State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
Pharmaceutical Animal Experimental Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
Pharmacol Res. 2020 Sep;159:104981. doi: 10.1016/j.phrs.2020.104981. Epub 2020 May 31.
Tumor initiation and progression are not only ascribed to the behavior of cancer cells, but also profoundly influenced by the tumor microenvironment. Inside, cancer-associated fibroblasts (CAFs) have become key factors to accelerate growth and metastasis for the abundance in most solid tumors. Our group previously reported that Oroxylin A (OA), a flavone from Scutellaria Baicalensis Georgi, possess the ability to suppress growth and invasion of several tumor cells. However, the regulatory effect of OA on stromal microenvironment is poorly understood. In this study, breast cancer-induced fibroblasts and primary breast CAFs from MMTV-PyMT mice were used to evaluate the influence of OA on the activation of fibroblasts. Results showed that OA could decrease the expression of α-SMA, fibronectin, vimentin and matrix metalloproteinases (MMPs). Thus, OA-deactivated CAFs did not further promote the proliferation and invasion in breast cancer cells. In vivo experiments, OA could also impede tumor metastasis through exhausting progressive CAFs. Mechanically, OA could specifically bind ACTN1 and significantly inhibit its expression to prevent CAF activation. As a consequence, OA could decrease the phosphorylation of FAK and STAT3, and reduce the secretion of CCL2 in CAFs. Altogether, OA could remodel stromal microenvironment and it is a potential therapeutic agent in breast cancer.
肿瘤的发生和发展不仅归因于癌细胞的行为，还受到肿瘤微环境的深刻影响。在肿瘤内部，癌相关成纤维细胞（CAFs）已成为加速大多数实体瘤生长和转移的关键因素。我们的研究小组先前报道，黄芩素（OA），一种来自黄芩的黄酮类化合物，具有抑制几种肿瘤细胞生长和侵袭的能力。然而，OA 对基质微环境的调节作用尚不清楚。在这项研究中，我们使用乳腺癌诱导的成纤维细胞和 MMTV-PyMT 小鼠的原代乳腺癌 CAFs 来评估 OA 对成纤维细胞激活的影响。结果表明，OA 可降低α-SMA、纤维连接蛋白、波形蛋白和基质金属蛋白酶（MMPs）的表达。因此，OA 失活的 CAFs 不会进一步促进乳腺癌细胞的增殖和侵袭。在体内实验中，OA 还可以通过耗尽进展性 CAFs 来抑制肿瘤转移。在机制上，OA 可以特异性结合 ACTN1 并显著抑制其表达，从而防止 CAF 激活。结果，OA 可以降低 CAFs 中 FAK 和 STAT3 的磷酸化，并减少 CCL2 的分泌。总之，OA 可以重塑基质微环境，是治疗乳腺癌的潜在药物。
