Skip to main content

Advertisement

SpringerLink
Log in

Clinical significance of CD166 and HER-2 in different types of gastric cancer

  • RESEARCH ARTICLE
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Introduction

Cluster of differentiation 166 (CD166), a cancer stem cell (CSC) marker, and human epidermal growth factor receptor 2 (HER-2) are expressed in a diversity of malignancies and is associated with tumor progression. Although studies regarding the importance of CSC markers and HER-2 in gastric cancer (GC) have rapidly developed, their clinicopathological, prognosis, and diagnosis value still remain unsatisfying in GC. Therefore, the present study aims to investigate the clinical, prognostic, and diagnostic significance of CD166 and HER-2 in different histological types of GC.

Materials and methods

Bioinformatic analysis was applied to determine the clinical importance of CD166 and HER-2 expression based on their tissue localization in primary GC tumors and the normal adjacent samples. The expression patterns, clinical significance, prognosis, and diagnosis value of CD166 and HER-2 proteins in tissue microarrays (TMAs) of 206 GC samples, including Signet Ring Cell (SRC) and intestinal types and also 28 adjacent normal tissues were evaluated using immunohistochemistry (IHC).

Results

The results indicated that the expression of CD166 (membranous and cytoplasmic) and HER-2 were significantly up-regulated in tumor cells compared to adjacent normal tissues (P = 0.010, P < 0.001, and P = 0.011, respectively). A statistically significant association was detected between a high level of membranous expression of CD166 and lymphovascular invasion (P = 0.006); We also observed a statistically significant association between high cytoplasmic expression of CD166 protein and more invasion of the subserosa (P = 0.040) in the SRC type. In contrast, there was no correlation between the expression of HER-2 and clinicopathologic characteristics. Both CD166 and HER-2 showed reasonable accuracy and high specificity as diagnostic markers.

Conclusion

Our results confirmed that increased membranous and cytoplasmic expression of CD166 showed clinical significance in the SRC type and is associated with the progression of the disease and more aggressive tumor behaviors. These findings can be used to assist in designating subgroups of patients that require different follow-up strategies, and also, they might be utilized as the prognostic or diagnostic biomarkers in these types of GC for prospective clinical application.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

The analyzed data during the current study are available from the corresponding author on reasonable request.

References

  1. Chandra R, Balachandar N, Wang S, Reznik S, Zeh H, Porembka M. The changing face of gastric cancer: epidemiologic trends and advances in novel therapies. Cancer Gene Ther. 2021;28(5):390–9.

    Article  CAS  PubMed  Google Scholar 

  2. Arnold M, Abnet CC, Neale RE, Vignat J, Giovannucci EL, McGlynn KA, et al. Global Burden of 5 Major Types of Gastrointestinal Cancer. Gastroenterology. 2020;159(1):335-49.e15.

    Article  PubMed  Google Scholar 

  3. Surveillance E (2021) Cancer Stat Facts: Stomach Cancer. https://seer.cancer.gov/statfacts/html/stomach.html

  4. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48.

    Article  PubMed  Google Scholar 

  5. Waldum HL, Fossmark R. Types of gastric carcinomas. Int J Mol Sci. 2018;19(12):4109.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Berlth F, Bollschweiler E, Drebber U, Hoelscher AH, Moenig S. Pathohistological classification systems in gastric cancer: diagnostic relevance and prognostic value. World J Gastroenterol. 2014;20(19):5679–84.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Henson DE, Dittus C, Younes M, Nguyen H, Albores-Saavedra J. Differential trends in the intestinal and diffuse types of gastric carcinoma in the United States, 1973–2000: increase in the signet ring cell type. Arch Pathol Lab Med. 2004;128(7):765–70.

