| Summary: | 碩士 === 國立成功大學 === 臨床醫學研究所 === 105 === In 2016, pancreatic cancer has the third highest incidence rate of cancer related fatality in the Unites States, with the 5 year overall survival rate of about 8%, exhibiting the lack of treatment strategies. To increase the chance of cure for locally advanced pancreatic cancer, extended resections such as vascular resections or the removal of spleen should be performed in patients. It has been suggested that preservation of spleen may contribute to increasing mortality rates in pancreatic cancer patients. Therefore, we planned to prove this phenomenon in mice model and sought to know the role of spleen-derived mesenchymal stem cells (spMSCs) in pancreatic cancer progression in this study. A number of inflammatory cytokines, chemokines, growth factors, and other factors in the tumors and their microenvironments can induce MSCs homing. After homing to tumor tissue, normal tissue-derived MSCs (NMSCs) are educated by tumor microenvironment and transform to tumor-derived MSCs (TMSCs). Interestingly, the function of NMSCs and TMSCs is quite different. NMSCs express a pro-inflammatory phenotype that is against tumor growth. On the contrary, TMSCs have an immunosuppressive capability that promotes tumor progression. We used an in vitro co-culture system and several functional assays to examine the characteristics of mouse spleen-derived NMSCs (mspNMSCs) and mouse spleen-derived TMSCs (mspTMSCs) on KrasG12D; Trp53R172H; Pdx1-Cre (KPC) pancreatic cancer cells. We observed that co-culture with mspMSCs (mouse spleen-derived MSCs) or mspTMSCs could enhance the migration and proliferation ability of KPC cells; however, co-culture with mspNMSCs could decrease this effect as compared to mspMSCs. In in vivo experiments, KPC cells were inoculated into the pancreas of C57B/L6 mice to form tumors, and then mspMSCs were intraperitoneally injected into mice to investigate the effect of mspNMSCs and mspTMSCs on pancreatic cancer progression. We found that tumor growth was enhanced by mspTMSCs and, to a lesser extent, mspNMSCs in the orthotopic pancreatic cancer mouse model. Previous studies have shown that NMSC can suppress tumor growth, but this effect was not observed in our results. Therefore, understanding the mechanism of mspMSC─mspTMSC transformation in the tumor progression may benefit in development of novel cancer treatment ideas and therapeutic strategies. Furthermore, tumor-associated fibroblasts (TAFs) have been reportedly shown to play an important role in tumor formation, growth and metastasis. We found that CXCL15 expression in KPC cells is increased after co-culture with mspMSCs. In addition, mspMSCs are observed to express TAF marker through the ERK signaling pathway after co-culture with KPC cells or treatment with CXCL15. Finally, we found that knockdown of CXCR2 in mspMSC could decrease TAF marker expression and repressed the migration and proliferation ability of KPC cells after co-culture. Taken together, these results revealed that KPC cells may secrete CXCL15 to induced mspMSCs transformation towards mspTMSCs which exhibit tumor-promoting ability by activating the ERK pathway. In this study, we have proved that spleen-derived mesenchymal stem cells are capable of promoting progression of pancreatic cancer in the orthotopc mouse model. Therefore, removal of spleen in the operation may benefit patients whose tumor cells grow in the tail of the pancreas or the tail and a part of the body of the pancreas.
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