Department of Urology
Dr. Andrea Morrione
Dr. Karen Knudsen
Dr. Marja Nevalainen
The main focus of our laboratory is the characterization of the role of growth factors and growth factor receptor signaling in transformation of bladder cancer cells. The growth factor proepithelin has emerged in recent years as an important regulator of transformation of several cellular systems. Proepithelin is over-expressed in a great variety of cancer cell lines and tumor samples including those derived from breast, ovary, kidney and brain. Recent results from our laboratory have established an important role of proepithelin in bladder cancer.
Studies & Results
Proepithelin as a target for therapy. Bladder cancer cells (T24 and 5637 urothelial carcinoma-derived cells) produce and secrete considerable amount of the growth factor proepithelin, which may contribute as autocrine growth factor in promoting transformation of bladder cancer cells. Targeted depletion of proepithelin severely reduce the ability of T24 bladder cancer cells to growth in the absence of serum, to migrate and invade suggesting that proepithelin may play a critical role in these biological processes which are hallmark of cell transformation (Lovat et al. 2009). Because proepithelin plays a critical role in promoting migration and invasion of bladder cancer cells and it is secreted by cancer cells, we believe that proepithelin may serve as a biomarker to identify bladder cancer that are likely to progress to a metastatic phenotype.
Characterize the mechanism(s) that regulates proepithelin signaling in bladder cells. Using 5637 and T24 urothelial carcinoma-derived cells as a model system for bladder cancer cells, we have established that proepithelin promotes migration, wound healing and invasion through a three-dimensional extracellular matrix (Matrigel) (Monami et al. 2006). These results suggest that proepithelin may promote the transition to the invasive phenotype in bladder cancer. We have also recently established that proepithelin plays a relevant role in promoting transformation of prostate cancer cells. Using PC3, LNCaP and DU145 prostate cancer cells we determined that proepithelin promotes migration and invasion of prostate cancer cells. We have also demonstrated that endogenous proepithelin acted in autocrine fashion and contributed to the ability of DU145 cells to grow in serum-deprived condition and form colonies in anchorage-independency. The reduction of proepithelin levels in DU145 cells inhibited cell proliferation in condition of serum deprivation and inhibited the capacity of DU145 cells to form colonies in soft-agar (Monami et al. 2009).
IGF-IR function in bladder cancer. We recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues compared to non-malignant controls. We have investigated the role of the IGF-IR in bladder cancer using urothelial carcinoma-derived 5637 and T24 cells. Although activation of the IGF-IR did not appreciably affect their growth, it did promote migration and stimulate in vitro wound closure and invasion. Our results provide the first evidence for a role of the IGF-IR in motility and invasion of bladder cancer cells, and support the hypothesis that the IGF-IR may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia. The IGF-IR may also serve as a novel biomarker for bladder cancer.
For additional information, please visit Dr. Morrione's Faculty Interest Page.
Dr. Knudsen’s research endeavors focus on the mechanisms by which androgen governs prostate cancer growth, pathways that deregulate this process in disease progression, and the influence of both environmental and genetic factors on therapeutic response. Dr. Knudsen currently heads the Thomas Jefferson University/Kimmel Cancer Center Prostate Cancer Working Group, striving to facilitate communication and collaborative research among the many talented basic, translational, and clinical researchers at TJU. This Group is also dedicated to increase awareness about the breadth of prostate cancer research at the institution. She is collaborating with Drs. Morrione, Trabulsi, and Gomella on a variety of translational research initiatives.
For more information on Dr. Knudsen, click here.
Dr. Nevalainen's research program focuses on identifying protein kinase signaling pathways that mediate castration-resistant and metastatic growth of prostate cancer cells, with special focus on Stat transcription factors. Recent work from Dr. Nevalainen's laboratory has validated transcription factor Stat5 as a molecular target for therapy development for prostate cancer. Moreover, recent results show that activation of Stat5 in primary prostate cancer predicts early disease recurrence. The current focus of Dr. Nevalainen's research program is on identification of the molecular mechanisms on how Stat5 contributes to castration-resistant growth of prostate cancer and determining the individual roles of Stat5a vs.Stat5b in metastatic dissemination of prostate cancer.
For more information on Dr. Nevalainen, click here.