三阴性乳腺癌的耐药机制及与DLG5的研究进展
Drug Resistance Mechanism of Tri-ple-Negative Breast Cancer and Research Progress with DLG5
DOI: 10.12677/ACM.2023.13112537, PDF,    科研立项经费支持
作者: 王旭升, 陈 波:西安医学院研究生工作部,陕西 西安;车景敏, 徐翠香:陕西省人民医院感染与免疫疾病重点实验,陕西 西安;王虎霞:陕西省肿瘤医院乳腺病院,陕西 西安;宋张骏*:陕西省人民医院肿瘤外科,陕西 西安
关键词: 三阴性乳腺癌DLG5耐药机制Triple-Negative Breast Cancer DLG5 Mechanisms of Drug Resistance
摘要: 三阴性乳腺癌(Triple Negative Breast Cancer, TNBC)是乳腺癌的一种特定亚型,因其不表达雌激素受体 (Estrogen Receptor, ER)、孕酮受体(Progesterone Receptor, PR)或人表皮生长因子受体-2 (Epi-dermal Growth Factor Receptor, HER-2)具有高侵袭能力,预后较其他类型乳腺癌差,在治疗上往往因为出现耐药性导致癌症进展和复发。早期应用化疗药物对三阴性乳腺癌有明显治疗效果,但随着化疗药物的应用,患者可逐渐出现耐药,导致总体生存率低下。因此,研究三阴性乳腺癌的化疗耐药性是目前乳腺癌的关注热点。本文回顾了三阴性乳腺癌耐药的研究进展,特别是极性蛋白DLG5在三阴性乳腺癌耐药中的作用以及影响,以期为临床治疗提供参考。
Abstract: Triple negative breast cancer (TNBC) is a specific subtype of breast cancer because it does not ex-press estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor re-ceptor (epidermal growth factor receptor, HER-2) has high aggressiveness, has a worse prognosis than other types of breast cancer, and is often treated because of drug resistance leading to cancer progression and recurrence. Early use of chemotherapy drugs has a significant therapeutic effect on triple-negative breast cancer, but with the application of chemotherapy drugs, patients can gradu-ally develop drug resistance, resulting in low overall survival. Therefore, the study of chemotherapy resistance in triple-negative breast cancer is currently a hot spot in breast cancer. This article re-views the research progress of triple-negative breast cancer drug resistance, especially the role and impact of polar protein DLG5 in triple-negative breast cancer drug resistance, in order to provide reference for clinical treatment.
文章引用:王旭升, 陈波, 车景敏, 王虎霞, 徐翠香, 宋张骏. 三阴性乳腺癌的耐药机制及与DLG5的研究进展[J]. 临床医学进展, 2023, 13(11): 18067-18076. https://doi.org/10.12677/ACM.2023.13112537

参考文献

[1] Waks, A.G. and Winer, E.P. (2019) Breast Cancer Treatment: A Review. JAMA, 321, 288-300. [Google Scholar] [CrossRef] [PubMed]
[2] Bianchini, G., de Angelis, C. and Licata, L. (2022) Treatment Land-scape of Triple-Negative Breast Cancer—Expanded Options, Evolving Needs. Nature Reviews Clinical Oncology, 19, 91-113. [Google Scholar] [CrossRef] [PubMed]
[3] Yin, L., Duan, J.J. and Bian, X.W. (2020) Tri-ple-Negative Breast Cancer Molecular Subtyping and Treatment Progress. Breast Cancer Research: BCR, 22, Article No. 61. [Google Scholar] [CrossRef] [PubMed]
[4] Derakhshan, F. and Reis-Filho, J.S. (2022) Pathogenesis of Triple-Negative Breast Cancer. Annual Review of Pathology: Mechanisms of Disease, 17, 181-204. [Google Scholar] [CrossRef] [PubMed]
[5] Won, K. and Spruck, C. (2020) Triple-Negative Breast Cancer Therapy: Current and Future Perspectives (Review). International Journal of Oncology, 57, 1245-1261. [Google Scholar] [CrossRef] [PubMed]
[6] Liedtke, C., Mazouni, C. and Hess, K.R. (2008) Response to Neoadju-vant Therapy and Long-Term Survival in Patients with Triple-Negative Breast Cancer. Journal of Clinical Oncology: Of-ficial Journal of the American Society of Clinical Oncology, 26, 1275-1281. [Google Scholar] [CrossRef
[7] Kumar, P. and Aggarwal, R. (2016) An Overview of Tri-ple-Negative Breast Cancer. Archives of Gynecology and Obstetrics, 293, 247-269. [Google Scholar] [CrossRef] [PubMed]
[8] Loibl, S., Poortmans, P. and Morrow, M. (2021) Breast Cancer. The Lancet (London, England), 397, 1750-1769. [Google Scholar] [CrossRef
[9] Early Breast Cancer Trialists’ Collaborative Group, et al. (2012) Comparisons between Different Polychemotherapy Regimens for Early Breast Cancer: Meta-Analyses of Long-Term Outcome among 100,000 Women in 123 Randomised Trials. The Lancet, 379, 432-444.
