Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China.
Centre for Cancer & Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
J Transl Med. 2023 Apr 16;21(1):260. doi: 10.1186/s12967-023-04087-6.
More than half of the colorectal cancer (CRC) patients will develop liver metastasis that underlies the cancer mortality. In the hepatic tumor microenvironment, the interplay between CRC cells and hepatic stellate cells (HSCs), and the activation of HSCs to become carcinoma-associated fibroblasts (CAFs) will further promote the cancer development. Nevertheless, the critical signaling molecule that involved in these processes remains unknown, which hinders the development of effective therapeutic agents for the treatment of metastatic CRC (mCRC).
Conditioned medium system and co-cultured system were used to examine the interplay between CRC cells and HSCs. Luminex liquid suspension chip detection and enzyme-linked immunosorbent assay were used to screen for the mediators in the conditioned medium that facilitated the CRC-HSCs interplay and HSCs-to-CAFs differentiation. Cell and animal models were used to examine whether brevilin A inhibited CRC liver metastasis via the VEGF-IL6-STAT3 axis.
In the CRC-HSCs interplay, CRC promoted HSCs-to-CAFs differentiation by releasing vascular endothelial growth factor (VEGF); and HSCs released interleukin 6 (IL6) that activated signal transducer and activator of transcription 3 (STAT3) in the CRC and hence increased the cancer metastatic potential. The functions of the VEGF-IL6-STAT3 axis in the HSCs-CRC interplay were further validated by VEGF recombinant protein and IL6 neutralizing antibody. More importantly, brevilin A, an active compound isolated from Centipeda minima (L.) A. Br. et Aschers, targeted the VEGF-IL6-STAT3 axis in the CRC-HSCs interplay, hence significantly inhibited colorectal liver metastasis and cancer growth both in vitro and in vivo.
We are the first to demonstrate brevilin A possesses potent anti-mCRC effect by targeting the VEGF-IL6-STAT3 axis in the CRC-HSCs interplay. Our findings not only support the development of brevilin A as a novel therapeutic agent for mCRC treatment, but also pave the path for the development of other VEGF-IL6-STAT3 targeting therapeutic strategies.
超过一半的结直肠癌（CRC）患者会发展为肝转移，这是癌症死亡的基础。在肝肿瘤微环境中，CRC 细胞与肝星状细胞（HSCs）之间的相互作用，以及 HSCs 激活为癌相关成纤维细胞（CAFs），将进一步促进癌症发展。然而，涉及这些过程的关键信号分子仍不清楚，这阻碍了用于治疗转移性 CRC（mCRC）的有效治疗剂的开发。
使用条件培养基系统和共培养系统来研究 CRC 细胞与 HSCs 之间的相互作用。使用 Luminex 液体悬浮芯片检测和酶联免疫吸附测定来筛选有助于 CRC-HSCs 相互作用和 HSCs 向 CAFs 分化的条件培养基中的介质。细胞和动物模型用于研究布氏灵菌 A 是否通过 VEGF-IL6-STAT3 轴抑制 CRC 肝转移。
在 CRC-HSCs 相互作用中，CRC 通过释放血管内皮生长因子（VEGF）促进 HSCs 向 CAFs 分化；HSCs 释放白细胞介素 6（IL6），激活 CRC 中的信号转导和转录激活因子 3（STAT3），从而增加癌症转移潜力。VEGF 重组蛋白和 IL6 中和抗体进一步验证了 VEGF-IL6-STAT3 轴在 HSCs-CRC 相互作用中的作用。更重要的是，从 Centipeda minima（L.）A. Br. et Aschers 中分离出的活性化合物布氏灵菌 A 靶向 CRC-HSCs 相互作用中的 VEGF-IL6-STAT3 轴，因此显著抑制结直肠癌的肝转移和体内外的肿瘤生长。
我们首次证明布氏灵菌 A 通过靶向 CRC-HSCs 相互作用中的 VEGF-IL6-STAT3 轴具有强大的抗 mCRC 作用。我们的研究结果不仅支持将布氏灵菌 A 开发为治疗 mCRC 的新型治疗剂，而且为开发其他靶向 VEGF-IL6-STAT3 的治疗策略铺平了道路。
