肿瘤相关成纤维细胞在大肠癌发生发展中的研究进展

doi:10.11904/j.issn.1002-3070.2018.03.018

摘要/Abstract

摘要： 肿瘤相关成纤维细胞(Cancer-associated-fibroblasts,CAFs)是肿瘤外部微环境中最重要的细胞成分之一。CAFs可以与肿瘤细胞发生相互作用,分泌多种可溶性因子如生长因子、趋化因子等,并通过调控大肠癌进展过程中发挥关键作用的多条信号通路,参与大肠癌的增殖、侵袭、转移以及耐药等生物学过程。近年研究发现,CAFs相关标记物及基因可作为大肠癌患者预后判断的参考指标,因此,靶向CAFs有望成为大肠癌早期诊断、治疗以及预后判断的关键靶点。本文主要就CAFs的特征、募集与活化过程以及在大肠癌发生发展中的作用进行总结,以期为CAFs在大肠癌中作用机制研究及临床应用提供新的科研方向。

关键词: 肿瘤相关成纤维细胞, 肿瘤微环境, 大肠癌

Abstract: Cancer-associated fibroblasts(CAFs)are one of the most important cellular components in the external microenvironment of tumors.CAFs can interact with tumor cells and secrete a variety of soluble factors such as growth factors,chemokines,and so on.CAFs are also involved in the proliferation,invasion,migration,metastasis and drug resistance of colorectal cancer through regulating multiple signaling pathways that play a key role in the progression of colorectal cancer.Recent studies have found that CAFs related markers and genes can be used as reference indicators for the predicting prognosis of colorectal cancer.Therefore,targeting CAFs may be a key target for early diagnosis,treatment and prognosis of colorectal cancer.This article summarizes the characteristics of CAFs,recruitment and activation process,and its role in the development of colorectal cancer in order to provide a new scientific direction for the mechanism of action and clinical application of CAFs in colorectal cancer.

Key words: Cancer-associated-fibroblasts, Tumor microenvironment, Colorectal cancer

中图分类号:

R735.3+4

吕强, 陈洪生, 李国东, 魏九峰(综述), 刘明(审校). 肿瘤相关成纤维细胞在大肠癌发生发展中的研究进展[J]. 实用肿瘤学杂志, 2018, 32(3): 275-279.

LV Qiang, CHEN Hongsheng, LI Guodong, WEI Jiufeng, LIU Ming. Effects of tumor-associated fibroblasts in the development of colorectal cancer and its research progress[J]. PRACTICAL ONCOLOGY JOURNAL, 2018, 32(3): 275-279.

参考文献

1 Kalluri R,Zeisberg M.Fibroblasts in cancer[J].Nat Rev Cancer,2006,6(5):392-401.
2 Tsujino T,Seshimo I,Yamamoto H,et al.Stromal myofibroblasts predict disease recurrence for colorectal cancer[J].Clin Cancer Res,2007,13(7):2082-2090.
3 Kalluri R.The biology and function of fibroblasts in cancer[J].Nat Rev Cancer,2016,16(9):582-598.
4 Ahlund D,Elyada E,Tuveson D.Fibroblast heterogeneity in the cancer wound[J].J Exp Med,2014,211(8):1503-1523.
5 Flaberg E,Markasz L,Petranyi G,et al.High-throughput live-cell imaging reveals differential inhibition of tumor cell proliferation by human fibroblasts[J].Int J Cancer,2011,128(12):2793-2802.
6 Koliaraki V,Roulis M,Kollias G.Tpl2 regulates intestinal myofibroblast HGF release to suppress colitis-associated tumorigenesis[J].J Clin Invest,2012,122(11):4231-4242.
7 Kojima Y,Acar A,Eaton EN,et al.Autocrine TGF-beta and stromal cell-derived factor-1(SDF-1)signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts[J].Proc Natl Acad Sci U S A,2010,107(46):20009-20014.
8 Valentina D,Maurizio C,Elisa G,et al.Integrated gene and miRNA expression analysis of prostate cancer associated fibroblasts supports a prominent role for interleukin-6 in fibroblast activation:[J].Oncotarget,2015,6(31):31441-31460.
9 Orimo A,Gupta PB,Sgroi DC,et al.Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion[J].Cell,2005,121(3):335-348.
10 Quante M,Tu SP,Tomita H,et al.Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth[J].Cancer Cell,2011,19(2):257-272.
11 Dubé PE,Yan F,Punit S,et al.Epidermal growth factor receptor inhibits colitis-associated cancer in mice[J].J Clin Invest,2012,122(8):2780-2792.
12 Sanchezlopez E,Flashnerabramson E,Shalapour S,et al.Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling[J].Oncogene,2016,35(20):2634-2644.
13 Evans J,Essex A,Xin H,et al.Wnt activity defines colon cancer stem cells and is regulated by the microenvironment[J].Nat Cell Biol,2015,12(5):468-476.
14 Lotti F,Jarrar AM,Pai RK,et al.Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A[J].J Exp Med,2013,210(13):2851-2872.
15 Kim HM,Jung WH,Koo JS.Expression of cancer-associated fibroblast related proteins in metastatic breastd cancer:an immunohistochemical analysis[J].J Transl Med,2015,13:222.
16 Berdielacer M,Sanzpamplona R,Calon A,et al.Differences between CAFs and their paired NCF from adjacent colonic mucosa reveal functional heterogeneity of CAFs,providing prognostic information[J].Mol Oncol,2014,8(7):1290-1305.
17 Werb Z.Matrix metalloproteinases:regulators of the tumor microenvironment[J].Cell,2010,141(1):52-67.
18 Vellinga TT,Den US,Rinkes IH,et al.Collagen-rich stroma in aggressive colon tumors induces mesenchymal gene expression and tumor cell invasion[J].Oncogene,2016,35(40):5263.
19 O′Connell JT,Sugimoto H,Cooke VG,et al.VEGF-A and Tenascin-C produced by S100A4 stromal cells are important for metastatic colonization[J].P Natl Acad Sci U S A,2011,108(38):16002-16007.
20 Calon A,Espinet E,Palomoponce S,et al.Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation[J].Cancer Cell,2012,22(5):571-584.
21 Holle AW,Young JL,Spatz JP.In vitro cancer cell-ECM interactions inform in vivo cancer treatment[J].Adv Drug Deliver Rev,2016,97:270-279.
22 Domanska UM,Timmerbosscha H,Nagengast WB,et al.CXCR4 inhibition with AMD3100 sensitizes prostate cancer to docetaxel chemotherapy[J].Neoplasia,2012,14(8):709-718.
23 Roulis M,Nikolaou C,Kotsaki E,et al.Intestinal myofibroblast-specific Tpl2-COX-2-PGE2 pathway links innate sensing to epithelial homeostasis[J].Proc Natl Acad Sci U S A,2014,111(43):4658-4667.
24 Malik R,Lelkes PI,Cukierman E.Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer[J].Trends Biotechnol,2015,33(4):230-236.
25 Nagasaki T,Hara M,Nakanishi H,et al.Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis:anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction[J].Brit J Cancer,2014,110(2):469-478.
26 Huijbers A,Tollenaar RA,v Pelt GW,et al.The proportion of tumor-stroma as a strong prognosticator for stage II and III colon cancer patients:validation in the VICTOR trial[J].Ann Oncol,2013,24(1):179-185.
27 Calon A,Lonardo E,Berenguerllergo A,et al.Stromal gene expression defines poor-prognosis subtypes in colorectal cancer[J].Nat Genet,2015,47(4):320-329.
28 Kraman M,Bambrough PJ,Arnold JN,et al.Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-α[J].Science,2010,330(6005):827-830.
29 Roberts EW,Deonarine A,Jones JO,et al.Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia[J].J Exp Med,2013,210(6):1137-1151.
30 Sasaki S,Baba T,Shinagawa K,et al.Crucial involvement of the CCL3‐CCR5 axis‐mediated fibroblast accumulation in colitis‐associated carcinogenesis in mice[J].Int J Cancer,2014,135(6):1297-1306.