    Article  PubMed  Google Scholar 

  8. Thrift AP, El-Serag HB. Burden of Gastric Cancer. Clin Gastroenterol Hepatol. 2020;18(3):534–42.

    Article  PubMed  Google Scholar 

  9. Johnston FM, Beckman M. Updates on Management of Gastric Cancer. Curr Oncol Rep. 2019;21(8):67.

    Article  PubMed  Google Scholar 

  10. Matsuoka T, Yashiro M. Biomarkers of gastric cancer: Current topics and future perspective. World J Gastroenterol. 2018;24(26):2818–32.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Yan M, Yang X, Wang L, Clark D, Zuo H, Ye D, et al. Plasma membrane proteomics of tumor spheres identify CD166 as a novel marker for cancer stem-like cells in head and neck squamous cell carcinoma. Mol Cell Proteomics. 2013;12(11):3271–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253–61.

    Article  CAS  PubMed  Google Scholar 

  13. Hashemi F, Razmi M, Tajik F, Zöller M, Dehghan Manshadi M, Mahdavinezhad F, et al. Efficacy of whole cancer stem cell-based vaccines: a systematic review of preclinical and clinical studies. Stem Cells. 2022. https://doi.org/10.1093/stmcls/sxac089.

    Article  Google Scholar 

  14. Darvishi B, Boroumandieh S, Majidzadeh AK, Salehi M, Jafari F, Farahmand L. The role of activated leukocyte cell adhesion molecule (ALCAM) in cancer progression, invasion, metastasis and recurrence: a novel cancer stem cell marker and tumor-specific prognostic marker. Exp Mol Pathol. 2020;115:104443.

    Article  CAS  PubMed  Google Scholar 

  15. van Kempen LC, Nelissen JM, Degen WG, Torensma R, Weidle UH, Bloemers HP, et al. Molecular basis for the homophilic activated leukocyte cell adhesion molecule (ALCAM)-ALCAM interaction. J Biol Chem. 2001;276(28):25783–90.

    Article  PubMed  Google Scholar 

  16. von Lersner A, Droesen L, Zijlstra A. Modulation of cell adhesion and migration through regulation of the immunoglobulin superfamily member ALCAM/CD166. Clin Exp Metastasis. 2019;36(2):87–95.

    Article  Google Scholar 

  17. Weidle UH, Eggle D, Klostermann S, Swart GWM. ALCAM/CD166: Cancer-related Issues. Cancer Genomics - Proteomics. 2010;7(5):231.

    CAS  PubMed  Google Scholar 

  18. Ferragut F, Vachetta VS, Troncoso MF, Rabinovich GA, Elola MT. ALCAM/CD166: A pleiotropic mediator of cell adhesion, stemness and cancer progression. Cytokine Growth Factor Rev. 2021;61:27–37.

    Article  CAS  PubMed  Google Scholar 

  19. Chen X, Liang R, Lin H, Chen K, Chen L, Tian G, et al. CD166 promotes cancer stem cell-like phenotype via the EGFR/ERK1/2 pathway in the nasopharyngeal carcinoma cell line CNE-2R. Life Sci. 2021;267: 118983.

    Article  CAS  PubMed  Google Scholar 

  20. Ni T, Wang H, Zhan D, Tao L, Lv M, Wang W, et al. CD133+/CD166+ human gastric adenocarcinoma cells present the properties of neoplastic stem cells and emerge more malignant features. Life Sci. 2021;269: 119021.

    Article  CAS  PubMed  Google Scholar 

  21. Kahlert C, Weber H, Mogler C, Bergmann F, Schirmacher P, Kenngott HG, et al. Increased expression of ALCAM/CD166 in pancreatic cancer is an independent prognostic marker for poor survival and early tumour relapse. Br J Cancer. 2009;101(3):457–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Eom DW, Hong SM, Kim G, Bae YK, Jang KT, Yu E. Prognostic Significance of CD44v6, CD133, CD166, and ALDH1 Expression in Small Intestinal Adenocarcinoma. Appl Immunohistochem Mol Morphol. 2015;23(10):682–8.

    Article  CAS  PubMed  Google Scholar 

  23. Zhao M, Zhang Y, Zhang H, Wang S, Zhang M, Chen X, et al. Hypoxia-induced cell stemness leads to drug resistance and poor prognosis in lung adenocarcinoma. Lung Cancer. 2015;87(2):98–106.

    Article  PubMed  Google Scholar 

  24. Kalantari E, Taheri T, Fata S, Abolhasani M, Mehrazma M, Madjd Z, et al. Significant co-expression of putative cancer stem cell markers, EpCAM and CD166, correlates with tumor stage and invasive behavior in colorectal cancer. World J Surg Oncol. 2022;20(1):15.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ishigami S, Ueno S, Arigami T, Arima H, Uchikado Y, Kita Y, et al. Clinical implication of CD166 expression in gastric cancer. J Surg Oncol. 2011;103(1):57–61.

    Article  PubMed  Google Scholar 

  26. Giannakis M, Chen SL, Karam SM, Engstrand L, Gordon JI. Helicobacter pylori evolution during progression from chronic atrophic gastritis to gastric cancer and its impact on gastric stem cells. Proc Natl Acad Sci USA. 2008;105(11):4358–63.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sigal M, Rothenberg ME, Logan CY, Lee JY, Honaker RW, Cooper RL, et al. Helicobacter pylori activates and expands Lgr5+ stem cells through direct colonization of the gastric glands. Gastroenterology. 2015;148(7):1392-404.e21.

    Article  CAS  PubMed  Google Scholar 

  28. Choi YJ, Kim N, Chang H, Lee HS, Park SM, Park JH, et al. Helicobacter pylori-induced epithelial-mesenchymal transition, a potential role of gastric cancer initiation and an emergence of stem cells. Carcinogenesis. 2015;36(5):553–63.

    Article  CAS  PubMed  Google Scholar 

  29. Sentani K, Imai T, Kobayashi G, Hayashi T, Sasaki N, Oue N, et al. Histological diversity and molecular characteristics in gastric cancer: relation of cancer stem cell-related molecules and receptor tyrosine kinase molecules to mixed histological type and more histological patterns. Gastric Cancer. 2021;24(2):368–81.

    Article  CAS  PubMed  Google Scholar 

  30. Fornaro L, Lucchesi M, Caparello C, Vasile E, Caponi S, Ginocchi L, et al. Anti-HER agents in gastric cancer: from bench to bedside. Nat Rev Gastroenterol Hepatol. 2011;8(7):369–83.

    Article  CAS  PubMed  Google Scholar 

  31. Shah D, Osipo C. Cancer stem cells and HER2 positive breast cancer: The story so far. Genes & diseases. 2016;3(2):114–23.

    Article  CAS  Google Scholar 

  32. Yang T, Xu R, You J, Li F, Yan B, Cheng J-N. Prognostic and clinical significance of HER-2 low expression in early-stage gastric cancer. BMC Cancer. 2022;22(1):1–6.

    Article  CAS  Google Scholar 

  33. Kanayama K, Imai H, Yoneda M, Hirokawa YS, Shiraishi T. Significant intratumoral heterogeneity of human epidermal growth factor receptor 2 status in gastric cancer: A comparative study of immunohistochemistry, FISH, and dual-color in situ hybridization. Cancer Sci. 2016;107(4):536–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jung DH, Bae YJ, Kim JH, Shin YK, Jeung HC. HER2 regulates cancer stem cell activities via the wnt signaling pathway in gastric cancer cells. Oncology. 2019;97(5):311–8.

    Article  CAS  PubMed  Google Scholar 

  35. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1(5):555–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jeong YJ, Oh HK, Park SH, Bong JGJM. Prognostic significance of activated leukocyte cell adhesion molecule (ALCAM) in association with promoter methylation of the ALCAM gene in breast cancer. Molecules. 2018;23(1):131.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47(W1):W556–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi B, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19(8):649–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021;49(D1):D605–12.

    Article  CAS  PubMed  Google Scholar 

  40. Rasti A, Abolhasani M, Zanjani LS, Asgari M, Mehrazma M, Madjd Z. Reduced expression of CXCR4, a novel renal cancer stem cell marker, is associated with high-grade renal cell carcinoma. J Cancer Res Clin Oncol. 2017;143(1):95–104.

    Article  CAS  PubMed  Google Scholar 

  41. Ghods R, Ghahremani MH, Madjd Z, Asgari M, Abolhasani M, Tavasoli S, et al. High placenta-specific 1/low prostate-specific antigen expression pattern in high-grade prostate adenocarcinoma. Cancer Immunol Immunother. 2014;63(12):1319–27.

    Article  CAS  PubMed  Google Scholar 

  42. Shayanfar N, Zare-Mirzaie A, Mohammadpour M, Jafari E, Mehrtash A, Emtiazi N, et al. Low expression of isocitrate dehydrogenase 1 (IDH1) R132H is associated with advanced pathological features in laryngeal squamous cell carcinoma. J Cancer Res Clin Oncol. 2022;149:4253–67.

    Article  PubMed  Google Scholar 

  43. Camp RL, Charette LA, Rimm DL. Validation of tissue microarray technology in breast carcinoma. Lab Invest. 2000;80(12):1943–9.

    Article  CAS  PubMed  Google Scholar 

  44. Rosen DG, Huang X, Deavers MT, Malpica A, Silva EG, Liu J. Validation of tissue microarray technology in ovarian carcinoma. Mod Pathol. 2004;17(7):790–7.

    Article  CAS  PubMed  Google Scholar 

  45. Sabet MN, Rakhshan A, Erfani E, Madjd Z. Co-expression of putative cancer stem cell markers, CD133 and Nestin, in skin tumors. Asian Pac J Cancer Prev. 2014;15(19):8161–9.

    Article  PubMed  Google Scholar 

  46. Fattahi F, Saeednejad Zanjani L, Vafaei S, Habibi Shams Z, Kiani J, Naseri M, et al. Expressions of TWIST1 and CD105 markers in colorectal cancer patients and their association with metastatic potential and prognosis. Diagn Pathol. 2021;16(1):26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Safaei S, Sajed R, Saeednejad Zanjani L, Rahimi M, Fattahi F, Ensieh Kazemi-Sefat G, et al. Overexpression of cytoplasmic dynamin 2 is associated with worse outcomes in patients with clear cell renal cell carcinoma. Cancer Biomark. 2022;35(1):27–45.

    Article  CAS  PubMed  Google Scholar 

  48. McCarty KS Jr, Szabo E, Flowers JL, Cox EB, Leight GS, Miller L, et al. Use of a monoclonal anti-estrogen receptor antibody in the immunohistochemical evaluation of human tumors. Cancer Res. 1986;46(8 Suppl):4244s-s4248.

    PubMed  Google Scholar 

  49. Grabsch H, Sivakumar S, Gray S, Gabbert HE, Müller W. HER2 expression in gastric cancer: Rare, heterogeneous and of no prognostic value - conclusions from 924 cases of two independent series. Cell Oncol. 2010;32(1–2):57–65.

    PubMed  PubMed Central  Google Scholar 

  50. Lin T, Peng W, Mai P, Zhang E, Peng L. Human gastric cancer stem cell (GCSC) markers are prognostic factors correlated with immune infiltration of gastric cancer. Front Mol Biosci. 2021;8: 626966.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    Article  PubMed  Google Scholar 

  52. Jones JO, Smyth EC. Gastroesophageal cancer: Navigating the immune and genetic terrain to improve clinical outcomes. Cancer Treat Rev. 2020;84: 101950.

    Article  CAS  PubMed  Google Scholar 

  53. Wei L, Sun J, Zhang N, Zheng Y, Wang X, Lv L, et al. Noncoding RNAs in gastric cancer: implications for drug resistance. Mol Cancer. 2020;19(1):62.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Hu B, El Hajj N, Sittler S, Lammert N, Barnes R, Meloni-Ehrig A. Gastric cancer: Classification, histology and application of molecular pathology. J Gastrointest Oncol. 2012;3(3):251–61.

