Imanishi Masaki, Yamakawa Yusuke, Fukushima Keijo, Ikuto Raiki, Maegawa Akiko, Izawa-Ishizawa Yuki, Horinouchi Yuya, Kondo Masateru, Kishuku Masatoshi, Goda Mitsuhiro, Zamami Yoshito, Takechi Kenshi, Chuma Masayuki, Ikeda Yasumasa, Tsuchiya Koichiro, Fujino Hiromichi, Tsuneyama Koichi, Ishizawa Keisuke
Department of Pharmacy, Tokushima University Hospital, 2-50-1, Kuramoto-cho, Tokushima, 770-8503, Japan.
Department of Pharmacology for Life Sciences, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 2020 Jul;393(7):1239-1250. doi: 10.1007/s00210-020-01859-5. Epub 2020 Apr 19.
The roles of cancer-associated fibroblasts (CAFs) have been studied in the tumor progression, and CAFs are expected to become the new targets for cancer pharmacotherapies. CAFs contribute to tumor cell survival and proliferation, tumor angiogenesis, immune suppression, tumor inflammation, tumor cell invasion and metastasis, and extracellular matrix remodeling. However, detailed mechanisms of how CAFs function in the living system remain unclear. CAFs include α-smooth muscle actin, expressing activated fibroblasts similar to myofibroblasts, and are highly capable of producing collagen. Several reports have demonstrated the contributions of extracellular-signal-regulated kinase 5 (ERK5) in fibroblasts to the fibrotic processes; however, the roles of CAF-derived ERK5 remain unclear. To investigate the roles of CAF-derived ERK5 in the tumor progression, we created mice lacking the ERK5 gene specifically in fibroblasts. Colon-26 mouse colon cancer cells were implanted into the mice subcutaneously, and the histological analyses of the tumor tissue were performed after 2 weeks. Immunofluorescence analyses showed that recipient-derived fibroblasts existed within the tumor tissue. The present study demonstrated that fibroblast-specific ERK5 deficiency exacerbated tumor progression and it was accompanied with thicker tumor vessel formation and the increase in the number of activated fibroblasts. We combined the results of The Cancer Genome Atlas (TCGA) database analysis with our animal studies, and indicated that regulating ERK5 activity in CAFs or CAF invasion into the tumor tissue can be important strategies for the development of new targets in cancer pharmacotherapies.
癌症相关成纤维细胞（CAFs）在肿瘤进展中的作用已得到研究，并且CAFs有望成为癌症药物治疗的新靶点。CAFs有助于肿瘤细胞的存活和增殖、肿瘤血管生成、免疫抑制、肿瘤炎症、肿瘤细胞侵袭和转移以及细胞外基质重塑。然而，CAFs在活体系统中发挥作用的详细机制仍不清楚。CAFs包括α平滑肌肌动蛋白，表达类似于肌成纤维细胞的活化成纤维细胞，并且具有高度的胶原蛋白生成能力。一些报告已经证明细胞外信号调节激酶5（ERK5）在成纤维细胞的纤维化过程中的作用；然而，CAF衍生的ERK5的作用仍不清楚。为了研究CAF衍生的ERK5在肿瘤进展中的作用，我们创建了在成纤维细胞中特异性缺失ERK5基因的小鼠。将结肠26小鼠结肠癌细胞皮下植入小鼠体内，并在2周后对肿瘤组织进行组织学分析。免疫荧光分析表明肿瘤组织中存在受体来源的成纤维细胞。本研究表明，成纤维细胞特异性ERK5缺陷加剧了肿瘤进展，并且伴随着更厚的肿瘤血管形成和活化成纤维细胞数量的增加。我们将癌症基因组图谱（TCGA）数据库分析结果与我们的动物研究结果相结合，并指出调节CAFs中的ERK5活性或CAF侵入肿瘤组织可能是癌症药物治疗新靶点开发的重要策略。
