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Pancreatic Cancer Stem Cell Resistance

Pancreatic Cancer Stem Cells are Resistant to Ionizing Radiation and the Chemotherapeutic Agent Gemcitabine

Background: Even though major advancements have been made in the management of many cancers, the prognosis for pancreatic cancer still remains dismal. A key characteristic of pancreatic cancer that makes this disease so lethal is its resistance to ionizing radiation and chemotherapy. Recent studies have suggested that tumor initiating "cancer stem cells" in breast and brain cancers may be responsible for conferring the property of chemo- and radio-resistance in solid tumors. We have recently identified human pancreatic cancer stem cells that express the cell surface markers CD44+CD24+ESA+ (0.2-0.8% of all pancreatic cancer cells). We hypothesize that pancreatic cancer stem cells are resistant to standard therapies used to treat this disease.

Method: Three samples of human pancreatic adenocarcinoma obtained following surgical resection were established as xenografts in immunocompromised NOD-SCID mice. All xenograft experiments were performed in triplicate. Xenografts approximately 1 cm2 in diameter were irradiated either with a single dose of 8 Gy or four fractionated doses of 2.5 Gy for a total of 10Gy. In separate experiments, mice bearing primary pancreatic cancer xenografts were treated with a 125mg/kg bi-weekly dose of gemcitabine for 4 weeks. The population of CD24+CD44+ESA+ cells in treated and control tumors was assessed by immunofluorescent staining and flow cytometry. TUNEL assays were performed on tissue sections of xenografts following ionizing radiation or chemotherapy treatment to assess the extent of apoptosis. Tumorigenicity of treated and control sorted cells was assessed following in vivo implantation. Results: The CD24+CD44+ESA+ subpopulation of pancreatic tumor cells increased 5.8 + 1.7 fold (p<0.05) following a single radiation dose of 8 Gy on pancreatic adenocarcinoma xenografts (n = 3 separate experiments). Administration of a more clinically relevant fractionated radiation dose of 2.5 Gy x 4 increased the cancer stem cell population 4.25 +1.3 fold (p < 0.05, n = 3). Irradiation did not induce CD24 or CD44 expression in marker negative tumor cells. The greatest percentage increase in CD24+CD44+ESA+ cells occurred 48 hours to 1 week following irradiation, the same time points where the highest rates of apoptosis occurred. CD24+CD44+ESA+ cell populations returned to basal levels (0.2-1% of tumor cells) by 3 weeks following treatment, suggesting that this enhanced cancer stem cell population may undergo differentiation. Of functional relevance, single cell suspensions of cancer cells from irradiated tumors showed enhanced tumorigenicity when implanted into NOD-SCID mice compared to non-irradiated cells, suggesting that the enriched cancer stem cell population following irradiation may enhance tumorigenicity. Similar results were obtained in animals treated with gemcitabine.

Conclustion: These data suggest that human pancreatic cancer stem cells are resistant to irradiation and chemotherapy. These findings have significant implications for treatment strategies of pancreatic cancer.

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