肿瘤微环境是由肿瘤细胞、肿瘤支持细胞、细胞基质、细胞因子等构成。其中肿瘤相关成纤维细胞(Cancer-Associated Fibroblasts, CAFs)在肿瘤微环境中含量最为丰富,其在肿瘤的形成、肿瘤血管生成、增殖、侵袭和转移等事件过程中起着重要作用。这促使一些研究人员对CAFs的分子和细胞特征进行研究,探索其在预防和治疗癌症方面的潜在应用。目前有大量关于CAFs的定义、起源以及其对肿瘤细胞的作用的研究。在此,本文总结了目前CAFs定义的分歧,来源的多样性,以及其在乳腺癌治疗中的可能机制,并对该领域未来研究方向做出了分析。
Tumor microenvironment is composed of tumor cells, tumor supporting cells, cell matrix and cy-tokines. Among these, cancer-associated fibroblasts (CAFs) are the most abundant in tumor mi-croenvironment and play an important role in tumorigenesis, angiogenesis, proliferation, invasion and metastasis. This has prompted some researchers to study the molecular and cellular characteristics of CAFs and explore their potential applications in cancer prevention and treatment. There are a lot of studies on the definition, origin and effect of CAFs on cancer cells. In this paper, we summarize the differences in the definition of CAFs, the diversity of their sources, and the possible mechanisms in the treatment of breast cancer, and the future research directions in this field are also predicted.
乳腺癌,肿瘤相关成纤维细胞,肿瘤微环境, Breast Cancer Cancer-Associated Fibroblasts Tumor Microenvironment乳腺癌相关成纤维细胞:乳腺癌治疗的新靶点
李俊杰,李 卉,龙启明,杨 业. 乳腺癌相关成纤维细胞:乳腺癌治疗的新靶点Breast Cancer-Associated Fibroblasts: A New Target for Breast Cancer Therapy[J]. 临床医学进展, 2019, 09(04): 606-612. https://doi.org/10.12677/ACM.2019.94092
参考文献ReferencesSiegel, R.L., Miller, K.D. and Jemal, A. (2018) Cancer Statistics, 2018. CA: A Cancer Journal for Clinicians, 68, 7-30.
<br>https://doi.org/10.3322/caac.21442Anderson, B., Yip, C., Smith, R., Shyyan, R., Sener, S., Eniu, A., et al. (2008) Guideline Implementation for Breast Healthcare in Low-Income and Middle Income Countries: Overview of the Breast Health Global Initiative Global Summit 2007. Cancer, 113, 2221-2243. <br>https://doi.org/10.1002/cncr.23844Han, S., Guo, Q. and Wang, T., et al. (2013) Prognostic Significance of Interactions between ER Alpha and ER Beta and Lymph Node Status in Breast Cancer Cases. Asian Pacific Journal of Cancer Prevention, 14, 6081-6084.
<br>https://doi.org/10.7314/APJCP.2013.14.10.6081Peng, J., Sengupta, S. and Jordan, V.C. (2009) Potential of Selective Estrogen Receptor Modulators as Treatments and Preventives of Breast Cancer. Anti-Cancer Agents in Me-dicinal Chemistry, 9, 481-99.
<br>https://doi.org/10.2174/187152009788451833Brenton, J.D., Carey, L.A., Ahmed, A.A. and Caldas, C. (2005) Molecular Classification and Molecular Forecasting of Breast Cancer: Ready for Clinical Application? Journal of Clinical Oncology, 23, 7350-7360.
<br>https://doi.org/10.1200/JCO.2005.03.3845Luo, H., Tu, G., Liu, Z. and Liu, M. (2015) Cancer-Associated Fibroblasts: A Multifaceted Driver of Breast Cancer Progression. Cancer Letters, 361, 155-163. <br>https://doi.org/10.1016/j.canlet.2015.02.018Tchou, J., Kossenkov, A.V., Chang, L., Satija, C., Herlyn, M., Showe, L.C. and Pure, E. (2012) Human Breast Cancer-Associated Fibroblasts Exhibit Subtype Specific Gene Expres-sion Profiles. BMC Medical Genomics, 5, 39.
