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Co-Targeting of CXCR4 and Hedgehog Pathways Disrupts Tumor-Stromal Crosstalk and Improves Chemotherapeutic Efficacy in Pancreatic Cancer

Co-Targeting of CXCR4 and Hedgehog Pathways Disrupts Tumor-Stromal Crosstalk and Improves Chemotherapeutic Efficacy in Pancreatic Cancer
Pancreatic cancer (PC) remains a therapeutic challenge because of its intrinsic and extrinsic chemoresistance mechanisms. Here, we report that C-X-C motif chemokine receptor 4 (CXCR4) and hedgehog pathways cooperate in PC chemoresistance via bi-directional tumor-stromal crosstalk. We show that when PC cells are co-cultured with pancreatic stellate cells (PSCs) they are significantly more resistant to gemcitabine toxicity than those grown in monoculture.

We also demonstrate that this co-culture-induced chemoresistance is abrogated by inhibition of the CXCR4 and hedgehog pathways. Similarly, the co-culture-induced altered expression of genes in PC cells associated with gemcitabine metabolism, antioxidant defense, and cancer stemness is also reversed upon CXCR4 and hedgehog inhibition. Read more . . . 


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