Molecular Oncology Department, Research Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Department of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Carcinogenesis. 2021 Dec 31;42(12):1439-1448. doi: 10.1093/carcin/bgab102.
Active breast cancer-associated fibroblasts (CAFs), the most influential cells in breast tumor microenvironment, express/secrete high levels of the proinvasive/metastatic interleukin-6 (IL-6). Therefore, we have tested here the effect of the IL-6 receptor (IL-6R) inhibitor tocilizumab (TCZ; Actemra) on different active breast CAFs. We have shown that TCZ potently and persistently suppresses the expression of various CAF biomarkers, namely α-SMA, SDF-1 as well as the STAT3 pathway and its downstream target AUF1. TCZ also inhibited the proliferation, migration and invasion abilities of active breast CAF cells. Additionally, TCZ repressed the ability of CAF cells in promoting epithelial-to-mesenchymal transition, and enhancing the migratory/invasive and proliferative capacities of breast cancer cells in vitro. Importantly, these findings were confirmed in orthotopic humanized breast tumors in mice. Furthermore, TCZ suppressed the expression of the pro-angiogenic factor VEGF-A and its transactivator HIF-1α in CAF cells, and consequently inhibited the angiogenic-promoting effect of active CAFs both in vitro and in orthotopic tumor xenografts. These results indicate that inhibition of the IL-6/STAT3/AUF1 pathway by TCZ can normalize active breast CAFs and suppress their paracrine pro-carcinogenic effects, which paves the way toward development of specific CAF-targeting therapy, badly needed for more efficient breast cancer treatments.
活性乳腺癌相关成纤维细胞（CAFs）是乳腺肿瘤微环境中最具影响力的细胞，其表达/分泌高水平的促侵袭/转移的白细胞介素-6（IL-6）。因此，我们在这里测试了 IL-6 受体（IL-6R）抑制剂托珠单抗（TCZ；Actemra）对不同活性乳腺癌 CAFs 的影响。我们已经表明，TCZ 能够强烈且持久地抑制各种 CAF 生物标志物的表达，即α-SMA、SDF-1 以及 STAT3 通路及其下游靶标 AUF1。TCZ 还抑制了活性乳腺癌 CAF 细胞的增殖、迁移和侵袭能力。此外，TCZ 抑制了 CAF 细胞促进上皮-间充质转化的能力，并增强了乳腺癌细胞在体外的迁移/侵袭和增殖能力。重要的是，这些发现已在小鼠的原位人源化乳腺癌肿瘤中得到证实。此外，TCZ 抑制了 CAF 细胞中促血管生成因子 VEGF-A 及其转录激活因子 HIF-1α 的表达，并因此抑制了活性 CAF 细胞在体外和原位肿瘤异种移植中的促血管生成作用。这些结果表明，TCZ 抑制 IL-6/STAT3/AUF1 通路可以使活性乳腺癌 CAFs 正常化并抑制其旁分泌致癌作用，为开发针对 CAF 的特异性靶向治疗铺平了道路，这对于更有效的乳腺癌治疗是迫切需要的。
