Key advancements have been made in understanding the complexity of reactive stroma microenvironments in prostate cancer during the previous progress period. Our studies show that TGF-?1 is overexpressed in prostate cancer epithelial cells and that a reactive stroma composed of myofibroblasts/carcinoma-associated fibroblasts co-evolve with cancer foci. We have shown that a reactive stroma grade 3 is predictive of prostate cancer progression. Moreover, xenograft models with engineered stroma recombined with carcinoma cells shows this stroma is tumor-promoting and TGF-?1 is a key regulator of this process. The target progenitor cells of tumor-promoting reactive stroma, the process of their recruitment, and the downstream genes that transduce the tumor-promoting biology of this reactive stroma are not understood. To address this biology, we have constructed transgenic mouse lines with TGF-?1 expression targeted to prostate epithelium. These mice exhibit focal stromal proliferative responses. The proposed studies are a direct extension of work in the previous period. We hypothesize that overexpression of TGF-?1 in premalignant prostate cancer induces a co-evolution of a spatially associated reactive stroma that may be recruited from either local or circulating, marrow-derived progenitor cells. To address this hypothesis in detail we propose 3 Specific Aims: 1). To assess the spatial and temporal correlation between overexpression of TGF-beta and reactive stroma grades in human prostate cancer. 2). To determine the role of TGF-beta in the co-evolution of reactive stroma in prostate cancer. 3). To determine the role of TGF-beta and reactive stroma in regulating prostate cancer progression. We propose the use of novel transgenic models with recombined xenograft and in vitro approaches to address these aims. Dissecting these processes and key pathways is important for long-range studies that will focus on directed therapeutics that target the reactive stroma compartment in human prostate cancer.
This project will provide pre-clinical data to help determine the recruitment and tumor-regulatory biology of the cancer stromal microenvironment. Data gained will help identify whether targeting TGF-?1 induced biology can be used as a strategic approach for the treatment of prostate cancer via its microenvironment.
|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|
|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|
|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|
|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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