Conophylline suppresses pancreatic cancer desmoplasia and cancer-promoting cytokines produced by cancer-associated fibroblasts.
Conophylline suppresses pancreatic cancer desmoplasia and cancer-promoting cytokines produced by cancer-associated fibroblasts.
复制标题
DOI：
10.1111/cas.13847
复制
发表时间：
2019-01
期刊：
影响因子：
5.7
通讯作者：
Shirabe K
中科院分区：
文献类型：
--
作者：
Ishii N;Araki K;Yokobori T;Hagiwara K;Gantumur D;Yamanaka T;Handa T;Tsukagoshi M;Igarashi T;Watanabe A;Kubo N;Harimoto N;Masamune A;Umezawa K;Kuwano H;Shirabe K
尽管癌症治疗近年来取得了进展，但胰腺癌是一种高度恶性的肿瘤，预后较差，其特点是癌组织中密集的结缔组织增生。癌症相关成纤维细胞（CAF）负责形成这种纤维化基质并促进癌症进展。我们之前报道过从热带植物叶子中提取的一种新型天然化合物康茶碱 (CnP) 通过抑制星状细胞来减少肝脏和胰腺纤维化。然而，目前还没有研究调查 CnP 对 CAF 的影响，而这正是本工作的目的。在这里，我们发现 CAF 刺激了胰腺癌恶性肿瘤的指标，例如增殖、侵袭性和化疗耐药性。我们还表明，CnP 抑制 CAF 活性和增殖，并抑制 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，例如白细胞介素 (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 在小鼠异种移植模型中促进肿瘤增殖和促纤维增生形成，CnP 减少由胰腺癌细胞 + CAF 组成的肿瘤的促纤维增生，并且 CnP 与吉西他滨联合治疗显着抑制肿瘤增殖。我们的研究结果表明，CnP 是一种与抗癌药物联合治疗以克服难治性胰腺癌的有前途的治疗策略。
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.
登录
查看更多内容
影响因子：
29.4
作者：
Apte MV;Wilson JS;Lugea A;Pandol SJ
通讯作者：
Pandol SJ
DOI：
10.1158/1078-0432.ccr-16-0870
发表时间：
2017-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kalbasi A;Komar C;Tooker GM;Liu M;Lee JW;Gladney WL;Ben-Josef E;Beatty GL
通讯作者：
Beatty GL
影响因子：
11.2
作者：
Hwang, Rosa F.;Moore, Todd;Logsdon, Craig D.
通讯作者：
Logsdon, Craig D.
影响因子：
4.3
作者：
Ilic M;Ilic I
通讯作者：
Ilic I
影响因子：
29.4
作者：
Bachem, MG;Sch端nemann, M;Adler, G
通讯作者：
Adler, G