肿瘤相关成纤维细胞在宫颈癌中的研究进展

doi:10.12280/gjszjk.20210603

摘要/Abstract

摘要：

宫颈癌的发生发展是肿瘤细胞与其周围微环境相互促进、共同演化的一个动态过程。肿瘤相关成纤维细胞（cancer-associated fibroblasts,CAFs）作为肿瘤微环境（tumor microenvironment,TME）中主要的细胞成分,可起源于不同细胞,具有来源多样性和功能异质性,不同来源的CAFs具有不同的分子标志物。CAFs参与宫颈癌细胞增殖、侵袭和转移等关键过程,是促进肿瘤血管生成的重要因素,通过多种机制使TME处于免疫抑制状态,促进肿瘤细胞的免疫逃逸,同时CAFs与宫颈癌的代谢重编程、临床预后等也密切相关。近年对CAFs及其介导宫颈癌进展相关机制的深入研究为针对CAFs的靶向治疗提供了初步的线索与依据。综述CAFs的特点和来源,对宫颈癌发生发展的作用,并对靶向CAFs的治疗现状进行总结,以期为宫颈癌的治疗提供新的思路。

关键词: 宫颈肿瘤, 成纤维细胞, 肿瘤微环境, 乳头状瘤病毒科, 治疗, 肿瘤相关成纤维细胞

Abstract:

The occurrence and development of cervical cancer is a dynamic process of mutual promotion and co-evolution of tumor cells and their surrounding microenvironment. Cancer-associated fibroblasts (CAFs), as the main cellular components in the tumor microenvironment (TME), which originate from different cells with diverse sources and functional heterogeneity. CAFs from different sources have different molecular markers. CAFs are involved in key processes such as cervical cancer cell proliferation, invasion and metastasis, and they are an important factor in promoting tumor angiogenesis. CAFs make the TME in an immunosuppressive state through various mechanisms and promote the immune escape of tumor cells. At the same time, CAFs are closely related to the metabolic reprogramming and clinical prognosis of cervical cancer. In recent years, with the in-depth research on CAFs and the mechanism of CAFs-mediated cervical cancer progression, some preliminary clues and evidences have been provided for the targeted therapy of CAFs. This article reviews the characteristics and sources of CAFs, their role in the occurrence and development of cervical cancer, as well as the current status of targeted CAFs therapy. These contents are expected to provide new ideas for the treatment of cervical cancer.

Key words: Uterine cervical neoplasms, Fibroblasts, Tumor microenvironment, Papillomaviridae, Therapy, Cancer-associated fibroblasts

滕飞, 薛凤霞. 肿瘤相关成纤维细胞在宫颈癌中的研究进展[J]. 国际生殖健康/计划生育, 2022, 41(2): 166-171.

TENG Fei, XUE Feng-xia. Research Progress of Cancer-Associated Fibroblasts in Cervical Cancer[J]. Journal of International Reproductive Health/Family Planning, 2022, 41(2): 166-171.

