Liang Minglong, Wang Jian, Wu Chuanjian, Wu Manman, Hu Jingping, Dai Jianfeng, Ruan Hang, Xiong Sidong, Dong Chunsheng
Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
Transl Oncol. 2021 Dec;14(12):101221. doi: 10.1016/j.tranon.2021.101221. Epub 2021 Sep 13.
In cancer, the extracellular matrix is extensively remodeled during chronic inflammation, thus affecting cell transcription, differentiation, migration and cell-cell interactions. Matrix metalloproteinases can degrade the extracellular matrix of tumor tissues and take important roles in disease progression. Numerous efforts to develop cancer treatments targeting matrix metalloproteinases have failed in clinical trials owing to the ineffectiveness and toxicity of the applied inhibitors. In this study, we investigated the potential of targeting matrix metalloproteinases and oncolytic virus combination in cancer therapy. We found that MMP3 expression was upregulated in various cancers and MMP3 expression in the tumor cells, but not in other tissues, was important for tumor growth and metastasis. Single treatment of colon cancer with multiple MMP3 inhibitors was not effective in mice. Nevertheless, the therapeutic effect of MMP3 was greatly improved by combination with an oncolytic virus. A potential mechanism of MMP3 in regulating tumor cell proliferation and invasion was mediated via Erk1/2 an NF-κB signaling. This study reveals that MMP3 is a promising target and the combined treatment with oncolytic virus is a potential strategy for cancer therapy.
在癌症中，细胞外基质在慢性炎症过程中会发生广泛重塑，从而影响细胞转录、分化、迁移以及细胞间相互作用。基质金属蛋白酶能够降解肿瘤组织的细胞外基质，并在疾病进展中发挥重要作用。由于所应用抑制剂的无效性和毒性，众多针对基质金属蛋白酶开发癌症治疗方法的努力在临床试验中均告失败。在本研究中，我们探究了靶向基质金属蛋白酶与溶瘤病毒联合用于癌症治疗的潜力。我们发现，MMP3在多种癌症中表达上调，且肿瘤细胞中的MMP3表达（而非其他组织中的表达）对肿瘤生长和转移至关重要。用多种MMP3抑制剂对结肠癌进行单一治疗在小鼠中无效。然而，与溶瘤病毒联合使用时，MMP3的治疗效果得到了极大提升。MMP3调节肿瘤细胞增殖和侵袭的潜在机制是通过Erk1/2和NF-κB信号传导介导的。本研究表明，MMP3是一个有前景的靶点，与溶瘤病毒联合治疗是一种潜在的癌症治疗策略。