[1]	李悦, 徐可, 韩增祥, 孙敏, 樊国华综述, 张勇审校. 结肠癌中肿瘤相关巨噬细胞的作用及靶向治疗的研究进展[J]. 实用肿瘤学杂志, 2018, 32(5): 450-454.
[2]	张培, 曹守波, 于雁. 自噬介导的肿瘤相关巨噬细胞调控机制的研究进展[J]. 实用肿瘤学杂志, 2018, 32(2): 130-134.
[3]	雷婉婷, 王静萱. 肿瘤微环境在肿瘤细胞有氧糖酵解中的作用[J]. 实用肿瘤学杂志, 2018, 32(2): 189-192.
[4]	申美莹, 庞达. 长链非编码RNA在肿瘤微环境中的调控作用[J]. 实用肿瘤学杂志, 2018, 32(1): 73-76.
[5]	秦琪,徐洋,赵红,张清媛. 肿瘤相关中性粒细胞的研究进展[J]. 实用肿瘤学杂志, 2017, 31(4): 367-370.
[6]	徐洋，秦琪，赵红，刘健鸿综述，张清媛审校. 肿瘤微环境异质性的研究进展[J]. 实用肿瘤学杂志, 2017, 31(3): 258-261.
[7]	段佩雯, 赵苗苗综述, 王松坡审校. NF-κB对大肠癌发生发展的影响及其相关治疗的研究现状[J]. 实用肿瘤学杂志, 2017, 31(1): 43-47.
[8]	吴杨佳子,鹿晓麟,赵琦,高玉艳,张艳桥. Arg-1在大肠炎症相关性肿瘤中的表达及意义[J]. 实用肿瘤学杂志, 2016, 30(4): 339-345.
[9]	王倩, 陈铁龙, 王彩芹, 罗微. 大肠癌中CD133、COX-2的表达及DNA倍体的研究[J]. 实用肿瘤学杂志, 2016, 30(3): 200-206.
[10]	张津宁, 李国东, 陈洪生综述, 刘明校审. 鞣花酸及其肠道代谢产物在大肠癌中的研究进展[J]. 实用肿瘤学杂志, 2016, 30(3): 262-265.
[11]	黄卫东, 于洪娟, 郑二维, 贺长志, 赵晓雯综述, 刘国祥校审. 大肠癌筛查经济学评价研究进展[J]. 实用肿瘤学杂志, 2015, 29(5): 462-466.
[12]	宫晨,周军德,迟强,崔滨滨,赵亚双,王帆. CYP24A1基因多态性与大肠癌发生及预后的关系[J]. 实用肿瘤学杂志, 2015, 29(4): 289-293.
[13]	方东, 王志红. 中性粒细胞/淋巴细胞比值在大肠癌癌变进展中的指示价值[J]. 实用肿瘤学杂志, 2015, 29(1): 44-48.
[14]	崔滨滨, 刘彦龙, 陈洪生, 周飞, 于雪峰, 徐海涛. 抑癌基因ING3在大肠癌中表达及意义[J]. 实用肿瘤学杂志, 2014, 28(6): 481-484.
[15]	王涛, 郑永光, 范康武综述, 李玉民审校. 胃癌与肿瘤微环境的研究进展[J]. 实用肿瘤学杂志, 2014, 28(6): 561-564.