Mechanism of arsenic-induced malignant transformation in human bladder cancer

Relevance to SWEHSC: 

Arsenic exposure to Southwest populations is widespread, and extends to the global community. Arsenic-associated cancers (including bladder cancer) and degenerative diseases are diverse, but no clear mechanism of action has been established. Bladder cancer is the endpoint used by federal regulators charged with setting drinking water limits for arsenic, pointing to a particular need to understand this disease process.

Cluster of Efforts: 

Investigators/Funding: Gandolfi (RFG1), Futscher (RFG1) NIEHS/ES004940 (Superfund Component Project)

    Jay GandolfiBernard Futscher

  • CarcinogenicsMonomethylarsonous acid (MMA(III)), a human metabolite 20 times more toxic than inorganic arsenic was synthesized by the MMSC (Chemical Synthetic) core of SWEHSC.
  • UROtsa, an immortalized human bladder epithelium cell line, was chronically exposed in vitro to environmentally relevant levels of MMA(III), resulting in malignant transformation, the first reported model of MMA(III) induced malignant transformation (loss of anchorage dependence and growth in nude mice). NIEHS/ES004940
  • Coincident with transformation, increases in COX-2 expression and a decrease in DBC1 ("deleted in bladder cancer" gene), both established biomarkers of bladder cancer in humans. NIEHS/ES004940
  • Epigenetic analysis of UROtsa defined a reproducible signature of epigenetic changes associated with the arsenic-induced malignant transformation. NCI/CA015159