Volume 7, Issue 3, September 2019, Page: 62-68
Prognostic Value of Tumor Stem Cells and Anaplastic Lymphoma Kinase Expression in Patients with Primary Cutaneous Melanoma
Titov Konstantin Sergeevich, Department of Surgical Treatment of Tumors of the Skin and Soft Tissues, Medical Faculty, Moscow Clinical Scientific Center Named After A. S. Loginova, Moscow, Russia.
Kazakov Alexey Mikhailovich, Chemotherapy Department No. 1, Faculty of Clinical Oncology N. N. Trapeznikov, Federal State Budgetary Institution «N. N. Blokhin National Medical Research Center of Oncology» оf the Ministry of Health of the Russian Federation, Moscow, Russia
Baryshnikova Maria Anatolievna, Chemotherapy Department No. 1, Faculty of Clinical Oncology N. N. Trapeznikov, Federal State Budgetary Institution «N. N. Blokhin National Medical Research Center of Oncology» оf the Ministry of Health of the Russian Federation, Moscow, Russia
Zaryanov Dmitry Albertovich, Department of Surgical Treatment of Tumors of the Skin and Soft Tissues, Medical Faculty, Moscow Clinical Scientific Center Named After A. S. Loginova, Moscow, Russia.
Ryabchikov Denis Anatolyevich, Chemotherapy Department No. 1, Faculty of Clinical Oncology N. N. Trapeznikov, Federal State Budgetary Institution «N. N. Blokhin National Medical Research Center of Oncology» оf the Ministry of Health of the Russian Federation, Moscow, Russia
Received: Sep. 16, 2019;       Accepted: Oct. 7, 2019;       Published: Oct. 20, 2019
DOI: 10.11648/j.jctr.20190703.13      View  355      Downloads  81
Abstract
Melanoma is the most aggressive cutaneous neoplasm. Cancer stem cells (CSCs) may be one of the reasons for the low sensitivity of melanoma to chemotherapy, the short curative effect and the development of resistance to the targeted therapy, as well as the lack of efficiency of immune checkpoint inhibitors and disease relapses. The aim of our the study was to determine the influence of the expression of stem cells markers (АВСВ5 и CD133) and tyrosine kinases of mutated Anaplastic Lymphoma Kinase (ALK) genes found in primary tumors on survival of patients with stage I-II cutaneous melanomas. Materials of 48 patients with melanoma were used, and their morphological parameters (tumor thickness, invasion level, lymphoid infiltration) were assessed. The expression of CSCs markers, mutant kinases was determined using the immunohistochemical method. The statistical significance of the influence of the parameters studied on the overall (OS) and 2-year relapse-free (RFS) survival was assessed by calculating the correlation coefficient using the rank method. Stem cell markers were found in 25 (52%) of 48 patients with cutaneous melanomas. ABCB5 was expressed in 20 (54%), CD133 was expressed in 17 (46%) patients. The co-expression of both markers was observed in 12 patients (32%). The 2-year OS in the group with CSC markers expressed (first group) was 76%, whereas in the group w/o such markers expressed (second group), the OS was 91.31%. The rates of RFS also differed between the two groups: in the first, RFS was 80%, and in the second one, it reached 91.31%. CD133 marker was found in 80% of the first group patients with metastases and relapses. A strong correlation was found between the increase percentage of cells expressing CD133 and the increase invasion level. (P=0.879 ±0.107). A strong correlation was found between the increase percentage of cells expressing ABCB5 and the increase tumor thickness. (P=0.943 ±0.088). The expression of mutant ALK was found in 28% of patients with CSC markers detected, and no statistically significant correlation between the prognosis and the presence of ALK was found. ABCB5 and CD133+ are promising markers of tumor stem cells applicable to predicting the clinical course of primary cutaneous melanomas. A correlation between АВСВ5 and CD133 markers and a number of morphological parameters shows the importance of their study for understanding the fundamental mechanisms of melanoma carcinogenesis. The inhibition of ABCB5 and CD133+ markers and mutant ALK may serve as a target for the therapy for melanoma in perspective.