参考文献 35

[1]	Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2021, 71(3):209-249. doi: 10.3322/caac.21660. doi: 10.3322/caac.21660 URL
[2]	Zeltz C, Primac I, Erusappan P, et al. Cancer-associated fibroblasts in desmoplastic tumors: emerging role of integrins[J]. Semin Cancer Biol, 2020, 62:166-181. doi: 10.1016/j.semcancer.2019.08.004. doi: 10.1016/j.semcancer.2019.08.004 URL
[3]	Ganguly D, Chandra R, Karalis J, et al. Cancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment[J]. Cancers(Basel), 2020, 12(9):2652. doi: 10.3390/cancers12092652. doi: 10.3390/cancers12092652
[4]	Sahai E, Astsaturov I, Cukierman E, et al. A framework for advancing our understanding of cancer-associated fibroblasts[J]. Nat Rev Cancer, 2020, 20(3):174-186. doi: 10.1038/s41568-019-0238-1. doi: 10.1038/s41568-019-0238-1 pmid: 31980749
[5]	Nurmik M, Ullmann P, Rodriguez F, et al. In search of definitions: Cancer-associated fibroblasts and their markers[J]. Int J Cancer, 2020, 146(4):895-905. doi: 10.1002/ijc.32193. doi: 10.1002/ijc.32193 URL
[6]	Wang Z, Yang Q, Tan Y, et al. Cancer-Associated Fibroblasts Suppress Cancer Development: The Other Side of the Coin[J]. Front Cell Dev Biol, 2021, 9:613534. doi: 10.3389/fcell.2021.613534. eCollection 2021. doi: 10.3389/fcell.2021.613534 URL
[7]	Liang LJ, Yang Y, Wei WF, et al. Tumor-secreted exosomal Wnt2B activates fibroblasts to promote cervical cancer progression[J]. Oncogenesis, 2021, 10(3):30. doi: 10.1038/s41389-021-00319-w. doi: 10.1038/s41389-021-00319-w URL
[8]	Sobierajska K, Ciszewski WM, Sacewicz-Hofman I, et al. Endothelial Cells in the Tumor Microenvironment[J]. Adv Exp Med Biol, 2020, 1234:71-86. doi: 10.1007/978-3-030-37184-5_6. doi: 10.1007/978-3-030-37184-5_6 pmid: 32040856
[9]	Ping Q, Yan R, Cheng X, et al. Cancer-associated fibroblasts: overview, progress, challenges, and directions[J]. Cancer Gene Ther, 2021, 28(9):984-999. doi: 10.1038/s41417-021-00318-4. doi: 10.1038/s41417-021-00318-4 URL
[10]	den Boon JA, Pyeon D, Wang SS, et al. Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling[J]. Proc Natl Acad Sci U S A, 2015, 112(25):E3255-E3264. doi: 10.1073/pnas.1509322112. doi: 10.1073/pnas.1509322112
[11]	Xiao L, Zhu H, Shu J, et al. Overexpression of TGF-beta1 and SDF-1 in cervical cancer-associated fibroblasts promotes cell growth, invasion and migration[J]. Arch Gynecol Obstet, 2022, 305(1):179-192. doi: 10.1007/s00404-021-06137-0. doi: 10.1007/s00404-021-06137-0 URL
[12]	Fullar A, Dudas J, Olah L, et al. Remodeling of extracellular matrix by normal and tumor-associated fibroblasts promotes cervical cancer progression[J]. BMC Cancer, 2015, 15:256. doi: 10.1186/s12885-015-1272-3. doi: 10.1186/s12885-015-1272-3 URL
[13]	Fullar A, Karaszi K, Hollosi P, et al. Two ways of epigenetic silencing of TFPI2 in cervical cancer[J]. PLoS One, 2020, 15(6):e234873. doi: 10.1371/journal.pone.0234873. eCollection 2020. doi: 10.1371/journal.pone.0234873
[14]	Zhang J, Wang Q, Quan Z. Long non-coding RNA CASC9 enhances breast cancer progression by promoting metastasis through the meditation of miR-215/TWIST2 signaling associated with TGF-beta expression[J]. Biochem Biophys Res Commun, 2019, 515(4):644-650. doi: 10.1016/j.bbrc.2019.05.080. doi: 10.1016/j.bbrc.2019.05.080 URL
[15]	Wang Z, Liu J, Huang H, et al. Metastasis-associated fibroblasts: an emerging target for metastatic cancer[J]. Biomark Res, 2021, 9(1):47. doi: 10.1186/s40364-021-00305-9. doi: 10.1186/s40364-021-00305-9 URL
[16]	Huang TH, Chu TY. Repression of miR-126 and upregulation of adrenomedullin in the stromal endothelium by cancer-stromal cross talks confers angiogenesis of cervical cancer[J]. Oncogene, 2014, 33(28):3636-3647. doi: 10.1038/onc.2013.335. doi: 10.1038/onc.2013.335 pmid: 24037526
[17]	Zhang X, Wang Y, Wang X, et al. Extracellular vesicles-encapsulated microRNA-10a-5p shed from cancer-associated fibroblast facilitates cervical squamous cell carcinoma cell angiogenesis and tumorigenicity via Hedgehog signaling pathway[J]. Cancer Gene Ther, 2021, 28(5):529-542. doi: 10.1038/s41417-020-00238-9. doi: 10.1038/s41417-020-00238-9 pmid: 33235271
[18]	Wu MP, Young MJ, Tzeng CC, et al. A novel role of thrombospondin-1 in cervical carcinogenesis: inhibit stroma reaction by inhibiting activated fibroblasts from invading cancer[J]. Carcinogenesis, 2008, 29(6):1115-1123. doi: 10.1093/carcin/bgn077. doi: 10.1093/carcin/bgn077 URL