<br>https://doi.org/10.1186/1755-8794-5-39Bergamaschi, A., Tagliabue, E., Sorlie, T., Naume, B., Triulzi, T., Orlandi, R., Russnes, H.G., Nesland, J.M., Tammi, R., Auvinen, P., et al. (2008) Extracellular Matrix Signature Identi-fies Breast Cancer Subgroups with Different Clinical Outcome. The Journal of Pathology, 214, 357-367. <br>https://doi.org/10.1002/path.2278Quail, D.F. and Joyce, J.A. (2013) Microenvironmental Regulation of Tumor Progression and Metastasis. Nature Medicine, 19, 1423-1437. <br>https://doi.org/10.1038/nm.3394Campbell, I., Qiu, W. and Haviv, I. (2011) Genetic Changes in Tumour Microenvironments. The Journal of Pathology, 223, 450-458. <br>https://doi.org/10.1002/path.2842Moinfar, F., Man, Y.G., Arnould, L., Bratthauer, G.L., Ratschek, M. and Tavassoli, F.A. (2000) Concurrent and Independent Genetic Alterations in the Stromal and Epithelial Cells of Mammary Carcinoma: Implications for Tumorigenesis. Cancer Research, 60, 2562-2566.Gabbiani, G., Ryan, G.B. and Majne, G. (1971) Presence of Modified Fibroblasts in Granulation Tissue and Their Possible Role in Wound Contraction. Experientia, 27, 549-550. <br>https://doi.org/10.1007/BF02147594Hasebe, T., Tamura, N., Okada, N., Hojo, T., Akashi-tanaka, S., Shimizu, C., Tsuda, H., Shibata, T., Sasajima, Y., Iwasaki, M., et al. (2010) p53 Expression in Tumor-Stromal Fibroblasts Is Closely Associated with the Nodal Metastasis and Outcome of Patients with Invasive Ductal Carcinoma Who Received Neoadjuvant Therapy. Human Pathology, 41, 262-270. <br>https://doi.org/10.1016/j.humpath.2009.07.021Dvorak, H.F. (1986) Tumors: Wounds that Do Not Heal. Similarities between Tumor Stroma Generation and Wound Healing. The New England Journal of Medicine, 315, 1650-1659. <br>https://doi.org/10.1056/NEJM198612253152606Bhowmick, N.A., Neilson, E.G. and Moses, H.L. (2004) Stromal Fibroblasts in Cancer Initiation and Progression. Nature, 432, 332-337. <br>https://doi.org/10.1038/nature03096Bauer, M., SU, G., Casper, C., HE, R., Rehrauer, W. and Friedl, A. (2010) Heterogeneity of Gene Expression in Stromal Fibroblasts of Human Breast Carcinomas and Normal Breast. Oncogene, 29, 1732-1740.
<br>https://doi.org/10.1038/onc.2009.463Hawsawi, N.M., Ghebeh, H., Hendrayani, S.F., Tulbah, A., Al-Eid, M., Al-Tweigeri, T., Ajarim, D., Alaiya, A., Dermime, S. and Aboussekhra, A. (2008) Breast Carcinoma—Associated Fi-broblasts and Their Counterparts Display Neoplastic-Specific Changes. Cancer Research, 68, 2717-2725. <br>https://doi.org/10.1158/0008-5472.CAN-08-0192Mao, Y., Keller, E.T., Garfield, D.H., Shen, K. and Wang, J. (2013) Stromal Cells in Tumor Microenvironment and Breast Cancer. Cancer and Metastasis Reviews, 32, 303-315. <br>https://doi.org/10.1007/s10555-012-9415-3Pula, B., Jethon, A., Piotrowska, A., Gomulkiewicz, A., Owcza-rek, T., Calik, J., Wojnar, A., Witkiewicz,W., Rys, J., Ugorski, M., et al. (2011) Podoplanin Expression by Can-cer-Associated Fibroblasts Predicts Poor Outcome in Invasive Ductal Breast Carcinoma. Histopathology, 59, 1249-1260. <br>https://doi.org/10.1111/j.1365-2559.2011.04060.xRonnov-Jessen, L., Petersen, O.W., Koteliansky, V.E. and Bissell, M.J. (1995) The Origin of the Myofibroblasts in Breast Cancer. Recapitulation of Tumor Environment in Culture Unravels Diversity and Implicates Converted Fibroblasts and Recruited Smooth Muscle Cells. Journal of Clinical Investigation, 95, 859-873.
