Liu Linxin, Li Hong, Guo Zhenzhen, Ma Xiaofang, Cao Ning, Zheng Yaqiu, Geng Shengnan, Duan Yongjian, Han Guang, Du Gangjun
Institute of Pharmacy, Pharmacy College of Henan University, Jinming District, Kaifeng, Henan Province 475004, China.
Department of Oncology, The first hospital Affiliated to Henan University, Kaifeng, Henan Province 475001, China.
PLoS One. 2015 Nov 23;10(11):e0143438. doi: 10.1371/journal.pone.0143438. eCollection 2015.
The tumor stroma has been described as "normal wound healing gone awry". We explored whether the restoration of a wound healing-like microenvironment may facilitate tumor healing. Firstly, we screened three natural compounds (shikonin, notoginsenoside R1 and aconitine) from wound healing agents and evaluated the efficacies of wound healing microenvironment for limiting single agent-elicited carcinogenesis and two-stage carcinogenesis. The results showed that three compounds used alone could promote wound healing but had unfavorable efficacy to exert wound healing, and that the combination of three compounds made up treatment disadvantage of a single compound in wound healing and led to optimal wound healing. Although individual treatment with these agents may prevent cancer, they were not effective for the treatment of established tumors. However, combination treatment with these three compounds almost completely prevented urethane-induced lung carcinogenesis and reduced tumor burden. Different from previous studies, we found that urethane-induced lung carcinogenesis was associated with lung injury independent of pulmonary inflammation. LPS-induced pulmonary inflammation did not increase lung carcinogenesis, whereas decreased pulmonary inflammation by macrophage depletion promoted lung carcinogenesis. In addition, urethane damaged wound healing in skin excision wound model, reversed lung carcinogenic efficacy by the combination of three compounds was consistent with skin wound healing. Further, the combination of these three agents reduced the number of lung cancer stem cells (CSCs) by inducing cell differentiation, restoration of gap junction intercellular communication (GJIC) and blockade of the epithelial-to-mesenchymal transition (EMT). Our results suggest that restoration of a wound healing microenvironment represents an effective strategy for cancer prevention.
肿瘤基质被描述为“异常的正常伤口愈合”。我们探究了恢复类似伤口愈合的微环境是否有助于肿瘤愈合。首先，我们从伤口愈合剂中筛选了三种天然化合物（紫草素、三七皂苷R1和乌头碱），并评估了伤口愈合微环境对限制单一药物引发的致癌作用和两阶段致癌作用的效果。结果表明，单独使用这三种化合物均可促进伤口愈合，但在发挥伤口愈合作用方面效果不佳，且三种化合物联合使用弥补了单一化合物在伤口愈合方面的治疗缺陷，实现了最佳的伤口愈合效果。尽管单独使用这些药物可能预防癌症，但它们对已形成的肿瘤治疗无效。然而，这三种化合物联合治疗几乎完全预防了氨基甲酸乙酯诱导的肺癌发生，并减轻了肿瘤负担。与以往研究不同的是，我们发现氨基甲酸乙酯诱导的肺癌发生与肺损伤有关，与肺部炎症无关。脂多糖诱导的肺部炎症并未增加肺癌发生，而通过巨噬细胞耗竭降低肺部炎症则促进了肺癌发生。此外，氨基甲酸乙酯在皮肤切除伤口模型中损害了伤口愈合，三种化合物联合使用逆转肺癌致癌效果与皮肤伤口愈合一致。进一步研究发现，这三种药物联合使用通过诱导细胞分化、恢复间隙连接细胞间通讯（GJIC）和阻断上皮-间质转化（EMT），减少了肺癌干细胞（CSC）的数量。我们的研究结果表明，恢复伤口愈合微环境是一种有效的癌症预防策略。
