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肿瘤转移是指恶性肿瘤细胞从原发部位经淋巴道、血管或体腔等途径,到达其他部位继续生长的过程。恶性肿瘤转移的方式包括直接蔓延到邻近部位、淋巴转移、血行转移和种植转移。恶性肿瘤的转移往往是肿瘤治疗失败的主要原因[1]。
肿瘤微环境由肿瘤细胞、多种基质细胞、细胞因子和趋化因子等组成。肿瘤的发生和转移与肿瘤细胞所处的环境关系密切,它不仅包括肿瘤细胞自身的内在环境(核和胞质),也与肿瘤所在组织的结构、功能和代谢有关[2]。
治疗恶性肿瘤的主要目标是根除患者的肿瘤细胞,包括原发性肿瘤细胞和明显或隐匿性转移的肿瘤细胞,这是影响患者预后的关键因素。超过50%的肿瘤患者将在疾病过程中接受放疗,其对于无法手术或不完全切除肿瘤的患者以及复发患者至关重要[3]。然而,即使应用先进的放疗或放化疗联合疗法,肿瘤仍可能发生复发和转移,导致预后不良。放疗本质上是对肿瘤进行局部控制,但会产生局部和全身效应,这就意味着肿瘤微环境会不可避免地受到影响。事实上,放疗诱导的肿瘤微环境变化可能在某些情况下促进肿瘤进展。越来越多的研究结果表明,电离辐射可能具有促进肿瘤转移的作用[1]。然而,几十年来,改进放疗的研究几乎完全集中于肿瘤细胞本身,却忽略了肿瘤微环境和肿瘤内复杂的生物相互作用,而这可能是影响肿瘤治疗成败的关键因素。因此,关注肿瘤微环境对提高肿瘤的治愈率至关重要。目前,国内外对放疗后肿瘤微环境变化促进肿瘤转移及其分子机制的研究较少。我们对放疗后肿瘤微环境变化与肿瘤转移的关系及其可能的分子机制进行综述。
放疗促进肿瘤转移的研究进展
Research progress of radiotherapy-induced tumor metastasis
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摘要: 肿瘤细胞从原发病灶迁移到远处部位形成转移病灶的过程增加了患者的病死率。放疗可通过电离直接或通过产生活性氧间接导致DNA损伤,从而杀死肿瘤细胞。然而,近年来的研究结果表明,放疗诱导的肿瘤微环境变化在某些情况下可促进肿瘤转移而导致治疗失败。放疗后肿瘤微环境变化与肿瘤转移的关系受到广泛关注,但其机制尚不明确。笔者对放疗如何通过诱导细胞因子表达、缺氧、整合素表达水平升高以及外泌体变化等因素从而促进肿瘤的转移进行综述。Abstract: The process of tumor cells migrating from the primary lesion to distant sites to form metastatic lesions increases the mortality of patients. Radiotherapy can cause DNA damage directly through ionization or indirectly through the production of reactive oxygen species, thereby destroying tumor cells. However, recent studies have shown that radiotherapy-induced changes in tumor microenvironment can promote tumor metastasis and cause treatment failure in some cases. The relationship between tumor microenvironment changes after radiotherapy and tumor metastasis has received widespread attention, but the mechanism remains unclear. This review discusses how radiotherapy promotes tumor metastasis by inducing cytokine expression, hypoxia, increased integrin expression and changes in exosome.
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Key words:
- Radiotherapy /
- Tumor microenvironment /
- Neoplasm metastasis
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[1] Sundahl N, Duprez F, Ost P, et al. Effects of radiation on the metastatic process[J]. Mol Med, 2018, 24(1): 16. DOI: 10.1186/s10020-018-0015-8. [2] Candido J, Hagemann T. Cancer-related inflammation[J]. J Clin Immunol, 2013, 33(Suppl 1): S79−84. DOI: 10.1007/s10875-012-9847-0. [3] Vilalta M, Rafat M, Graves EE. Effects of radiation on metastasis and tumor cell migration[J]. Cell Mol Life Sci, 2016, 73(16): 2999−3007. DOI: 10.1007/s00018-016-2210-5. [4] Kim ES, Choi YE, Hwang SJ, et al. IL-4, a direct target of miR-340/429, is involved in radiation-induced aggressive tumor behavior in human carcinoma cells[J/OL]. Oncotarget, 2016, 7(52): 86836−86856[2019-07-11]. http://www.oncotarget.com/article/13561/text. DOI: 10.18632/oncotarget.13561. [5] Zang CB, Liu XJ, Li B, et al. IL-6/STAT3/TWIST inhibition reverses ionizing radiation-induced EMT and radioresistance in esophageal squamous carcinoma[J/OL]. Oncotarget, 2017, 8(7): 11228−11238[2019-07-11]. http://www.oncotarget.com/article/14495/text. DOI: 10.18632/oncotarget.14495. [6] Moncharmont C, Levy A, Guy JB, et al. Radiation-enhanced cell migration/invasion process: a review[J]. Crit Rev Oncol Hematol, 2014, 92(2): 133−142. DOI: 10.1016/j.critrevonc.2014.05.006. [7] Nambiar DK, Rajamani P, Singh RP. Silibinin attenuates ionizing radiation-induced pro-angiogenic response and EMT in prostate cancer cells[J]. Biochem Biophys Res Commun, 2015, 456(1): 262−268. DOI: 10.1016/j.bbrc.2014.11.069. [8] Jin H, Ko YS, Kim HJ. P2Y2R-mediated inflammasome activation is involved in tumor progression in breast cancer cells and in radiotherapy-resistant breast cancer[J]. Int J Oncol, 2018, 53(5): 1953−1966. DOI: 10.3892/ijo.2018.4552. [9] Chen XL, Zhang LR, Jiang YJ, et al. Radiotherapy-induced cell death activates paracrine HMGB1-TLR2 signaling and accelerates pancreatic carcinoma metastasis[J]. J Exp Clin Cancer Res, 2018, 37(1): 77. DOI: 10.1186/s13046-018-0726-2. [10] Feys L, Descamps B, Vanhove C, et al. Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling[J/OL]. Oncotarget, 2015, 6(29): 26615−26632[2019-07-11]. http://www.oncotarget.com/article/5666/text. DOI: 10.18632/oncotarget.5666. [11] Lee SY, Jeong EK, Ju MK, et al. Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation[J/OL]. Mol Cancer, 2017, 16(1): 10[2019-07-11]. https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-016-0577-4. DOI: 10.1186/s12943-016-0577-4. [12] Ohuchida K, Mizumoto K, Murakami M, et al. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions[J]. Cancer Res, 2004, 64(9): 3215−3222. DOI: 10.1158/0008-5472.can-03-2464. [13] Rüegg C, Monnier Y, Kuonen F, et al. Radiation-induced modifications of the tumor microenvironment promote metastasis[J]. Bull Cancer, 2011, 98(6): 47−57. DOI: 10.1684/bdc.2011.1372. [14] Teng F, Tian WY, Wang YM, et al. Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis[J/OL]. J Hematol Oncol, 2016, 9: 8[2019-07-11]. https://jhoonline.biomedcentral.com/articles/10.1186/s13045-015-0231-4. DOI: 10.1186/s13045-015-0231-4. [15] Ji XQ, Zhu XX, Lu XG. Effect of cancer-associated fibroblasts on radiosensitivity of cancer cells[J]. Future Oncol, 2017, 13(17): 1537−1550. DOI: 10.2217/fon-2017-0054. [16] Luo GJ, He YD, Yu XJ. Bone marrow adipocyte: an intimate partner with tumor cells in bone metastasis[J/OL]. Front Endocrinol (Lausanne), 2018, 9: 339[2019-07-11]. https://www.frontiersin.org/articles/10.3389/fendo.2018.00339/full. DOI: 10.3389/fendo.2018.00339. [17] Gu Q, He Y, Ji JF, et al. Hypoxia-inducible factor 1α (HIF-1α) and reactive oxygen species (ROS) mediates radiation-induced invasiveness through the SDF-1α/CXCR4 pathway in non-small cell lung carcinoma cells[J/OL]. Oncotarget, 2015, 6(13): 10893−10907[2019-07-11]. http://www.oncotarget.com/article/3535/text. DOI: 10.18632/oncotarget.3535. [18] Kuonen F, Secondini C, Rüegg C. Molecular pathways: emerging pathways mediating growth, invasion, and metastasis of tumors progressing in an irradiated microenvironment[J]. Clin Cancer Res, 2012, 18(19): 5196−5202. DOI: 10.1158/1078-0432.CCR-11-1758. [19] Arnold KM, Flynn NJ, Raben A, et al. The impact of radiation on the tumor microenvironment: effect of dose and fractionation schedules[J/OL]. Cancer Growth Metastasis, 2018, 11: 1−17[2019-07-11]. https://journals.sagepub.com/doi/pdf/10.1177/1179064418761639. DOI: 10.1177/1179064418761639. [20] Purdy JA. Dose to normal tissues outside the radiation therapy patient's treated volume: a review of different radiation therapy techniques[J]. Health Phys, 2008, 95(5): 666−676. DOI: 10.1097/01.HP.0000326342.47348.06. [21] Rofstad EK, Mathiesen B, Galappathi K. Increased metastatic dissemination in human melanoma xenografts after subcurative radiation treatment: radiation-induced increase in fraction of hypoxic cells and hypoxia-induced up-regulation of urokinase-type plasminogen activator receptor[J]. Cancer Res, 2004, 64(1): 13−18. DOI: 10.1158/0008-5472.can-03-2658. [22] Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities[J]. Nat Rev Cancer, 2010, 10(1): 9−22. DOI: 10.1038/nrc2748. [23] Rajput S, Kumar BN, Banik P, et al. Thymoquinone restores radiation-induced TGF-β expression and abrogates EMT in chemoradiotherapy of breast cancer cells[J]. J Cell Physiol, 2015, 230(3): 620−629. DOI: 10.1002/jcp.24780. [24] Mutschelknaus L, Azimzadeh O, Heider T, et al. Radiation alters the cargo of exosomes released from squamous head and neck cancer cells to promote migration of recipient cells[J/OL]. Sci Rep, 2017, 7(1): 12423[2019-7-11]. http://www.nature.com/articles/s41598-017-12403-6. DOI: 10.1038/s41598-017-12403-6. [25] Arscott WT, Tandle AT, Zhao SP, et al. Ionizing radiation and glioblastoma exosomes: implications in tumor biology and cell migration[J/OL]. Transl Oncol, 2013, 6(6): 638−648[2019-07-11]. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890698. DOI: 10.1593/tlo.13640.
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