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Recent studies in breast, brain, and lung tumors suggest that a small fraction of tumor cells actually display stem cell features. However, the biological properties with respect to tumor progression and in particular metastasis still remain enigmatic to date. Therefore, the purpose of the present study was to identify cancer stem cells (CSC) in pancreatic cancer and define their role in tumor metastasis.

Methods and Results: Human pancreatic cancer tissue contained a variable, but distinct CD133+ CSC population ranging from 1 to 3% of the total cell count. Cultured non-metastatic human FG pancreatic cancer cells contained only very few CD133 positive cells (0.02%) whereas highly-metastatic human L3.6pl pancreatic cancer cells were characterized by a relatively large pool of CD133+ stem cells ranging from 1 to 2%. The migratory capacity of isolated L3.6pl CSC was significantly higher (+242%) as compared to CD133- tumor cells (P<0.01) and primarily mediated by the CXCR4 receptor. A significantly lower migratory activity was observed for cancer cells isolated from FG tumors with no difference between CD133+ and CD133- cells. After orthotopic implantation in athymic mice, FG tumors contained a very small population of CD133+ cells (0.2 to 0.4%; n=8) whereas L3.6pl tumors included a robust CD133 pos CSC population representing about 2% of the tumor cell population (n=10). Intriguingly, as few as 103 CD133+ CSC isolated from L3.6pl tumors were capable of inducing new tumors (5/8 animals) with 80% metastatic lesions whereas no tumor developed in mice receiving up to 106 CD133- tumor cells (0/8 animals). Similar findings were observed in secondary transplants. Although the anti-metabolite gemcitabine was capable of inducing apoptosis of CD133- tumor cells, it completely failed to induce apoptosis in CD133+ CSC. Long-term in vitro as well as in vivo treatment generated a tumor cell population that was markedly enriched for tumor stem cells that formed colony-like structures under appropriate culture conditions.

Conclusions: Here we demonstrate that human pancreatic cancers contain a low, but persistent percentage of CD133+ cells with stem cell characteristics. Intriguingly, the highly-invasive human L3.6pl pancreatic cancer cells contained a distinct cancer stem cell population with high invasive activity whereas the non-metastatic FG pancreatic cancer cells contained a much smaller and most importantly less invasive stem cell population. These data may at least in part explain the different biological properties of these two cell types. Cancer stem cells are highly resistant to standard treatment which resulted in small tumors highly enriched for cancer stem cells. Thus, cancer stem cells represent a challenging novel target for the development of advanced molecular and pharmaceutical therapeutics.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA