DOI QR코드

DOI QR Code

Co-Expression of Putative Cancer Stem Cell Markers, CD133 and Nestin, in Skin Tumors

  • Sabet, Mehrdad Nasrollahzadeh (Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences) ;
  • Rakhshan, Azadeh (Department of Pathology, Shohada-e-Tajrish Hospital, Shahid Beheshti University of Medical Sciences) ;
  • Erfani, Elham (Oncopathology Research Center, Iran University of Medical Sciences) ;
  • Madjd, Zahra (Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences)
  • Published : 2014.10.23

Abstract

Background: Cancer stem cells (CSC) are populations of cells responsible for tumor initiation, progression and therapeutic resistance in many cancers. In the present study, we aimed to investigate the expression pattern and clinical significance of two CSC markers, CD133 and Nestin, in a series of skin tumors. Materials and Methods: One hundred and thirteen paraffin blocks from skin cancers including 16 (14%) cases of melanoma, 37 (33%) of squamous cell cancer (SCC) and 60 (53%) of basal cell cancer (BCC) were collected and assembled in a tissue microarray (TMA). The samples were immunohistochemically examined for the expression of CD133 and Nestin. Expression of these markers was also correlated with clinicopathological parameters. Results: A significant difference was observed in the expression of CD133 and Nestin in melanomas, SCC and BCC (p value=0.001). Furthermore, the level of expression was significantly higher in the melanomas compared to the SCC and BCC tumors. Expression of CD133 in the melanoma was significantly associated with increased tumor invasiveness (p value=0.05), a higher rate of metastasis (p value=0.04) and the presence of ulceration (p value=0.02). Increased expression of Nestin was observed in metastatic melanoma (p value=0.04), while no statistically significant correlation was found with other clinicopathological parameters including Breslow thickness, Clark level and ulceration. Conclusions: Elevated expression levels of CD133 and Nestin in the melanomas are associated with advanced disease, with more aggressive and metastatic skin tumors. Therefore, these markers could be potential therapeutic targets for malignant tumors of the skin.

Keywords

Cancer stem cells;melanoma;SCC;BCC;CD133;Nestin

Acknowledgement

Supported by : Iran University of Medical Sciences

References

  1. Andrade P, Brites MM, Vieira R, et al (2012). Epidemiology of basal cell carcinomas and squamous cell carcinomas in a Department of Dermatology: a 5 year review. An Bras Dermatol, 87, 212-19. https://doi.org/10.1590/S0365-05962012000200004
  2. Abbas O, Bhawan J (2011). Expression of stem cell markers Nestin and cytokeratin 15 and 19 in cutaneous malignancies. J Eur Acad Dermatol Venereol, 25, 311-16. https://doi.org/10.1111/j.1468-3083.2010.03791.x
  3. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al (2003). Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA, 100, 3983-88. https://doi.org/10.1073/pnas.0530291100
  4. Al Dhaybi R, Sartelet H, Powell J, et al (2010). Expression of CD133+ cancer stem cells in childhood malignant melanoma and its correlation with metastasis. Mod Pathol, 23, 376-80. https://doi.org/10.1038/modpathol.2009.163
  5. Boiko AD, Razorenova OV, van de Rijn M, et al (2010). Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature, 466, 133-7. https://doi.org/10.1038/nature09161
  6. Bapat SA, Mali AM, Koppikar CB, et al (2005). Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res, 65, 3025-9.
  7. Belicchi M, Pisati F, Lopa R, et al (2004). Human skin-derived stem cells migrate throughout forebrain and differentiate into astrocytes after injection into adult mouse brain. J Neurosci Res, 77, 475-86. https://doi.org/10.1002/jnr.20151
  8. Blackwood MA, Holmes R, Synnestvedt M , et al (2002). Multiple primary melanoma revisited. Cancer, 94, 2248-55. https://doi.org/10.1002/cncr.10454
  9. Bongiorno MR, Doukaki S, Malleo F, et al (2008). Identification of progenitor cancer stem cell in lentigo maligna melanoma. Dermatol Ther, 21, 1-5. https://doi.org/10.1111/j.1529-8019.2008.00162.x
  10. Bonnet D, Dick JE (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med, 3,730-7. https://doi.org/10.1038/nm0797-730
  11. Civenni G, Walter A, Kobert N, et al (2011). Human CD271-positive melanoma stem cells associated with metastasis establish tumor heterogeneity and long-term growth. Cancer Res, 71, 3098-109. https://doi.org/10.1158/0008-5472.CAN-10-3997
  12. Clarke MF, Dick JE, Dirks PB, et al (2006). Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res, 66, 9339-344. https://doi.org/10.1158/0008-5472.CAN-06-3126
  13. Clarke MF, Fuller M (2006). Stem cells and cancer: two faces of eve. Cell, 124, 1111-15. https://doi.org/10.1016/j.cell.2006.03.011
  14. Collins AT, Berry PA, Hyde C, et al (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res, 65, 10946-951. https://doi.org/10.1158/0008-5472.CAN-05-2018
  15. Florenes VA, Holm R, Myklebost O, et al (1994). Expression of the neuroectodermal intermediate filament Nestin in human melanomas. Cancer Res, 54, 354-6.
  16. Dahlstrand J, Zimmerman LB, McKay RD, et al (1992). Characterization of the human Nestin gene reveals a close evolutionary relationship to neurofilaments. J Cell Sci, 103, 589-97.
  17. Fang D, Nguyen TK, Leishear K, et al (2005). A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res, 65, 9328-37. https://doi.org/10.1158/0008-5472.CAN-05-1343
  18. Fernandez-Figueras MT, Ariza A, Calatrava A, et al. (1996). CD44 and melanocytic tumors: a possible role for standard CD44 in the epidermotropic spread of melanoma. J Cutan Pathol, 23, 133-9. https://doi.org/10.1111/j.1600-0560.1996.tb01286.x
  19. Frank NY, Margaryan A, Huang Y, et al (2005). ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res, 65, 4320-33. https://doi.org/10.1158/0008-5472.CAN-04-3327
  20. Frank NY, Pendse SS, Lapchak PH, et al (2003). Regulation of progenitor cell fusion by ABCB5 P-glycoprotein, a novel human ATP-binding cassette transporter. J Biol Chem, 278, 47156-65. https://doi.org/10.1074/jbc.M308700200
  21. Fusi A, Reichelt U, Busse A, et al (2011). Expression of the stem cell markers Nestin and CD133 on circulating melanoma cells. J Invest Dermatol, 131, 487-94. https://doi.org/10.1038/jid.2010.285
  22. Gajda M, Kaminska-winciorek G (2014). Do not let to be late: overview of reasons for melanoma delayed diagnosis. Asian Pac J Cancer Prev, 15, 3873-7. https://doi.org/10.7314/APJCP.2014.15.9.3873
  23. Gyrylova SN, Aksenenko MB, Gavrilyuk DV, et al (2014). Melanoma incidence mortality rates and clinico-pathological types in the Siberian area of the Russian Federation. Asian Pac J Cancer Prev, 15, 2201-4. https://doi.org/10.7314/APJCP.2014.15.5.2201
  24. Hamburger A W, Salmon SE (1977). Primary bioassay of human tumor stem cells. Science, 197, 461-3. https://doi.org/10.1126/science.560061
  25. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90. https://doi.org/10.3322/caac.20107
  26. Hemmati HD, Nakano I, Lazareff JA, et al (2003). Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA, 100, 15178-183. https://doi.org/10.1073/pnas.2036535100
  27. Houghton J, Stoicov C, Nomura S, et al (2004). Gastric cancer originating from bone marrow-derived cells. Science, 306, 1568-71. https://doi.org/10.1126/science.1099513
  28. Ishiwata T, Matsuda Y, Naito Z (2011). Nestin in gastrointestinal and other cancers: effects on cells and tumor angiogenesis. World J Gastroenterol, 17, 409-18. https://doi.org/10.3748/wjg.v17.i4.409
  29. Keshet G I, Goldstein I, Itzhaki O, et al (2008). MDR1 expression identifies human melanoma stem cells. Biochem Biophys Res Commun, 368, 930-6. https://doi.org/10.1016/j.bbrc.2008.02.022
  30. Kim CF, Jackson EL, Woolfenden AE, et al (2005). Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell, 121, 823-35. https://doi.org/10.1016/j.cell.2005.03.032
  31. Klein wm, Wu BP, Zhao S, et al (2006). Increased expression of stem cell markers in malignant melanoma. Mod Pathol, 20, 102-7.
  32. Kononen J, Bubendorf L, Kallioniemi A, et al (1998). Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med, 4, 844-7. https://doi.org/10.1038/nm0798-844
