Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan.
Research Program for Omics-based Medical Science, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Japan.
Cancer Sci. 2019 Jan;110(1):334-344. doi: 10.1111/cas.13847. Epub 2018 Dec 13.
Despite recent advances in cancer treatment, pancreatic cancer is a highly malignant tumor type with a dismal prognosis and it is characterized by dense desmoplasia in the cancer tissue. Cancer-associated fibroblasts (CAF) are responsible for this fibrotic stroma and promote cancer progression. We previously reported that a novel natural compound conophylline (CnP) extracted from the leaves of a tropical plant reduced liver and pancreatic fibrosis by suppression of stellate cells. However, there have been no studies to investigate the effects of CnP on CAF, which is the aim of this work. Here, we showed that CAF stimulated indicators of pancreatic cancer malignancy, such as proliferation, invasiveness, and chemoresistance. We also showed that CnP suppressed CAF activity and proliferation, and inhibited the stimulating effects of CAF on pancreatic cancer cells. Moreover, CnP strongly decreased the various cytokines involved in cancer progression, such as interleukin (IL)-6, IL-8, C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine ligand 12 (CXCL12), secreted by CAF. In vivo, CAF promoted tumor proliferation and desmoplastic formation in a mouse xenograft model, CnP reduced desmoplasia of tumors composed of pancreatic cancer cells + CAF, and combination therapy of CnP with gemcitabine remarkably inhibited tumor proliferation. Our findings suggest that CnP is a promising therapeutic strategy of combination therapy with anticancer drugs to overcome refractory pancreatic cancers.
尽管癌症治疗最近取得了进展，但胰腺癌仍然是一种高度恶性的肿瘤类型，预后极差，其特征是癌症组织中存在密集的纤维母细胞增生。癌症相关成纤维细胞（CAF）是这种纤维基质的主要来源，并促进癌症进展。我们之前报道过，从热带植物叶子中提取的新型天然化合物柯诺辛（CnP）通过抑制星状细胞来减少肝和胰腺纤维化。然而，目前还没有研究调查 CnP 对 CAF 的影响，这是这项工作的目的。在这里，我们表明 CAF 刺激了胰腺癌恶性的指标，如增殖、侵袭和化学抗性。我们还表明 CnP 抑制了 CAF 的活性和增殖，并抑制了 CAF 对胰腺癌细胞的刺激作用。此外，CnP 强烈降低了 CAF 分泌的各种参与癌症进展的细胞因子，如白细胞介素（IL）-6、IL-8、C-C 基序趋化因子配体 2（CCL2）和 C-X-C 基序趋化因子配体 12（CXCL12）。在体内，CAF 促进了小鼠异种移植模型中肿瘤的增殖和纤维母细胞增生，CnP 减少了由胰腺癌细胞+CAF 组成的肿瘤的纤维母细胞增生，CnP 与吉西他滨联合治疗显著抑制了肿瘤的增殖。我们的研究结果表明，CnP 是一种很有前途的联合治疗策略，与抗癌药物联合使用，以克服难治性胰腺癌。
