DNA損傷分泌程序.docx

DNA損傷分泌程序腫瘤的發(fā)生和發(fā)展是一個(gè)復(fù)雜的、動(dòng)態(tài)的過(guò)程。早在1889年，Steven Paget提出了“種子和土壤”的假說(shuō)，他認(rèn)為建立一個(gè)肥沃的“土壤”（微環(huán)境）是為傳播“種子”（腫瘤細(xì)胞）的關(guān)鍵1。作為腫瘤細(xì)胞生長(zhǎng)的土壤，腫瘤微環(huán)境為腫瘤細(xì)胞的發(fā)生、發(fā)展、轉(zhuǎn)移等提供了保障2。腫瘤微環(huán)境由細(xì)胞（如巨噬細(xì)胞，樹(shù)突細(xì)胞，T細(xì)胞，內(nèi)皮細(xì)胞和成纖維細(xì)胞等）、細(xì)胞外基質(zhì)（ECM），蛋白酶，和細(xì)胞因子等構(gòu)成3。在實(shí)體瘤中，營(yíng)造適于腫瘤存活的微環(huán)境是腫瘤發(fā)生、發(fā)展的第一步，其在免疫調(diào)節(jié)中具有關(guān)鍵作用4。除此之外，微環(huán)境還可以調(diào)節(jié)腫瘤內(nèi)生長(zhǎng)因子、細(xì)胞因子、趨化因子的表達(dá)，以進(jìn)一步促進(jìn)腫瘤的形成5。腫瘤微環(huán)境的形成會(huì)引發(fā)遺傳突變和DNA雙鏈斷裂等DNA損傷現(xiàn)象，破壞基因組的穩(wěn)定性。事實(shí)上，DNA損傷的腫瘤細(xì)胞可誘導(dǎo)DNA損傷應(yīng)答(DNA Damage Response ;DDR)，它可以誘導(dǎo)細(xì)胞周期延遲，長(zhǎng)期阻滯細(xì)胞生長(zhǎng)（衰老）和受損細(xì)胞凋亡6。DDR一方面通過(guò)磷脂酰肌醇3-激酶相關(guān)激酶（PIKKs）ATM，ATR和DNA-PKcs等引起DNA修復(fù)，另一方面通過(guò)Chk1/ 2-P53-P21信號(hào)通路激活細(xì)胞周期進(jìn)程和凋亡7。DDR除了影響細(xì)胞自主組分，影響受損細(xì)胞本身外，還能夠通過(guò)細(xì)胞非自治程序，促進(jìn)細(xì)胞因子的分泌，影響其他細(xì)胞，例如放化療后在腫瘤微環(huán)境中幸存下來(lái)的腫瘤細(xì)胞。在激活的腫瘤微環(huán)境中，DNA損傷性的基因治療方法(主要為放療和化療)會(huì)產(chǎn)生脫靶作用，對(duì)于腫瘤的遷移、侵襲、轉(zhuǎn)移潛力等造成了一定的影響。研究表明，DDR是腫瘤微環(huán)境激活的重要媒介。最近，Yu Sun等在Clin Cancer Res上首次報(bào)道了DNA損傷應(yīng)答可以在生物體內(nèi)引發(fā)一種特別的細(xì)胞分泌表型， 即DNA損傷分泌程序(DNA DamageSecretory Program, DDSP)8。DDSP程序的組成復(fù)雜，包括促炎細(xì)胞因子(如IL-6、IL-8)，可改變蛋白酶的細(xì)胞外基質(zhì)，神經(jīng)因子前體，血管生長(zhǎng)因子和包括表皮生長(zhǎng)因子受體（EGFR）激動(dòng)劑在內(nèi)的上皮細(xì)胞有絲分裂原等9, 10。這些因子在腫瘤微環(huán)境中可以傳播組織損傷的信號(hào)，一方面通過(guò)免疫清除及時(shí)消除受損細(xì)胞，另一方面，通過(guò)誘導(dǎo)血管新生或促進(jìn)細(xì)胞發(fā)生EMT（上皮間質(zhì)轉(zhuǎn)化），促進(jìn)腫瘤的增殖11和遷移9, 10，或者使腫瘤細(xì)胞獲得對(duì)于化療或放療的耐受性12，對(duì)預(yù)后產(chǎn)生不良效果。參考文獻(xiàn)1.Gao D, Vahdat LT, Wong S, Chang JC, Mittal V. Microenvironmental regulation of epithelial-mesenchymal transitions in cancer. Cancer research. 2012; 72(19): 4883-9.2.Wood SL, Pernemalm M, Crosbie PA, Whetton AD. The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer treatment reviews. 2014; 40(4): 558-66.3.Chou J, Shahi P, Werb Z. microRNA-mediated regulation of the tumor microenvironment. Cell cycle. 2013; 12(20): 3262-71.4.Vitale M, Cantoni C, Pietra G, Mingari MC, Moretta L. Effect of tumor cells and tumor microenvironment on NK-cell function. European journal of immunology. 2014; 44(6): 1582-92.5.Stetler-Stevenson WG, Gavil NV. Normalization of the tumor microenvironment: evidence for tissue inhibitor of metalloproteinase-2 as a cancer therapeutic. Connective tissue research. 2014; 55(1): 13-9.6.Colin DJ, Limagne E, Ragot K, Lizard G, Ghiringhelli F, Solary E, et al. The role of reactive oxygen species and subsequent DNA-damage response in the emergence of resistance towards resveratrol in colon cancer models. Cell death & disease. 2014; 5: e1533.7.Smith J, Tho LM, Xu N, Gillespie DA. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Advances in cancer research. 2010; 108: 73-112.8.Sun Y, Nelson PS. Molecular pathways: involving microenvironment damage responses in cancer therapy resistance. Clinical cancer research : an official journal of the American Association for Cancer Research. 2012; 18(15): 4019-25.9.Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS biology. 2008; 6(12): 2853-68.10.Bavik C, Coleman I, Dean JP, Knudsen B, Plymate S, Nelson PS. The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. Cancer research. 2006; 66(2): 794-802.11.Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. The EMBO journal. 2011; 30(8): 1536-48.12.McConkey DJ, Choi W, Marquis L, Martin F, Williams MB