Cellular Mechanisms of Cancer Stem Cells

The concept of cancer stem cells is based on the presence of adult stem cells within tissues that can transform and give rise to tumors that also retain stem-like properties. Although advanced solid human tumors are treated with chemotherapy and/or radiotherapy, in most cases there are only partial responses and tumors generally recur. These observations suggest that here is a resilient 'rare' cancer cell type that survives therapy, which gives precedence to the following cancer stem cell hypothesis. Hypothesis: Cancer cells retain stem-like characteristics that may reflect their degree of malignancy and resistance to conventional therapy. The experiments presented in this thesis report focus on identification of cancer stem cells by exploiting conserved cellular mechanisms of normal stem cells such as; label retention (LRC) and transit amplification (TAC). Panc-1 human pancreatic cancer cells pulsed with BrdU gave rise to tumors that contain a 'rare' quiescent population of cells retaining their BrdU label up to one month in vivo. Transit amplification of these cells was explored in vitro by using a stem cell marker, the 'side population' SP), that gave rise to two distinct cell populations after one week in culture. Isolated Panc-1 clones with varying degrees of the SP phenotype and metastatic potential demonstrated that loss of SP coincides with increased metastasis. Treatment of these clones with the chemotherapeutic drug gemcitabine showed that the presence of SP and decreased metastatic potential conferred resistance. Combined treatment of a telomerase inhibitor (GRN163L) and gemcitabine sensitized cancer stem cells in vitro. These findings suggest that cancer stem cells may retain stem-like characteristics such as label retention, symmetric and asymmetric divisions, and drug sensitivity to govern tumor progression and resistance. These finding may in the future allow the dissection of underlying molecular mechanisms regulating cancer stem cells and provide opportunities to discover therapies that specifically target these cancer stem cells.