    PubMed  PubMed Central  Google Scholar 

  55. Nguyen PH, Giraud J, Chambonnier L, Dubus P, Wittkop L, Belleannée G, et al. Characterization of biomarkers of tumorigenic and chemoresistant cancer stem cells in human gastric carcinoma. Clin Cancer Res. 2017;23(6):1586–97.

    Article  CAS  PubMed  Google Scholar 

  56. Sainz B Jr, Carron E, Vallespinós M, Machado HL. Cancer stem cells and macrophages: implications in tumor biology and therapeutic strategies. Mediat Inflamm. 2016;2016:9012369.

    Article  Google Scholar 

  57. Katzka DA, Kahrilas PJ. Advances in the diagnosis and management of gastroesophageal reflux disease. BMJ. 2020. https://doi.org/10.1136/bmj.m3786.

    Article  PubMed  Google Scholar 

  58. Scheiblecker L, Kollmann K, Sexl V. CDK4/6 and MAPK—crosstalk as opportunity for cancer treatment. Pharmaceuticals. 2020;13(12):418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Aggelis V, Cunningham D, Lordick F, Smyth EC. Peri-operative therapy for operable gastroesophageal adenocarcinoma: past, present and future. Ann Oncol. 2018;29(6):1377–85.

    Article  CAS  PubMed  Google Scholar 

  60. Fu Y, Du P, Zhao J, Hu C, Qin Y, Huang G. Gastric Cancer stem cells: mechanisms and therapeutic approaches. Yonsei Med J. 2018;59(10):1150–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19(9):1523–9.

    Article  CAS  PubMed  Google Scholar 

  62. Levin TG, Powell AE, Davies PS, Silk AD, Dismuke AD, Anderson EC, et al. Characterization of the intestinal cancer stem cell marker CD166 in the human and mouse gastrointestinal tract. Gastroenterology. 2010;139(6):2072-82.e5.

    Article  CAS  PubMed  Google Scholar 

  63. Weidle UH, Eggle D, Klostermann S, Swart GW. ALCAM/CD166: cancer-related issues. Cancer Genomics Proteomics. 2010;7(5):231–43.

    CAS  PubMed  Google Scholar 

  64. Kim DK, Ham MH, Lee SY, Shin MJ, Kim YE, Song P, et al. CD166 promotes the cancer stem-like properties of primary epithelial ovarian cancer cells. BMB Rep. 2020;53(12):622–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Adisakwattana P, Suwandittakul N, Petmitr S, Wongkham S, Sangvanich P, Reamtong O. ALCAM is a novel cytoplasmic membrane protein in TNF-α stimulated invasive cholangiocarcinoma cells. Asian Pacific J Cancer Prevent APJCP. 2015;16(9):3849–56.

    Article  Google Scholar 

  66. Jezierska A, Matysiak W, Motyl T (2006) ALCAM/CD166 protects breast cancer cells against apoptosis and autophagy. Med Sci Monit 12(8):Br263–73

  67. Hansen AG, Arnold SA, Jiang M, Palmer TD, Ketova T, Merkel A, et al. ALCAM/CD166 is a TGF-β-responsive marker and functional regulator of prostate cancer metastasis to bone. Can Res. 2014;74(5):1404–15.

    Article  CAS  Google Scholar 

  68. Park DI, Yun JW, Park JH, Oh SJ, Kim HJ, Cho YK, et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci. 2006;51(8):1371–9.

    Article  CAS  PubMed  Google Scholar 

  69. García I, Vizoso F, Martín A, Sanz L, Abdel-Lah O, Raigoso P, et al. Clinical significance of the epidermal growth factor receptor and HER2 receptor in resectable gastric cancer. Ann Surg Oncol. 2003;10(3):234–41.