Keywords
Tumor Stem Cell, ABCB5, CD133, ALK, Lymphoid Infiltration, 2-Year Survival
To cite this article
Titov Konstantin Sergeevich, Kazakov Alexey Mikhailovich, Baryshnikova Maria Anatolievna, Zaryanov Dmitry Albertovich, Ryabchikov Denis Anatolyevich, Prognostic Value of Tumor Stem Cells and Anaplastic Lymphoma Kinase Expression in Patients with Primary Cutaneous Melanoma, Journal of Cancer Treatment and Research. Vol. 7, No. 3, 2019, pp. 62-68. doi: 10.11648/j.jctr.20190703.13
Copyright
Copyright © 2019 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Reference
[1]
Valko-Rokytovska M, Bruchata K, Simkova J, etc. Current trends in the treatment of malignant melanoma. Neoplasma. 2016; 63 (3): 333-41. doi: 10.4149/301_151015N533.
[2]
Beatriz Domingues, José Manuel Lopes, Paula Soares, etc. Melanoma treatment in review. Published online 2018 Jun 7. doi: 10.2147/ITT.S134842.
[3]
Nicholas Nguyen, Kasey L Couts, Yuchun Luo, etc. Understanding melanoma stem cells. Melanoma Manag. 2015 May; 2 (2): 179–188. Published online 2015 May 18. doi: 10.2217/mmt.15.4.
[4]
Hartman ML, Czyz M. MITF in melanoma: mechanisms behind its expression and activity. Cell Mol Life Sci 2015; 72: 1249–60. doi: 10.1007/s00018-014-1791-0.
[5]
Chatterjee A, Stockwell PA, Ahn A, etc. Genome-wide methylation sequencing of paired primary and metastatic cell lines identifies common DNA methylation changes and a role for EBF3 as a candidate epigenetic driver of melanoma metastasis. Oncotarget 2016; 8: 6085–101. doi: 10.18632/oncotarget.14042.
[6]
Busam KJ, Villain RE, Lum T, et al.: Primary and Metastatic Cutaneous Melanomas Express ALK Through Alternative Transcriptional Initiation. Am J Surg Pathol. 2016; 40 (6): 786–95. DOI: 10.1097/PAS.0000000000000611.
[7]
K. S. Titov, D. L. Rotin, A. M. Kazakov etc. The Frequency of Expression of Tyrosine Kinase of ALK Gene and TAG-72 Oncoprotein in Primary Cutaneous Melanoma. Russian Journal of Biotherapy. 2018. 3. 50-54. DOI: 10.17650/1726-9784-2018-17-3-50-54.
[8]
Giorgio Parmiani. Melanoma Cancer Stem Cells: Markers and Functions. Cancers (Basel). 2016 Mar; 8 (3): 34. Published online 2016 Mar 11. doi: 10.3390/cancers8030034.
[9]
Setia N, Abbas O, Sousa Y, Garb JL, Mahalingam M. Profiling of ABC transporters ABCB5, ABCF2 and nestin-positive stem cells in nevi, in situ and invasive melanoma. Mod Pathol. 2012; 25: 1169–75. DOI: 10.1038/modpathol.2012.71.
[10]
Brian J. Wilson, Karim R. Saab, Jie Ma, etc. ABCB5 maintains melanoma-initiating cells through a pro-inflammatory cytokine signaling circuit. Cancer Res. 2014 Aug 1; 74 (15): 4196–4207. Published online 2014 Jun 16. doi: 10.1158/0008-5472.CAN-14-0582.
[11]
Frank NY, Margaryan A, Huang Y, Schatton T, etc. ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res. 2005 May 15; 65 (10): 4320-33. DOI: 10.1158/0008-5472.CAN-04-3327.