<br>https://doi.org/10.1172/JCI117736Kojima, Y., Acar, A., Eaton, E.N., Mellody, K.T., Scheel, C., Ben-Porath, I., Onder, T.T., Wang, Z.C., Richardson, A.L., Weinberg, R.A., et al. (2010) Autocrine TGF-Beta and Stromal Cell-Derived Factor-1 (SDF-1) Signaling Drives the Evolution of Tumor-Promoting Mammary Stromal Myofibroblasts. PNAS, 107, 20009-20014.
<br>https://doi.org/10.1073/pnas.1013805107Omary, M.B., Lugea, A., Lowe, A.W. and Pandol, S.J. (2007) The Pancreatic Stellate Cell: A Star on the Rise in Pancreatic Diseases. Journal of Clinical Investigation, 117, 50-59. <br>https://doi.org/10.1172/JCI30082Yin, C., Evason, K.J., Asahina, K. and Stainier, D.Y. (2013) Hepatic Stellate Cells in Liver Development, Regeneration, and Cancer. Journal of Clinical Investigation, 123, 1902-1910. <br>https://doi.org/10.1172/JCI66369Barth, P.J., Ebrahimsade, S., Ramaswamy, A. and Moll, R. (2002) CD34+ Fibrocytes in Invasive Ductal Carcinoma, Ductal Carcinoma in Situ, and Benign Breast Lesions. Virchows Archiv, 440, 298-303.
<br>https://doi.org/10.1007/s004280100530Jung, Y., et al. (2013) Recruitment of Mesenchymal Stem Cells into Prostate Tumours Promotes Metastasis. Nature Communications, 4, Article No. 1795. <br>https://doi.org/10.1038/ncomms2766Mishra, P.J., et al. (2008) Carcinoma-Associated Fibroblast—Like Differentiation of Human Mesenchymal Stem Cells. Cancer Research, 68, 4331-4339. <br>https://doi.org/10.1158/0008-5472.CAN-08-0943Zhu, Q., et al. (2014) The IL-6-STAT3 Axis Mediates a Reciprocal Crosstalk between Cancer-Derived Mesenchymal Stem Cells and Neutrophils to Synergistically Prompt Gastric Cancer Progression. Cell Death & Disease, 5, e1295.
<br>https://doi.org/10.1038/cddis.2014.263Weber, C.E., et al. (2015) Osteopontin Mediates an MZF1-TGF-β1-Dependent Transformation of Mesenchymal Stem Cells into Cancer-Associated Fibroblasts in Breast Cancer. Oncogene, 34, 4821-4833.
<br>https://doi.org/10.1038/onc.2014.410Shi, Y., Du, L., Lin, L. and Wang, Y. (2017) Tumour-Associated Mesenchymal Stem/Stromal Cells: Emerging Therapeutic Targets. Nature Reviews Drug Discovery, 16, 35-52. <br>https://doi.org/10.1038/nrd.2016.193Zeisberg, E.M., Potenta, S., Xie, L., Zeisberg, M. and Kalluri, R. (2007) Discovery of Endothelial to Mesenchymal Transition as a Source for Carcinoma-Associated Fibroblasts. Cancer Re-search, 67, 10123-10128.
<br>https://doi.org/10.1158/0008-5472.CAN-07-3127Kalluri, R. and Weinberg, R.A. (2009) The Basics of Epi-thelial-Mesenchymal Transition. Journal of Clinical Investigation, 119, 1420-1428. <br>https://doi.org/10.1172/JCI39104Massague, J. (2008) TGF-β in Cancer. Cell, 134, 215-230. <br>https://doi.org/10.1016/j.cell.2008.07.001Trimmer, C., Sotgia, F., Whitaker-Menezes, D., Balliet, R.M., Eaton, G., Martinez-Outschoorn, U.E., Pavlides, S., Howell, A., Iozzo, R.V., Pestell, R.G., et al. (2011) Caveolin-1 and Mitochondrial SOD2 (MnSOD) Function as Tumor Suppressors in the Stromal Microenvironment: A New Genetically Tractable Model for Human Cancer-Associated Fibroblasts. Cancer Biology & Therapy, 11, 383-394. <br>https://doi.org/10.4161/cbt.11.4.14101Witkiewicz, A.K., Dasgupta, A., Sammons, S., Er, O., Potoczek, M.B., Guiles, F., Sotgia, F., Brody, J.R., Mitchell, E.P. and Lisanti, M.P. (2010) Loss of Stromal Caveolin-1 Expression Predicts Poor Clinical Outcome in Triple Negative and Basal-Like Breast Cancers. Cancer Biology & Therapy, 10, 135-143. <br>https://doi.org/10.4161/cbt.10.2.11983Witkiewicz, A.K., Dasgupta, A., Sotgia, F., Mercier, I., Pestell, R.G., Sabel, M., Kleer, C.G., Brody, J.R. and Lisanti, M.P. (2009) An Absence of Stromal Caveolin-1 Expres-sion Predicts Early Tumor Recurrence and Poor Clinical Outcome in Human Breast Cancers. The American Journal of Pathology, 174, 2023-2034.
