Chronic Cadmium Exposure <i>in Vitro</i> Causes Acquisition of Multiple Tumor Cell Characteristics in Human Pancreatic Epithelial Cells

Abstract

BACKGROUND: Cancer may be a stem cell (SC)-based disease involving formation of cancer SCs (CSCs) potentially arising from transformation of normal SCs. Cadmium has been linked to human pancreatic cancer. OBJECTIVE: We studied cadmium exposure of human pancreatic ductal epithelial (HPDE) cells and whether SCs may be targeted in this process. METHODS: We chronically exposed HPDE cells to low level cadmium (1 μM) for ≤ 29 weeks. Nonadherent spheroid formation was used to indicate CSC-like cell production, and we assessed tumor cell characteristics in such spheres. Assessed tumor cell characteristics including secretion of matrix metalloproteinase-9 (MMP-9), invasion, and colony formation were fortified by evaluating expression of relevant genes by real-time reverse transcription polymerase chain reaction and by Western blot. RESULTS: Increased MMP-9 secretion and overexpression of the pancreatic cancer marker S100P occurred in chronic (29 weeks of exposure) cadmium-exposed (CCE) cells. CCE cells also showed markedly higher colony formation and invasion, typical of cancer cells. Floating "spheres" of viable cells, known to contain an abundance of normal SCs or CSCs, form in vitro with many cell types. CCE cells produced 3-fold more spheres than control cells and were more invasive, secreted more MMP-9, and overexpressed markers for pancreatic SCs/CSCs (i.e., CXCR4, OCT4, CD44) and S100P, a marker for pancreatic cancer. CCE-derived spheres rapidly produced aggressive, highly branched, and poorly differentiated glandular-like structures in Matrigel. CONCLUSIONS: Chronic cadmium exposure produced multiple tumor cell characteristics in HPDE cells and CCE cell-derived spheres. These data support the plausibility of cadmium as a human pancreatic carcinogen.