https://pubmed.ncbi.nlm.nih.gov/22152853/
[10] Blum, J.L., Flynn, P.J., Yothers, G., et al. (2023) Anthracyclines in Early Breast Cancer: The ABC Trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG On-cology). Journal of Clinical Oncology, 35, 2647-2655.
https://pubmed.ncbi.nlm.nih.gov/28398846/
[11] Nitz, U., Gluz, O. and Clemens, M. (2019) West German Study PlanB Trial: Adjuvant Four Cycles of Epirubicin and Cyclophos-phamide plus Docetaxel versus Six Cycles of Docetaxel and Cyclophosphamide in HER2-Negative Early Breast Cancer. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 37, 799-808. [Google Scholar] [CrossRef
[12] Poggio, F., Bruzzone, M. and Ceppi, M. (2018) Platinum-Based Neo-adjuvant Chemotherapy in Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis. Annals of Oncology: Official Journal of the European Society for Medical Oncology, 29, 1497-1508. [Google Scholar] [CrossRef] [PubMed]
[13] Von Minckwitz, G., Schneeweiss, A. and Loibl, S. (2014) Neoadju-vant Carboplatin in Patients with Triple-Negative and HER2-Positive Early Breast Cancer (GeparSixto; GBG 66): A Randomised Phase 2 Trial. The Lancet Oncology, 15, 747-756. [Google Scholar] [CrossRef
[14] Sikov, W.M., Berry, D.A. and Perou, C.M. (2015) Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic Complete Response Rates in Stage II to III Triple-Negative Breast Cancer: CALGB 40603 (Alliance). Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 33, 13-21.
[15] Zhu, Y., Hu, Y. and Tang, C. (2022) Platinum-Based Systematic Therapy in Triple-Negative Breast Cancer. Biochimica et Biophysica Acta. Reviews on Cancer, 1877, Article ID: 188678. [Google Scholar] [CrossRef] [PubMed]
[16] Wang, X.L., Chen, T., Li, C., et al. (2022) CircRNA-CREIT In-hibits Stress Granule Assembly and Overcomes Doxorubicin Resistance in TNBC by Destabilizing PKR. Journal of Hematology & Oncology, 15, 122.
https://pubmed.ncbi.nlm.nih.gov/36038948/
[17] Nedeljković, M. and Damjanović, A. (2019) Mechanisms of Chemotherapy Resistance in Triple-Negative Breast Cancer—How We Can Rise to the Challenge. Cells, 8, Article No. 957. [Google Scholar] [CrossRef] [PubMed]
[18] Sissung, T.M., Baum, C.E., Kirkland, C.T., et al. (2010) Phar-macogenetics of Membrane Transporters: An Update on Current Approaches. Molecular Biotechnology, 44, 152-167.
