Abstract
Abstract In recent years, cancer-initiating cells or cancer stem cells have been demonstrated in a variety of solid tumors including pancreatic cancer. This subpopulation of cancer cells has the ability to initiate and perpetuate tumor growth, and may be highly resistant to radiation or chemotherapy. Therefore, this subpopulation could be a very important and novel target for cancer therapy. Persistent activation of STAT3 is detected in many types of cancer including in pancreatic cancer. However, whether STAT3 is activated in pancreatic cancer-initiating cells and what role STAT3 signaling may play in them is still unknown. It has been reported that pancreatic cancer stem cells can be identified and isolated with several cancer stem cell markers, such as ALDH1, CD44, and CD24. Therefore, we examined STAT3 phosphorylation and ALDH1, CD44, CD24 expression in 30 cases of human pancreatic cancer tissues using tissue microarray slides. We observed there is a significant association between the nuclear staining of STAT3 phosphorylation and ALDH1 (p<0.01). In addition, the tumor samples express elevated levels of phosphorylated STAT3 also associated with CD44+ and CD24+ (p<0.01). These results indicate constitutive STAT3 signaling may be a novel therapeutic target in pancreatic cancer initiating cells. We next separated pancreatic cancer-initiating cells from human pancreatic cancer cell lines using ALDH1, CD44, and CD24 markers by flow cytometry. We found ALDH+ or CD44+/CD24+ pancreatic cells had more potent tumorspheres formation ability than ALDH− or CD44−/CD24− cells. Interestingly, we observed the ALDH+ and CD44+/CD24+ subpopulation of pancreatic cancer cells expressed higher levels of phosphorylated STAT3, compared to ALDH− or CD44−/CD24− subpopulation of pancreatic cancer cells. These results are consistent to the data using pancreatic cancer tissues from cancer patients suggesting that STAT3 is activated in pancreatic cancer-initiating cells. Furthermore, we demonstrated that three small molecular STAT3 inhibitors, LLL12, FLLL32, and Stattic inhibited STAT3 phosphorylation, cell viability, tumorsphere growth and induced apoptosis in pancreatic cancer-initiating cells. The inhibitory efficacy of the novel STAT3 inhibitor on pancreatic cancer-initiating cells in mouse tumor model will be examined. In conclusion, this is the first report to demonstrate that persistent STAT3 phosphorylation is expressed in pancreatic cancer-initiating cells. Our study is also the first attempt to target STAT3 in pancreatic cancer-initiating cells and we demonstrated for the first time that pancreatic cancer stem cells are indeed sensitive to the inhibition by three small molecular STAT3 inhibitors. Our results suggest STAT3 is a novel therapeutic target in pancreatic cancer-initiating cells and inhibition of activated STAT3 in cancer-initiating cells may offer an effective therapy approach for pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2444. doi:10.1158/1538-7445.AM2011-2444
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