Malchiodi Zoe X, Cao Hong, Gay Martha D, Safronenka Anita, Bansal Sunil, Tucker Robin D, Weinberg Benjamin A, Cheema Amrita, Shivapurkar Narayan, Smith Jill P
Department of Oncology, Georgetown University, Washington, DC 20057, USA.
Department of Medicine, Georgetown University, Washington, DC 20057, USA.
Cancers (Basel). 2021 Sep 30;13(19):4949. doi: 10.3390/cancers13194949.
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.
胰腺癌对化疗具有抗性，部分原因在于肿瘤周围致密的促结缔组织增生性纤维化、肿瘤微环境（TME）中的免疫抑制细胞以及早期转移率。在本研究中，我们在胰腺癌小鼠模型中研究了一种CCK受体拮抗剂丙谷胺单独使用以及与吉西他滨联合使用的效果。在用PBS（对照）、吉西他滨、丙谷胺或吉西他滨与丙谷胺联合治疗的携带同基因小鼠或人胰腺肿瘤的小鼠中评估肿瘤生长速率、转移情况和存活率。对切除的肿瘤进行组织学评估，以检测纤维化、免疫细胞、分子标志物以及通过质谱法检测化疗药物的摄取情况。用与纤维化和肿瘤发生相关的微小RNA生物标志物面板分析外周血。通过RNA测序比较接受吉西他滨单药治疗和联合治疗的小鼠肿瘤之间的差异表达基因。两种化合物联合使用时，通过将肿瘤生长速率降低70%、减少转移并延长生存期而表现出抑制作用。丙谷胺单药治疗通过减少纤维化、增加肿瘤内CD8 T细胞以及减少精氨酸酶阳性细胞来改变肿瘤微环境，从而使肿瘤对化疗敏感。丙谷胺改变了参与纤维化、上皮-间质转化和侵袭的基因的表达。用丙谷胺进行CCK受体拮抗作用可使胰腺癌对化疗敏感。
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