https://pubmed.ncbi.nlm.nih.gov/19950006/
[19] Sharom, F.J. (2008) ABC Multidrug Transporters: Structure, Function and Role in Chemoresistance. Pharmacogenomics, 9, 105-127. [Google Scholar] [CrossRef] [PubMed]
[20] Yamada, A., Ishikawa, T. and Ota, I. (2013) High Expression of ATP-Binding Cassette Transporter ABCC11 in Breast Tumors Is Associated with Aggressive Subtypes and Low Dis-ease-Free Survival. Breast Cancer Research and Treatment, 137, 773-782. [Google Scholar] [CrossRef] [PubMed]
[21] Guestini, F., Ono, K. and Miyashita, M. (2019) Impact of Topoi-somerase IIα, PTEN, ABCC1/MRP1, and KI67 on Triple-Negative Breast Cancer Patients Treated with Neoadjuvant Chemotherapy. Breast Cancer Research and Treatment, 173, 275-288. [Google Scholar] [CrossRef] [PubMed]
[22] Das, S., Samant, R.S. and Shevde, L.A. (2013) Nonclassical Ac-tivation of Hedgehog Signaling Enhances Multidrug Resistance and Makes Cancer Cells Refractory to Smooth-ened-Targeting Hedgehog Inhibition. The Journal of Biological Chemistry, 288, 11824-11833. [Google Scholar] [CrossRef
[23] Skoda, A.M., Simovic, D. and Karin, V. (2018) The Role of the Hedgehog Signaling Pathway in Cancer: A Comprehensive Review. Bosnian Journal of Basic Medical Sciences, 18, 8-20. [Google Scholar] [CrossRef] [PubMed]
[24] Harris, L.G., Pannell, L.K. and Singh, S. (2012) Increased Vascularity and Spontaneous Metastasis of Breast Cancer by Hedgehog Signaling Mediated Upregulation of cyr61. On-cogene, 31, 3370-3380. [Google Scholar] [CrossRef] [PubMed]
[25] Kwon, Y.-J., Hurst, D.R., Steg, A.D., et al. (2011) Gli1 Enhances Migration and Invasion via Up-Regulation of MMP-11 and Promotes Metastasis in ERα Negative Breast Cancer Cell Lines. Clinical & Experimental Metastasis, 28, 437-449.
https://pubmed.ncbi.nlm.nih.gov/21442356/
[26] Di Mauro, C., Rosa, R. and D’amato, V. (2017) Hedgehog Sig-nalling Pathway Orchestrates Angiogenesis in Triple-Negative Breast Cancers. British Journal of Cancer, 116, 1425-1435. [Google Scholar] [CrossRef] [PubMed]
[27] Shibata, M. and Hoque, M.O. (2019) Targeting Cancer Stem Cells: A Strategy for Effective Eradication of Cancer. Cancers, 11, Article No. 732. [Google Scholar] [CrossRef] [PubMed]
[28] Creighton, C.J., Li, X. and Landis, M. (2009) Residual Breast Can-cers after Conventional Therapy Display Mesenchymal as Well as Tumor-Initiating Features. Proceedings of the National Academy of Sciences of the United States of America, 106, 13820-13825. [Google Scholar] [CrossRef] [PubMed]
[29] Lee, H.E., Kim, J.H. and Kim, Y.J. (2011) An Increase in Cancer Stem Cell Population after Primary Systemic Therapy Is a Poor Prognostic Factor in Breast Cancer. British Journal of Cancer, 104, 1730-1738. [Google Scholar] [CrossRef] [PubMed]
[30] Park, S.Y., Lee, H.E., Li, H.L., et al. (2010) Heterogeneity for Stem Cell-Related Markers According to Tumor Subtype and Histologic Stage in Breast Cancer. Clinical Cancer Research, 16, 876-887.
https://pubmed.ncbi.nlm.nih.gov/20103682/
[31] Ma, F., Li, H.H., Wang, H.J., et al. (2014) Enriched CD44(+)/CD24(−) Population Drives the Aggressive Phenotypes Presented in Triple-Negative Breast Cancer (TNBC). Cancer Letters, 353, 153-159.
https://pubmed.ncbi.nlm.nih.gov/25130168/
[32] Zhou, S., Schuetz, J.D., Bunting, K.D., et al. (2001) The ABC Transporter Bcrp1/ABCG2 Is Expressed in a Wide Variety of Stem Cells and Is a Molecular Determinant of the Side-Population Phenotype. Nature Medicine, 7, 1028-1034.
