Role of Arsenic and cadmium in the development of bladder cancer:
My Lab is intrested in studying the role of arsenic and cadmium in the development of bladder cancer. Previously it was unknown if either cadmium (Cd+2) or arsenite (As+3) could directly cause the malignant transformation of human urothelial cells. In my lab, we have been able to directly transform the non-tumorigenic urothelial cell line UROtsa, by exposing them long term in vitro to Cd+2 and As+3. The histology of the tumor heterotransplants produced by UROtsa cells malignantly transformed by Cd+2 and As+3 had epithelial features consistent with those of a classic transitional-cell carcinoma (TCC) of the bladder. However, a unique feature of these tumors were the presence of areas that showed prominent squamous differentiation. Of particular interest was the expression of the protein, keratin 6 which was restricted to the areas of the tumors that displayed some squamous features. In fact, keratin 6 immunoreactivity allowed one to focus on, and more easily identify, areas in the tumors having features of squamous differentiation. This suggests that keratin 6 could not only be a potential biomarker for metal exposure but it could also identify areas in a tumor that may eventually display prominent squamous diffentiation. In the United States and Europe, TCC’s that contain a prominent squamous component are rare; however, there is some evidence that the presence of a squamous component within transitional cell carcinomas may indicate a poor prognosis for the patient. Furthermore, we have recently shown that the expression of keratin 6 is regulated by the activation of the ERK1/2 pathway.