Department of General Surgery, Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, 1# Shuai Fu Yuan, Dongcheng District, Beijing, 100730, China.
Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
Cancer Immunol Immunother. 2021 Aug;70(8):2165-2177. doi: 10.1007/s00262-020-02816-0. Epub 2021 Jan 17.
Pancreatic cancer is an inflammatory malignancy, and tumor-associated macrophages (TAMs) are the predominant inflammatory cells in tumor tissue. TAMs have complicated interactions with pancreatic cancer cells, however, the details and mechanisms remain largely unknown. In this study, transcriptomics and proteomics analyses were performed to explore the interactions between murine pancreatic cancer cells and TAMs. Dopamine (DA) has been reported to suppress inflammations. However, its roles in TAMs of pancreatic cancer have not been reported. Herein, the roles and mechanisms of DA to affect the chemotherapeutic efficacy for pancreatic cancer were studied. Multi-omics results revealed that there was a tumor-promoting vicious cycle involving murine pancreatic cancer cells and TAMs. DA substantially improved the chemotherapeutic efficacy both in vitro study and in immunocompetent murine pancreatic cancer models by suppression of the M2 characters of TAMs. Further studies found that activation of DRD4 by DA led to the decrease of cAMP, and then inhibited the activation of PKA/p38 signal pathway, which suppressed the tumor-promoting inflammation of TAMs. This study uncovers the reciprocal interactions between TAMs and pancreatic cancer cells using multi-omics techniques and presents that DA has synergistic roles with chemotherapy for pancreatic cancer by suppressing of TAM-derived inflammations.
胰腺癌是一种炎症性恶性肿瘤，肿瘤相关巨噬细胞（TAMs）是肿瘤组织中主要的炎症细胞。TAMs 与胰腺癌细胞之间存在复杂的相互作用，但细节和机制在很大程度上尚不清楚。在这项研究中，进行了转录组学和蛋白质组学分析，以探讨鼠胰腺癌细胞与 TAMs 之间的相互作用。多巴胺（DA）已被报道可抑制炎症。然而，其在胰腺癌 TAMs 中的作用尚未见报道。本文研究了 DA 影响胰腺癌化疗疗效的作用和机制。多组学结果表明，鼠胰腺癌细胞和 TAMs 之间存在涉及肿瘤促进的恶性循环。DA 通过抑制 TAMs 的 M2 特征，在体外研究和免疫功能正常的鼠胰腺癌模型中均显著提高了化疗疗效。进一步的研究发现，DA 通过激活 DRD4 导致 cAMP 减少，进而抑制 PKA/p38 信号通路的激活，从而抑制了 TAMs 的促肿瘤炎症。本研究使用多组学技术揭示了 TAMs 和胰腺癌细胞之间的相互作用，并提出 DA 通过抑制 TAM 来源的炎症与化疗具有协同作用，可用于治疗胰腺癌。