https://pubmed.ncbi.nlm.nih.gov/11533706/
[33] Vaupel, P. (2008) Hypoxia and Aggressive Tumor Phenotype: Implications for Therapy and Prognosis. The Oncologist, 13, 21-26. [Google Scholar] [CrossRef
[34] Gerweck, L.E., Vijayappa, S. and Kozin, S. (2006) Tumor pH Controls the in Vivo Efficacy of Weak Acid and Base Chemotherapeutics. Molecular Cancer Therapeutics, 5, 1275-1279.
https://pubmed.ncbi.nlm.nih.gov/16731760/
[35] Cosse, J.P. and Michiels, C. (2008) Tumour Hypoxia Affects the Responsiveness of Cancer Cells to Chemotherapy and Promotes Cancer Progression. Anti-Cancer Agents in Medicinal Chemistry, 8, 790-797. [Google Scholar] [CrossRef] [PubMed]
[36] Kim, H., Lin, Q., Glazer, P.M. and Yun, Z. (2018) The Hy-poxic Tumor Microenvironment in Vivo Selects the Cancer Stem Cell Fate of Breast Cancer Cells. Breast Cancer Re-search, 20, 16.
https://pubmed.ncbi.nlm.nih.gov/29510720/
[37] Chouaib, S., Noman, M.Z. and Kosmatopoulos, K. (2017) Hypoxic Stress: Obstacles and Opportunities for Innovative Immunotherapy of Cancer. Oncogene, 36, 439-445. [Google Scholar] [CrossRef] [PubMed]
[38] Xiang, L., Liu, Z.-H., Huan, Q., et al. (2012) Hypox-ia-Inducible Factor-2a Is Associated with ABCG2 Expression, Histology-Grade and Ki67 Expression in Breast Invasive Ductal Carcinoma. Diagnostic Pathology, 7, 32.
https://pubmed.ncbi.nlm.nih.gov/22452996/
[39] Lv, Y., Zhao, S. and Han, J. (2015) Hypoxia-Inducible Factor-1α Induces Multidrug Resistance Protein in Colon Cancer. OncoTargets and Therapy, 8, 1941-1948. [Google Scholar] [CrossRef
[40] Daskalaki, I., Gkikas, I. and Tavernarakis, N. (2018) Hypoxia and Selec-tive Autophagy in Cancer Development and Therapy. Frontiers in Cell and Developmental Biology, 6, Article No. 104.
https://pubmed.ncbi.nlm.nih.gov/30250843/
[41] Livasy, C.A., Karaca, G. and Nanda, R. (2006) Phenotypic Eval-uation of the Basal-Like Subtype of Invasive Breast Carcinoma. Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc, 19, 264-271. [Google Scholar] [CrossRef] [PubMed]
[42] Tan, E.Y., Yan, M. and Campo, L. (2009) The Key Hypoxia Reg-ulated Gene CAIX Is Upregulated in Basal-Like Breast Tumours and Is Associated with Resistance to Chemotherapy. British Journal of Cancer, 100, 405-411. [Google Scholar] [CrossRef] [PubMed]
[43] Chen, X., Iliopoulos, D., Zhang, Q., et al. (2014) XBP1 Promotes Tri-ple-Negative Breast Cancer by Controlling the HIF1α Pathway. Nature, 508, 103-107.
https://pubmed.ncbi.nlm.nih.gov/24670641/
[44] Lei, J., Fan, L. and Wei, G. (2015) Gli-1 Is Crucial for Hypox-ia-Induced Epithelial-Mesenchymal Transition and Invasion of Breast Cancer. Tumour Biology: The Journal of the In-ternational Society for Oncodevelopmental Biology and Medicine, 36, 3119-3126. [Google Scholar] [CrossRef] [PubMed]
[45] Klionsky, D.J. and Emr, S.D. (2000) Autophagy as a Regulated Pathway of Cellular Degradation. Science (New York, N.Y.), 290, 1717-1721. [Google Scholar] [CrossRef] [PubMed]
[46] Chen, Y., Jia, Y. and Mao, M. (2021) PLAC8 Promotes Adriamycin Resistance via Blocking Autophagy in Breast Cancer. Journal of Cellular and Molecular Medicine, 25, 6948-6962. [Google Scholar] [CrossRef] [PubMed]
[47] Wang, L., Zhang, H. and Sun, M. (2015) High Mobility Group Box 1-Mediated Autophagy Promotes Neuroblastoma Cell Chemoresistance. Oncology Reports, 34, 2969-2976. [Google Scholar] [CrossRef] [PubMed]
[48] Yang, L., Yu, Y. and Kang, R. (2012) Up-Regulated Autophagy by En-dogenous High Mobility Group Box-1 Promotes Chemoresistance in Leukemia Cells. Leukemia & Lymphoma, 53, 315-322. [Google Scholar] [CrossRef] [PubMed]
[49] Zhao, Y., Meng, Q. and Gao, X. (2017) Down-Regulation of Mediator Complex Subunit 19 (Med19) Induces Apoptosis in Human Laryngocarcinoma HEp2 Cells in an Apaf-1-Dependent Pathway. American Journal of Translational Research, 9, 755-761.