[19]	Walch-Ruckheim B, Stroder R, Theobald L, et al. Cervical Cancer-Instructed Stromal Fibroblasts Enhance IL23 Expression in Dendritic Cells to Support Expansion of Th17 Cells[J]. Cancer Res, 2019, 79(7):1573-1586. doi: 10.1158/0008-5472.CAN-18-1913. doi: 10.1158/0008-5472.CAN-18-1913 pmid: 30696656
[20]	Galazka K, Oplawski M, Windorbska W, et al. The immunohistochemical analysis of antigens such as RCAS1 and B7H4 in the cervical cancer nest and within the fibroblasts and macrophages infiltrating the cancer microenvironment[J]. Am J Reprod Immunol, 2012, 68(1):85-93. doi: 10.1111/j.1600-0897. 2012.01134.x. doi: 10.1111/j.1600-0897. 2012.01134.x URL
[21]	Li B, Sui L. Metabolic reprogramming in cervical cancer and metabolomics perspectives[J]. Nutr Metab(Lond), 2021, 18(1):93. doi: 10.1186/s12986-021-00615-7. doi: 10.1186/s12986-021-00615-7
[22]	Druzhkova IN, Shirmanova MV, Lukina MM, et al. The metabolic interaction of cancer cells and fibroblasts-coupling between NAD(P)H and FAD, intracellular pH and hydrogen peroxide[J]. Cell Cycle, 2016, 15(9):1257-1266. doi: 10.1080/15384101. 2016.1160974. doi: 10.1080/15384101.2016.1160974 pmid: 26986068
[23]	Martinez-Outschoorn UE, Lisanti MP, Sotgia F. Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth[J]. Semin Cancer Biol, 2014, 25:47-60. doi: 10.1016/j.semcancer.2014.01.005. doi: 10.1016/j.semcancer.2014.01.005 pmid: 24486645
[24]	Li Z, Sun C, Qin Z. Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming[J]. Theranostics, 2021, 11(17):8322-8336. doi: 10.7150/thno.62378. doi: 10.7150/thno.62378 URL
[25]	郭楚鸿, 陈晓静, 王梓慈, 等. TAMs与CAFs联合预测子宫颈癌淋巴结转移研究[J]. 中国实用妇科与产科杂志, 2021, 37(4):478-481. doi: 10.19538/j.fk2021040117. doi: 10.19538/j.fk2021040117
[26]	Carvalho FM, Zaganelli FL, Almeida BG, et al. Prognostic value of podoplanin expression in intratumoral stroma and neoplastic cells of uterine cervical carcinomas[J]. Clinics (Sao Paulo), 2010, 65(12):1279-1283. doi: 10.1590/s1807-59322010001200009. doi: 10.1590/s1807-59322010001200009 URL
[27]	Wei WF, Chen XJ, Liang LJ, et al. Periostin(+) cancer-associated fibroblasts promote lymph node metastasis by impairing the lymphatic endothelial barriers in cervical squamous cell carcinoma[J]. Mol Oncol, 2021, 15(1):210-227. doi: 10.1002/1878-0261. 12837. doi: 10.1002/1878-0261. 12837 URL
[28]	Chu TY, Yang JT, Huang TH, et al. Crosstalk with cancer-associated fibroblasts increases the growth and radiation survival of cervical cancer cells[J]. Radiat Res, 2014, 181(5):540-547. doi: 10.1667/RR13583.1. doi: 10.1667/RR13583.1 URL
[29]	Kim KH, Chang JS, Byun HK, et al. A novel gene signature associated with poor response to chemoradiotherapy in patients with locally advanced cervical cancer[J]. J Gynecol Oncol, 2022, 33(1):e7. doi: 10.3802/jgo.2022.33.e7. doi: 10.3802/jgo.2022.33.e7 URL
[30]	Walter SG, Scheidt S, Nissler R, et al. In-Depth Characterization of Stromal Cells within the Tumor Microenvironment Yields Novel Therapeutic Targets[J]. Cancers (Basel), 2021, 13(6):1466. doi: 10.3390/cancers13061466. doi: 10.3390/cancers13061466 URL
[31]	Pietras K, Pahler J, Bergers G, et al. Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting[J]. PLoS Med, 2008, 5(1):e19. doi: 10.1371/journal.pmed.0050019. doi: 10.1371/journal.pmed.0050019 URL
[32]	Hassan RN, Luo H, Jiang W. Effects of Nicotinamide on Cervical Cancer-Derived Fibroblasts: Evidence for Therapeutic Potential[J]. Cancer Manag Res, 2020, 12:1089-1100. doi: 10.2147/CMAR.S229395. doi: 10.2147/CMAR.S229395 pmid: 32104089
[33]	Bromma K, Bannister A, Kowalewski A, et al. Elucidating the fate of nanoparticles among key cell components of the tumor microenvironment for promoting cancer nanotechnology[J]. Cancer Nanotechnol, 2020, 11(1):8. doi: 10.1186/s12645-020-00064-6. doi: 10.1186/s12645-020-00064-6 pmid: 32849921
[34]	De Gregorio V, La Rocca A, Urciuolo F, et al. Modeling the epithelial-mesenchymal transition process in a 3D organotypic cervical neoplasia[J]. Acta Biomater, 2020, 116:209-222. doi: 10.1016/j.actbio.2020.09.006. doi: 10.1016/j.actbio.2020.09.006 URL
[35]	Zhou B, Yu Y, Yu L, et al. Sipi soup inhibits cancer-associated fibroblast activation and the inflammatory process by downregulating long noncoding RNA HIPK1AS[J]. Mol Med Rep, 2018, 18(2):1361-1368. doi: 10.3892/mmr.2018.9144. doi: 10.3892/mmr.2018.9144