[12]
Roesch A, Fukunaga-Kalabis M, Schmidt EC, etc. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell. 2010 May 14; 141 (4): 583-94. doi: 10.1016/j.cell.2010.04.020.
[13]
Murphy GF, Wilson BJ, Girouard SD, Frank NY, Frank MH. Stem cells and targeted approaches to melanoma cure. Mol Aspects Med. 2013 doi: 10.1016/j.mam.2013.10.003. Epub 2013 Oct 19.
[14]
Antonio Ahn, Aniruddha Chatterjee and Michael R. Eccles. The Slow Cycling Phenotype: A Growing Problem for Treatment Resistance in Melanoma. Molecular cancer Therapeutics. Published June 2017 DOI: 10.1158/1535-7163.MCT-16-0535.
[15]
M Perego, M Maurer, J X Wang, etc. A slow-cycling subpopulation of melanoma cells with highly invasive properties. Oncogene volume 37, pages 302–312 (18 January 2018). DOI: https://doi.org/10.1038/onc.2017.341
[16]
Luo Y, Ellis LZ, Dallaglio K, et al. Side Population Cells from Human Melanoma Tumors Reveal Diverse Mechanisms for Chemoresistance. The Journal of investigative dermatology. 2012. doi: 10.1038/jid.2012.161. Epub 2012 May 24.
[17]
Zhong Li. CD133: a stem cell biomarker and beyond. Exp Hematol Oncol. 2013; 2: 17. Published online 2013 Jul 1. doi: 10.1186/2162-3619-2-17.
[18]
Zhang M, Liu Y, Feng H, Bian X, Zhao W, Yang Z, Gu B, Li Z. CD133 Affects the Invasive Ability of HCT116 Cells by Regulating TIMP-2. Am J Pathol. 2013; 182 (2): 565–576. doi: 10.1016/j.ajpath.2012.10.015.
[19]
Chiou-Yan Lai, Brian E. Schwartz, and Mei-Yu Hsu. CD133+ Melanoma Subpopulations Contribute to Perivascular Niche Morphogenesis and Tumorigenicity through Vasculogenic Mimicry. Cancer Res. 2012 Oct 1; 72 (19): 5111–5118. Published online 2012 Aug 3. doi: 10.1158/0008-5472.CAN-12-0624.
[20]
Yashwant m. deo, Tibor keler. Bispecific molecules directed to tumor associated glycoprotein-72 and fc receptor. 1997.
[21]
Alamodi AA, Eshaq AM, Hassan SY, etc. Cancer stem cell as therapeutic target for melanoma treatment. Histol Histopathol. 2016 Dec; 31 (12): 1291-301. doi: 10.14670/HH-11-791.
[22]
Zahra Madjd, MD, PhD, Elham Erfani, Elmira Gheytanchi, et all. Expression of CD133 Cancer Stem Cell Marker in Melanoma: A Systematic Review and Meta-Analysis doi: https://doi.org/10.5301/jbm.5000209.
[23]
Lai CY, Schwartz BE, Hsu MY. CD133+ melanoma subpopulations contribute to perivascular niche morphogenesis and tumorigenicity through vasculogenic mimicry. Cancer Res. 2012 Oct 1; 72 (19): 5111-8. doi: 10.1158/0008-5472.CAN-12-0624. Epub 2012 Aug 3.
[24]
Klein WM, Wu BP, Zhao S, et all. Increased expression of stem cell markers in malignant melanoma. Mod Pathol. 2007 Jan; 20 (1): 102-7. Epub 2006 Nov 24. DOI: 10.1038/modpathol.3800720.
[25]
Radoslav Janostiak, Parmanand Malvi, and Narendra Wajapeyee. Anaplastic Lymphoma Kinase Confers Resistance to BRAF Kinase Inhibitors in Melanoma. iScience. 2019 Jun 28; 16: 453–467. Published online 2019 Jun 8. doi: 10.1016/j.isci.2019.06.001.
Browse journals by subject