2.) To test the hypothesis that FGF-2 functions as a co-regulator with TGF-beta1 in reactive stroma induced angiogenesis and tumor progression; 3.) To test the hypothesis that CTGF functions as a key downstream mediator of TGF-beta1 and FGF-2 action in reactive stroma. These studies will dissect the paracrine and autocrine actions of these growth factors in reactive stroma regulation of prostate cancer using novel transgenic and DRS model approaches. The proposed studies will expand our understanding of the role of interdependent epithelial-stromal signaling in prostate cancer and may lead to new therapeutic approaches targeted to specific mechanisms in the reactive stroma compartment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA058093-11
Application #
6733062
Study Section
Pathology B Study Section (PTHB)
Program Officer
Yang, Shen K
Project Start
1992-09-30
Project End
2009-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
11
Fiscal Year
2004
Total Cost
$270,900
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
San Martin, Rebeca; Pathak, Ravi; Jain, Antrix et al. (2017) Tenascin-C and Integrin ?9 Mediate Interactions of Prostate Cancer with the Bone Microenvironment. Cancer Res 77:5977-5988
San Martin, Rebeca; Barron, David A; Tuxhorn, Jennifer A et al. (2014) Recruitment of CD34(+) fibroblasts in tumor-associated reactive stroma: the reactive microvasculature hypothesis. Am J Pathol 184:1860-70
Carstens, Julienne L; Shahi, Payam; Van Tsang, Susan et al. (2014) FGFR1-WNT-TGF-? signaling in prostate cancer mouse models recapitulates human reactive stroma. Cancer Res 74:609-20
Yang, Feng; Chen, Yizhen; Shen, Tao et al. (2014) Stromal TGF-? signaling induces AR activation in prostate cancer. Oncotarget 5:10854-69
Kim, Woosook; Barron, David A; San Martin, Rebeca et al. (2014) RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation. Proc Natl Acad Sci U S A 111:16389-94
Ressler, Steven J; Dang, Truong D; Wu, Samuel M et al. (2014) WFDC1 is a key modulator of inflammatory and wound repair responses. Am J Pathol 184:2951-64
Yang, Feng; Zhang, Yongyou; Ressler, Steven J et al. (2013) FGFR1 is essential for prostate cancer progression and metastasis. Cancer Res 73:3716-24
Rogers, Erin; Wang, Ben X; Cui, Zhu et al. (2012) WFDC1/ps20: a host factor that influences the neutrophil response to murine hepatitis virus (MHV) 1 infection. Antiviral Res 96:158-68
Barron, David A; Rowley, David R (2012) The reactive stroma microenvironment and prostate cancer progression. Endocr Relat Cancer 19:R187-204
Ayala, Gustavo E; Muezzinoglu, Bahar; Hammerich, Kai H et al. (2011) Determining prostate cancer-specific death through quantification of stromogenic carcinoma area in prostatectomy specimens. Am J Pathol 178:79-87

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