<br>https://doi.org/10.2353/ajpath.2009.080873Pula, B., Wojnar, A., Werynska, B., Ambicka, A., Kruczak, A., Witkiewicz, W., Ugorski, M., Podhorska-Okolow, M. and Dziegiel, P. (2013) Impact of Different Tumour Stroma As-sessment Methods Regarding Podoplanin Expression on Clinical Outcome in Patients with Invasive Ductal Breast Car-cinoma. Anticancer Research, 33, 1447-1455.Schoppmann, S.F., Berghoff, A., Dinhof, C., Jakesz, R., Gnant, M., Dubsky, P., Jesch, B., Heinzl, H. and Birner, P. (2012) Podoplanin-Expressing Cancer-Associated Fibroblasts Are As-sociated with Poor Prognosis in Invasive Breast Cancer. Breast Cancer Research and Treatment, 134, 237-244. <br>https://doi.org/10.1007/s10549-012-1984-xMartinez-Outschoorn, U.E., Pavlides, S., Whitaker-Menezes, D., et al. (2010) Tumor Cells Induce the Cancer Associated Fibroblast Phenotype via Caveolin-1 Degradation: Implications for Breast Cancer and DCIS Therapy with Autophagy Inhibitors. Cell Cycle, 9, 2423-2433. <br>https://doi.org/10.4161/cc.9.12.12048Orimo, A. and Weinberg, R.A. (2007) Heterogeneity of Stromal Fi-broblasts in Tumors. Cancer Biology & Therapy, 6, 618-619. <br>https://doi.org/10.4161/cbt.6.4.4255Qiao, A., Gu, F., Guo, X., et al. (2016) Breast Cancer-Associated Fibroblasts: Their Roles in Tumor Initiation, Progression and Clinical Applications. Frontiers of Medicine, 10, 33-40. <br>https://doi.org/10.1007/s11684-016-0431-5Paulsson, J., Sjoblom, T., Micke, P., Ponten, F., Landberg, G., Heldin, C.H., Bergh, J., Brennan, D.J., Jirstrom, K. and Ostman, A. (2009) Prognostic Significance of Stromal Platelet-Derived Growth Factor Beta-Receptor Expression in Human Breast Cancer. The American Journal of Pathology, 175, 334-341. <br>https://doi.org/10.2353/ajpath.2009.081030Pontiggia, O., Sampayo, R., Raffo, D., Motter, A., Xu, R., Bissell, M.J., Joffe, E.B. and Simian, M. (2012) The Tumor Microenvironment Modulates Tamoxifen Resistance in Breast Cancer: A Role for Soluble Stromal Factors and Fibronectin through β1 Integrin. Breast Cancer Research and Treatment, 133, 459-471.
<br>https://doi.org/10.1007/s10549-011-1766-xPavlides, S., Tsirigos, A., Vera, I., Flomenberg, N., Frank, P.G., Casimiro, M.C., Wang, C., Fortina, P., Addya, S., Pestell, R.G., et al. (2010) Loss of Stromal Caveolin-1 Leads to Ox-idative Stress, Mimics Hypoxia and Drives Inflammation in the Tumor Microenvironment, Conferring the “Reverse Warburg Effect”: A Transcriptional Informatics Analysis with Validation. Cell Cycle, 9, 2201-2219. <br>https://doi.org/10.4161/cc.9.11.11848