  33. La Porta CA, Zapperi S (2013). Human breast and melanoma cancer stem cells biomarkers. Cancer Lett, 338, 69-73 https://doi.org/10.1016/j.canlet.2012.03.017
  34. Ladstein RG, Bachmann IM, Straume Om, et al (2014). Nestin expression is associated with aggressive cutaneous melanoma of the nodular type. Mod Pathol, 27, 396-401.
  35. Laga AC, Zhan Q, Weishaupt C, et al (2011). SOX2 and Nestin expression in human melanoma: an immunohistochemical and experimental study. Exp Dermatol, 20, 339-45. https://doi.org/10.1111/j.1600-0625.2011.01247.x
  36. Madjd Z, Karimi A, Molanae S, et al (2011). BRCA1 protein expression level and CD44 (+) phenotype in breast cancer patients. Cell Journal, 13, 155-62.
  37. Leiter U, Garbe C (2008). Epidemiology of melanoma and nonmelanoma skin cancer--the role of sunlight. Adv Exp Med Biol, 624, 89-103. https://doi.org/10.1007/978-0-387-77574-6_8
  38. Lendahl U, Zimmerman LB, McKay RD (1990). CNS stem cells express a new class of intermediate filament protein. Cell, 60, 585-95. https://doi.org/10.1016/0092-8674(90)90662-X
  39. Li JC, Liu D, Yang Y, et al (2013). Growth, clonability, and radiation resistance of esophageal carcinoma-derived stemlike cells. Asian Pac J Cancer Prev: APJCP, 14, 4891-6. https://doi.org/10.7314/APJCP.2013.14.8.4891
  40. Mehrazma M, Madjd Z, Kalantari E, et al (2013). Expression of stem cell markers, CD133 and CD44, in pediatric solid tumors: a study using tissue microarray. Fetal Pediatr Pathol, 32, 192-204. https://doi.org/10.3109/15513815.2012.701266
  41. Mohsenzadegan M, Madjd Z, Asgari M, et al (2013). Reduced expression of NGEP is associated with high-grade prostate cancers: a tissue microarray analysis. Cancer Immunol Immunother, 62, 1609-18. https://doi.org/10.1007/s00262-013-1463-1
  42. Monzani E, Facchetti F, Galmozzi E, et al (2007). Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential. Eur J Cancer, 43, 935-46. https://doi.org/10.1016/j.ejca.2007.01.017
  43. Mueller DW, Bosserhoff AK (2009). Role of miRNAs in the progression of malignant melanoma. Br J Cancer, 101, 551-6. https://doi.org/10.1038/sj.bjc.6605204
  44. Passegue E, Jamieson CH, Ailles LE, et al (2003). Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci USA, 100, 11842-9. https://doi.org/10.1073/pnas.2034201100
  45. Patel M, Lu L, Zande DS, et al (2008). ALDH1A1 and ALDH3A1 expression in lung cancers: correlation with histologic type and potential precursors. Lung Cancer, 59, 340-9. https://doi.org/10.1016/j.lungcan.2007.08.033
  46. Quintana E, Shackleton M, Foster Hannah R, et al (2010). Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell, 18, 510-23. https://doi.org/10.1016/j.ccr.2010.10.012
  47. Piras F, Perra MT, Murtas D, et al (2010). The stem cell marker Nestin predicts poor prognosis in human melanoma. Oncol Rep, 23, 17-24.
  48. Ponti D, Costa A, Zaffaroni N, et al (2005). Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res, 65, 5506-11. https://doi.org/10.1158/0008-5472.CAN-05-0626
  49. Porta C (2009). Cancer stem cells: lessons from melanoma. Stem Cell Reviews Reports, 5, 61-5. https://doi.org/10.1007/s12015-008-9048-7
  50. Rajabpour FV, Raoofian R, Youssefian L, et al (2014). BMI1 and TWIST1 downregulated mRNA expression in basal cell carcinoma. Asian Pac J Cancer Prev, 15, 3797-800. https://doi.org/10.7314/APJCP.2014.15.8.3797
  51. Rangwala F, Omenetti A, Diehl AM (2011). Cancer stem cells: repair gone awry? J Oncol, 2011, 465343
  52. Rappa G, Fodstad O, Lorico A (2008). The stem cell-associated antigen CD133 (Prominin-1) is a molecular therapeutic target for metastatic melanoma. STEM CELLS, 26, 3008-17. https://doi.org/10.1634/stemcells.2008-0601
  53. Reya T, Morrison SJ, Clarke MF, et al (2001). Stem cells, cancer, and cancer stem cells. Nature, 414, 105-11. https://doi.org/10.1038/35102167
  54. Satpute PS, Hazarey V, Ahmed R, et al (2013). Cancer stem cells in head and neck squamous cell carcinoma: A review. Asian Pac J Cancer Prev, 14, 5579-87. https://doi.org/10.7314/APJCP.2013.14.10.5579
  55. Schatton T, Murphy GF, Frank NY, et al (2008). Identification of cells initiating human melanomas. Nature, 451, 345-9. https://doi.org/10.1038/nature06489
  56. Semnani V , Toussy JA, Soltany S , et al (2008). Epidemiologic pattern of skin malignancies in semnan, Iran between 1999 and 2007 and comparing it with meta-analysis of published papers in world between 2000 and 2008.
  57. Siclari VA, Qin L (2010). Targeting the osteosarcoma cancer stem cell. J Orthop Surg Res, 5, 78. https://doi.org/10.1186/1749-799X-5-78
  58. Shakhova O, Sommer L (2013). Testing the cancer stem cell hypothesis in melanoma: The clinics will tell. Cancer Lett, 338, 74-81. https://doi.org/10.1016/j.canlet.2012.10.009
  59. Sharma BK, Manglik V, Elias E George (2010). Immunoexpression of human melanoma stem cell markers in tissues at different stages of the disease. J Surg Res, 163, 11-15. https://doi.org/10.1016/j.jss.2010.03.043
  60. Shmelkov SV, St Clair R, Lyden D, et al (2005). AC133/CD133/Prominin-1. Int J Biochem Cell Biol, 37, 715-19. https://doi.org/10.1016/j.biocel.2004.08.010
  61. Singh SK, Clarke ID, Terasaki M, et al (2003). Identification of a cancer stem cell in human brain tumors. Cancer Res, 63, 5821-8.
  62. Tanabe K, Amoh Y, Kanoh M, et al (2010). Prognostic significance of the hair follicle stem cell marker Nestin in patients with malignant melanoma. Eur J Dermatol, 20, 283-8.
  63. Thill M, Berna MJ, Grierson R, et al (2011). Expression of CD133 and other putative stem cell markers in uveal melanoma. Melanoma Res, 21, 405-16. https://doi.org/10.1097/CMR.0b013e328348db10
  64. Tohyama T, Lee VM, Rorke LB, et al (1992). Nestin expression in embryonic human neuroepithelium and in human neuroepithelial tumor cells. Lab Invest, 66, 303-13.
  65. Wang Q, Chen ZG, Du CZ, et al (2009). Cancer stem cell marker CD133+ tumour cells and clinical outcome in rectal cancer. Histopathology, 55, 284-93. https://doi.org/10.1111/j.1365-2559.2009.03378.x

