Cholecystokinin Receptor Antagonist Improves Efficacy of Chemotherapy in Murine Models of Pancreatic Cancer by Altering the Tumor Microenvironment

Cancers

Narayan Shivapurkar¹  Martha D. Gay¹  Hong Cao¹  Benjamin A. Weinberg¹  Anita Safronenka¹  Sunil Bansal²  Amrita Cheema²  Zoe X. Malchiodi²  Jill P. Smith²  Robin D. Tucker³ 

[1] Department of Medicine, Georgetown University, Washington, DC 20057, USA;Department of Oncology, Georgetown University, Washington, DC 20057, USA;Department of Pathology, Georgetown University, Washington, DC 20057, USA;

关键词: metastases;    pancreatic cancer;    tumor microenvironment;    epithelial-to-mesenchymal transition;    fibrosis;    CCK receptor;   

DOI  :  10.3390/cancers13194949

来源: DOAJ

【 摘 要 】

Pancreatic cancer is resistant to chemotherapy in part due to the dense desmoplastic fibrosis surrounding the tumor, the immunosuppressive cells in the tumor microenvironment (TME), and the early rate of metastases. In this study, we examined the effects of a CCK receptor antagonist, proglumide, alone and in combination with gemcitabine in murine models of pancreatic cancer. Tumor growth rate, metastases, and survival were assessed in mice bearing syngeneic murine or human pancreatic tumors treated with PBS (control), gemcitabine, proglumide, or the combination of gemcitabine and proglumide. Excised tumors were evaluated histologically for fibrosis, immune cells, molecular markers, and uptake of chemotherapy by mass spectroscopy. Peripheral blood was analyzed with a microRNAs biomarker panel associated with fibrosis and oncogenesis. Differentially expressed genes between tumors of mice treated with gemcitabine monotherapy and combination therapy were compared by RNAseq. When given in combination the two compounds exhibited inhibitory effects by decreasing tumor growth rate by 70%, metastases, and prolonging survival. Proglumide monotherapy altered the TME by decreasing fibrosis, increasing intratumoral CD8⁺ T-cells, and decreasing arginase-positive cells, thus rendering the tumor sensitive to chemotherapy. Proglumide altered the expression of genes involved in fibrosis, epithelial–mesenchymal transition, and invasion. CCK-receptor antagonism with proglumide renders pancreatic cancer susceptible to chemotherapy.

【 授权许可】

Unknown