    Article  PubMed  Google Scholar 

  70. Abrahao-Machado LF, Scapulatempo-Neto C. HER2 testing in gastric cancer: an update. World J Gastroenterol. 2016;22(19):4619–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet (London, England). 2007;369(9555):29–36.

    Article  CAS  PubMed  Google Scholar 

  72. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–92.

    Article  CAS  PubMed  Google Scholar 

  73. Chan G, Kalaitzidis D, Neel BG. The tyrosine phosphatase Shp2 (PTPN11) in cancer. Cancer Metastasis Rev. 2008;27(2):179–92.

    Article  CAS  PubMed  Google Scholar 

  74. Chan RJ, Feng GS. PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. Blood. 2007;109(3):862–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Xu D, Qu CK. Protein tyrosine phosphatases in the JAK/STAT pathway. Front Biosci. 2008;13:4925–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Neel BG, Gu H, Pao L. The ’Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci. 2003;28(6):284–93.

    Article  CAS  PubMed  Google Scholar 

  77. Xu D, Wang S, Yu WM, Chan G, Araki T, Bunting KD, et al. A germline gain-of-function mutation in Ptpn11 (Shp-2) phosphatase induces myeloproliferative disease by aberrant activation of hematopoietic stem cells. Blood. 2010;116(18):3611–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Liu X, Qu CK. Protein Tyrosine Phosphatase SHP-2 (PTPN11) in Hematopoiesis and Leukemogenesis. J Signal Transduction. 2011;2011: 195239.

    Article  Google Scholar 

  79. Yu W, Wang J, Ma L, Tang X, Qiao Y, Pan Q, et al. CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT. Oncol Rep. 2014;32(2):677–83.

    Article  PubMed  Google Scholar 

  80. Ma L, Wang J, Lin J, Pan Q, Yu Y, Sun F. Cluster of differentiation 166 (CD166) regulated by phosphatidylinositide 3-Kinase (PI3K)/AKT signaling to exert its anti-apoptotic role via yes-associated protein (YAP) in liver cancer. J Biol Chem. 2014;289(10):6921–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Ohhara Y, Kinoshita I, Suzuki A, Imagawa M, Taguchi J, Noguchi T, et al. Expression of Karyopherin alpha 2 and Karyopherin beta 1 correlate with poor prognosis in gastric cancer. Oncology. 2022;100(12):685–95.

    Article  CAS  PubMed  Google Scholar 

  82. Zhang Y, Li KF. Karyopherin β1 deletion suppresses tumor growth and metastasis in colorectal cancer (CRC) by reducing MET expression. Biomed Pharmacother. 2019;120: 109127.

    Article  CAS  PubMed  Google Scholar 

  83. Zhu ZC, Liu JW, Li K, Zheng J, Xiong ZQ. KPNB1 inhibition disrupts proteostasis and triggers unfolded protein response-mediated apoptosis in glioblastoma cells. Oncogene. 2018;37(22):2936–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang T, Huang Z, Huang N, Peng Y, Gao M, Wang X, et al. Inhibition of KPNB1 inhibits proliferation and promotes apoptosis of chronic myeloid leukemia cells through regulation of E2F1. Onco Targets Ther. 2019;12:10455–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. van der Watt PJ, Ngarande E, Leaner VD. Overexpression of Kpnβ1 and Kpnα2 importin proteins in cancer derives from deregulated E2F activity. PLoS ONE. 2011;6(11): e27723.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  86. Ye M, Du YL, Nie YQ, Zhou ZW, Cao J, Li YF. Overexpression of activated leukocute cell adhesion molecule in gastric cancer is associated with advanced stages and poor prognosis and miR-9 deregulation. Mol Med Rep. 2015;11(3):2004–12.