Cited by

  1. Nestin as a marker of cancer stem cells vol.106, pp.7, 2015, https://doi.org/10.1111/cas.12691
  2. Correlation of Overexpression of Nestin with Expression of Epithelial-Mesenchymal Transition-Related Proteins in Gastric Adenocarcinoma vol.16, pp.7, 2015, https://doi.org/10.7314/APJCP.2015.16.7.2777
  3. Emerging Roles of Krüppel-Like Factor 4 in Cancer and Cancer Stem Cells vol.16, pp.9, 2015, https://doi.org/10.7314/APJCP.2015.16.9.3629
  4. Current approaches in identification and isolation of human renal cell carcinoma cancer stem cells vol.6, pp.1, 2015, https://doi.org/10.1186/s13287-015-0177-z
  5. Cancer stem cell research in Iran: potentials and challenges vol.13, pp.20, 2017, https://doi.org/10.2217/fon-2017-0091
  6. The footprint of the ageing stroma in older patients with breast cancer vol.19, pp.1, 2017, https://doi.org/10.1186/s13058-017-0871-0
  7. Co-Expression of Putative Cancer Stem Cell Markers CD44 and CD133 in Prostate Carcinomas vol.23, pp.4, 2017, https://doi.org/10.1007/s12253-016-0169-z
  8. The role of cancer stem cells in tumor heterogeneity and resistance to therapy vol.95, pp.1, 2017, https://doi.org/10.1139/cjpp-2016-0079
  9. D10 melanoma cells vol.11, pp.17, 2015, https://doi.org/10.2217/fon.15.174
  10. Comparative Expression Analysis of Putative Cancer Stem Cell Markers CD44 and ALDH1A1 in Various Skin Cancer Subtypes vol.31, pp.1, 2016, https://doi.org/10.5301/jbm.5000165
  11. Expression of CD133 Cancer Stem Cell Marker in Melanoma: A Systematic Review and Meta-Analysis vol.31, pp.2, 2016, https://doi.org/10.5301/jbm.5000209
  12. Nestin expression in primary and metastatic uveal melanoma - possible biomarker for high-risk uveal melanoma vol.96, pp.5, 2018, https://doi.org/10.1111/aos.13645