[50] Liu, B., Qi, X. and Zhang, X. (2019) Med19 Is Involved in Chemoresistance by Mediating Autophagy through HMGB1 in Breast Cancer. Journal of Cellular Biochemistry, 120, 507-518. [Google Scholar] [CrossRef] [PubMed]
[51] Ng, L.F., Kaur, P. and Bunnag, N. (2019) WNT Signaling in Disease. Cells, 8, 826. [Google Scholar] [CrossRef] [PubMed]
[52] Duchartre, Y., Kim, Y.-M. and Kahn, M. (2016) The Wnt Signaling Pathway in Cancer. Critical Reviews in Oncology/Hematology, 99, 141-149.
https://pubmed.ncbi.nlm.nih.gov/26775730/
[53] Liu, S., Wang, Z. and Liu, Z. (2018) miR-221/222 Activate the Wnt/β-Catenin Signaling to Promote Triple-Negative Breast Cancer. Journal of Molecular Cell Biology, 10, 302-315. [Google Scholar] [CrossRef] [PubMed]
[54] Xu, J.H., Prosperi, J.R., Choudhury, N., et al. (2015) β-Catenin Is Re-quired for the Tumorigenic Behavior of Triple-Negative Breast Cancer Cells. PLOS ONE, 10, e0117097.
https://pubmed.ncbi.nlm.nih.gov/25658419/
[55] Vicens, Q. and Westhof, E. (2014) Biogenesis of Circular RNAs. Cell, 159, 13-14. [Google Scholar] [CrossRef] [PubMed]
[56] Chen, C., Zhou, Z. and Sheehan, C.E. (2009) Overexpression of WWP1 Is Associated with the Estrogen Receptor and Insulin-Like Growth Factor Receptor 1 in Breast Carcinoma. In-ternational Journal of Cancer, 124, 2829-2836. [Google Scholar] [CrossRef] [PubMed]
[57] Lee, Y.R., Chen, M. and Lee, J.D. (2019) Reactivation of PTEN Tumor Suppressor for Cancer Treatment through Inhibition of a MYC-WWP1 Inhibitory Pathway. Science (New York, N.Y.), 364, eaau0159.
[58] Nechiporuk, T., Fernandez, T.E. and Vasioukhin, V. (2007) Failure of Epithelial Tube Maintenance Causes Hydrocephalus and Renal Cysts in Dlg5-/-Mice. Developmental Cell, 13, 338-350.
https://pubmed.ncbi.nlm.nih.gov/17765678/
[59] Sarrió, D., Rodriguez-Pinilla, S.M., et al. (2008) Epitheli-al-Mesenchymal Transition in Breast Cancer Relates to the Basal-Like Phenotype. Cancer Research, 68, 989-997.
