“癌症进化发育学”理论的关键功能分子及其在恶性肿瘤防治中的作用

Key functional molecules supporting"Cancer Evo⁃Dev"and their roles in the prophylaxis and treatment of cancer

恶性肿瘤的发生和发展遵循“变异-选择-适应”的进化轨迹,外源性和内源性促癌因素直接或通过慢性非可控性炎症促进染色体变异以及主要功能基因变异。在癌前病变阶段,慢性炎症促进了变异驱动力量的积累,其中在50%以上的癌症病变中肿瘤抑制基因脆弱组蛋白三联体(fragile histidine triad,FHIT)的转录和翻译被严重抑制。外源性致癌因素通过对启动子CpG岛甲基化、复制应激导致杂合性缺失,使FHIT表达受损,导致染色体非整数倍扩增,形成染色体不稳定为特征的大变异;同时产生单链DNA促进了APOBEC3B致突变作用,形成以单碱基替换为特征的显微变异。炎症分子如IL-6反式激活APOBEC3B表达,反式抑制UNG表达,造成APOBEC3B/UNG平衡失调,促进体细胞变异和病毒变异,加速癌症进化。变异细胞在炎症条件下通过改造周围纤维母细胞为癌症相关纤维母细胞,招引抑制性免疫细胞,在缺氧环境下形成肿瘤微环境,通过选择和适应,促进变异细胞逆向进化为肿瘤起始细胞,从而促进癌症细胞逆向发育。据此认为,FHIT与APOBEC3B/UNG可能是肿瘤防控的新靶标。解除抑制FHIT和增强AID/APOBEC3s表达的内外因素,通过有氧运动和免疫治疗以消除促进癌症逆向分化的肿瘤微环境,通过靶向治疗阻断癌症逆向发育过程,有望为癌症特异性防治开拓新的途径。

The occurrence and development of malignant tumors follow an evolutionary trajectory of"mutation‑selection‑adaption".External and internal carcinogenic factors promote alterations in chromosomes and mutations in the major functional genes of affected cells directly or indirectly via arousing chronic non‑resolving inflammation.At the stage of precancerous lesion,chronic inflammation facilitates the accumulation of mutation‑driving forces,of which the transcription and translation of an important tumor suppressor,the fragile histidine triad(FHIT),are seriously inhibited in more than 50%precancerous lesions.External carcinogenic factors induces the promoter CpG methylation and replication stress leads to loss of heterozygosity,both of which result in the defect of FHIT expression.The defect of FHIT expression leads to aneuploidy,resulting in macroevolution characterized by chromosome instability;while the defect of FHIT expression promotes the formation of single‑stranded DNA,which facilitates the mutagenic effect of APOBEC3B,resulting in microevolution characterized by single base substitutions.Inflammatory factors such as interleukin‑6 trans‑activates the expression of APOBEC3B and trans‑inactivates the expression of uracil glycosylase(UNG),thus dis‑balancing APOBEC3B and UNG.This promotes somatic mutations and viral mutations,facilitating cancer evolution.The mutated cells actively transform surrounding fibroblasts into cancer‑associated fibroblasts that recruit suppressive immune cells to establish tumor microenvironment under hypoxia conditions.The mutated cells are selected and adapted to tumor microenvironment and then retro‑differentiated into cancer initiation cells,thus facilitating retro‑development of cancer cells.Based on this theory,FHIT and APOBEC3B/UNG should be novel targets for the prophylaxis and control of malignancies.It will develop a novel avenue for the specific prophylaxis and control of cancers to remove external and internal factors that inhibit the function of FHIT and/or upregulate the expression of AID/APOBEC3s,rectify tumor microenvironment that facilitates cancer retro‑differentiation via aerobic exercise and immunotherapy,and interrupt the retro‑development of cancer via targeted therapy.