David R. Rowley, Ph.D.
Department of Molecular and Cellular Biology
Ph.D.: University of Iowa, Iowa City
Postdoctoral training: Baylor College of Medicine, Houston
Reactive Stroma in Cancer Progression
Reactive stroma is associated with each of the major human carcinomas. Our laboratory is interested in mechanisms of stromal cell recruitment, in the reciprocal signaling mechanisms between tumor cells and adjacent reactive stroma cells and how these mechanisms regulate cancer progression. These studies are focused on the role of the tumor microenvironment in both the development of early cancer foci and cancer progression to malignancy. Our studies have shown that reactive stroma initiates early during carcinoma formation and that co-evolution of reactive stroma is predictive of the rate of cancer progression in human prostate cancer. Little is know about specific mechanisms.
We have developed several mouse model systems to address mechanisms. A nude mouse xenograft system is used to co-inoculate human prostate carcinoma cells with prostate stromal cells. Both cell types are differentially engineered for overexpression and /or attenuated expression of select genes using a number of strategic approaches. We have also developed a transgenic mouse that overexpresses interleukin-8 (IL-8) in prostate epithelium. This mouse develops a hyperplastic phenotype with an associated reactive stroma. We are also in the process of evaluating a transgenic mouse made to overexpress transforming growth factor beta1 (TGF-β1). In addition, we have developed a mice that have a conditional knockout of FGF receptor 1 in prostate epithelium and a mice with a knockout of the WFDC1 / ps20 gene. Through these models and with in vitro approaches we have shown that the TGF- β1 and FGF signaling axis is critically important for the development and tumor-promoting function of the reactive stroma microenvironment. These studies have also shown that connective tissue growth factor (CTGF) and IL-8 are also involved in regulating reactive stroma biology.
Currently, the laboratory is addressing mechanisms involved in the recruitment of reactive stroma progenitor cells from the local tissue and circulating pool of mesenchymal stem / progenitor population in order to better define the specific genesis and co-evolution of the reactive stroma microenvironment in cancer.
Baylor College of Medicine
One Baylor Plaza, Jewish 325D
Houston, TX 77030
- Ayala GE, Muezzinoglu B, Hammerich KH, Frolov A, Liu H, Scardino PT, Li R, Sayeeduddin M, Ittmann MM, Kadmon D, Miles BJ, Wheeler TM, and Rowley DR. (2011). Determining prostate cancer specific death through quantitation of stromogenic carcinoma area in prostatectomy specimens. Am. J. Pathology. 178: 79-87
- Barron D, Strand D, Ressler SJ, Dang TD, Hayward S, Yang F, Ayala G, Ittmann M and Rowley DR. (2010). TGF-β1 Induces an Age-Dependent Inflammation of Nerve Ganglia and Fibroplasia in the Prostate Gland Stroma of a Novel Transgenic Mouse. PLoS ONE 5(10): e13751.
- Yang F, Strand DW and Rowley DR. (2007). Fibroblast Growth Factor-2 Mediates Transforming Growth Factor-β Action in Prostate Cancer Reactive Stroma. Oncogene 27: 450-459.
- Yang F, Tuxhorn JA, Ressler SJ, McAlhany SJ, Dang TD and Rowley DR. (2005). Stromal expression of connective tissue growth factor promotes angiogenesis and prostate cancer tumorigenesis. Cancer Research 65:8887-8895.
- McAlhany SJ, Ressler SJ, Larsen M, Tuxhorn JA, Yang F, Dang TD and Rowley DR. (2003). Promotion of angiogenesis by ps20 in the differential reactive stroma prostate cancer xenograft model. Cancer Research 63:5859-5865.
- Tuxhorn JA, McAlhany SJ, Yang F, Dang TD and Rowley DR. (2002). Inhibition of transforming growth factor-beta activity decreases angiogenesis in a human prostate cancer-reactive stroma xenograft model. Cancer Research 62:6021-6025.
- Tuxhorn JA, McAlhany SJ, Dang TD, Ayala GE and Rowley DR. (2002). Stromal cells promote angiogenesis and growth of human prostate tumors in a differential reactive stroma (DRS) xenograft model. Cancer Research 62:3298-3307.
- Tuxhorn JA, Ayala GE, Smith MJ, Smith VC, Dang TD and Rowley DR. (2002). Reactive stroma in human prostate cancer: Induction of myofibroblast phenotype and extracellular matrix remodeling. Clinical Cancer Research 8:2912-2923.