https://pubmed.ncbi.nlm.nih.gov/18281472/
[60] Liu, J., Li, J. and Li, P. (2017) Loss of DLG5 Promotes Breast Cancer Malignancy by Inhibiting the Hippo Signaling Pathway. Scientific Reports, 7, Article No. 42125. [Google Scholar] [CrossRef] [PubMed]
[61] Qiao, X., Roth, I. and Féraille, E. (2014) Different Effects of ZO-1, ZO-2 and ZO-3 Silencing on Kidney Collecting Duct Principal Cell Proliferation and Adhesion. Cell Cycle (Georgetown, Tex.), 13, 3059-3075. [Google Scholar] [CrossRef] [PubMed]
[62] Liu, J., Li, J. and Ren, Y. (2014) DLG5 in Cell Polarity Maintenance and Cancer Development. International Journal of Biological Sciences, 10, 543-549. [Google Scholar] [CrossRef] [PubMed]
[63] Caunt, C.J., Sale, M.J. and Smith, P.D. (2015) MEK1 and MEK2 Inhibitors and Cancer Therapy: The Long and Winding Road. Nature Reviews. Cancer, 15, 577-592. [Google Scholar] [CrossRef] [PubMed]
[64] Zhan, L., Rosenberg, A. and Bergami, K.C. (2008) Deregulation of Scribble Promotes Mammary Tumorigenesis and Reveals a Role for Cell Polarity in Carcinoma. Cell, 135, 865-878. [Google Scholar] [CrossRef] [PubMed]
[65] Martin-Belmonte, F. and Perez-Moreno, M. (2011) Epithelial Cell Polarity, Stem Cells and Cancer. Nature Reviews. Cancer, 12, 23-38. [Google Scholar] [CrossRef] [PubMed]
[66] Pan, D. (2010) The Hippo Signaling Pathway in Development and Cancer. Developmental Cell, 19, 491-505. [Google Scholar] [CrossRef] [PubMed]
[67] Zhao, B., Lei, Q.Y. and Guan, K.L. (2008) The Hippo-YAP Pathway: New Connections between Regulation of Organ Size and Cancer. Current Opinion in Cell Biology, 20, 638-646. [Google Scholar] [CrossRef] [PubMed]
[68] Grzeschik, N.A., Parsons, L.M. and Allott, M.L. (2010) Lgl, aPKC, and Crumbs Regulate the Salvador/Warts/Hippo Pathway through Two Distinct Mechanisms. Current Biol-ogy: CB, 20, 573-581. [Google Scholar] [CrossRef] [PubMed]
[69] Zhao, B., Wei, X.M., Li, W.Q., et al. (2007) Inactivation of YAP Oncoprotein by the Hippo Pathway Is Involved in Cell Contact Inhibition and Tissue Growth Control. Genes & Devel-opment, 21, 2747-2761.
https://pubmed.ncbi.nlm.nih.gov/17974916/
[70] Sezaki, T., Inada, K., Sogabe, T., et al. (2012) Role of Dlg5/lp-dlg, a Membrane-Associated Guanylate Kinase Family Protein, in Epithelial-Mesenchymal Transition in LLc-PK1 Renal Epithelial Cells. PLOS ONE, 7, e35519.
https://pubmed.ncbi.nlm.nih.gov/22539977/
[71] Neuzillet, C., Tijeras-Raballand, A. and Cohen, R. (2015) Tar-geting the TGFβ Pathway for Cancer Therapy. Pharmacology & Therapeutics, 147, 22-31. [Google Scholar] [CrossRef] [PubMed]
[72] Asiedu, M.K., Ingle, J.N. and Behrens, M.D. (2011) TGF-beta/TNF(alpha)-Mediated Epithelial-Mesenchymal Transition Generates Breast Cancer Stem Cells with a Claudin-Low Phenotype. Cancer Research, 71, 4707-4719. [Google Scholar] [CrossRef
[73] Brabletz, T., Kalluri, R. and Nieto, M.A. (2018) EMT in Cancer. Nature Reviews. Cancer, 18, 128-134. [Google Scholar] [CrossRef] [PubMed]
[74] Puisieux, A., Brabletz, T. and Caramel, J. (2014) Oncogenic Roles of EMT-Inducing Transcription Factors. Nature Cell Biology, 16, 488-494.
https://pubmed.ncbi.nlm.nih.gov/24875735/
[75] Lamouille, S., Xu, J. and Derynck, R. (2014) Molecular Mecha-nisms of Epithelial-Mesenchymal Transition. Nature Reviews. Molecular Cell Biology, 15, 178-196. [Google Scholar] [CrossRef] [PubMed]
[76] Chen, B., Yuan, Y. and Sun, L. (2020) MKL1 Mediates TGF-β Induced RhoJ Transcription to Promote Breast Cancer Cell Migration and Invasion. Frontiers in Cell and Developmental Biology, 8, Article No. 832. [Google Scholar] [CrossRef] [PubMed]