    Article  CAS  PubMed  Google Scholar 

  87. Barros-Silva JD, Leitão D, Afonso L, Vieira J, Dinis-Ribeiro M, Fragoso M, et al. Association of ERBB2 gene status with histopathological parameters and disease-specific survival in gastric carcinoma patients. Br J Cancer. 2009;100(3):487–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sasano H, Date F, Imatani A, Asaki S, Nagura H. Double immunostaining for c-erbB-2 and p53 in human stomach cancer cells. Hum Pathol. 1993;24(6):584–9.

    Article  CAS  PubMed  Google Scholar 

  89. Tateishi M, Toda T, Minamisono Y, Nagasaki S. Clinicopathological significance of c-erbB-2 protein expression in human gastric carcinoma. J Surg Oncol. 1992;49(4):209–12.

    Article  CAS  PubMed  Google Scholar 

  90. Uprak TK, Attaallah W, Çelikel ÇA, Ayrancı G, Yeğen C. HER-2 incidence in gastric cancer, its association with prognosis and clinicopathological parameters. Ulusal cerrahi dergisi. 2015;31(4):207–13.

    PubMed  PubMed Central  Google Scholar 

  91. Ohguri T, Sato Y, Koizumi W, Saigenji K, Kameya T. An immunohistochemical study of c-erbB-2 protein in gastric carcinomas and lymph-node metastases: is the c-erbB-2 protein really a prognostic indicator? Int J Cancer. 1993;53(1):75–9.

    Article  CAS  PubMed  Google Scholar 

  92. Yonemura Y, Ninomiya I, Yamaguchi A, Fushida S, Kimura H, Ohoyama S, et al. Evaluation of immunoreactivity for erbB-2 protein as a marker of poor short term prognosis in gastric cancer. Can Res. 1991;51(3):1034–8.

    CAS  Google Scholar 

  93. Ahadi M, Moradi A, Musavinejad L, Movafagh A, Moradi A. The expression of p53, CD44, Ki-67, and HER-2/neu markers in gastric cancer and its association with histopathological indicators: A retrospective study. Asian Pacific J Cancer Prevent APJCP. 2020;21(6):1607.

    Article  CAS  Google Scholar 

  94. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet (London, England). 2010;376(9742):687–97.

    Article  CAS  PubMed  Google Scholar 

  95. Mizutani T, Onda M, Tokunaga A, Yamanaka N, Sugisaki Y. Relationship of C-erbB-2 protein expression and gene amplification to invasion and metastasis in human gastric cancer. Cancer. 1993;72(7):2083–8.

    Article  CAS  PubMed  Google Scholar 

  96. Lam L, McAndrew N, Yee M, Fu T, Tchou JC, Zhang H. Challenges in the clinical utility of the serum test for HER2 ECD. Biochem Biophys Acta. 2012;1826(1):199–208.

    CAS  PubMed  Google Scholar 

  97. Shi HZ, Wang YN, Huang XH, Zhang KC, Xi HQ, Cui JX, et al. Serum HER2 as a predictive biomarker for tissue HER2 status and prognosis in patients with gastric cancer. World J Gastroenterol. 2017;23(10):1836–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. El-Bagory IM, El-Aleem AA, Mohamed NME-D, Shendy SAE-L (2019) Serum level of cluster of differentiation 166 as novel biomarker in hepatocellular carcinoma. Scient J Al-Azhar Medical Faculty Girls. 3(3):573–82.

  99. Ma L, Lin J, Qiao Y, Weng W, Liu W, Wang J, et al. Serum CD166: a novel hepatocellular carcinoma tumor marker. Clin Chim Acta. 2015;441:156–62.

    Article  CAS  PubMed  Google Scholar 

  100. Dai SQ, An X, Wang F, Shao Q, Chen YC, Kong YN, et al. Serum HER 2 extracellular domain level is correlated with tissue HER 2 status in metastatic gastric or gastro-oesophageal junction adenocarcinoma. PLoS ONE. 2013;8(5): e63458.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was conducted as part of a resident thesis and was financially supported by a grant from the Oncopathology Research Center, Iran University of Medical Sciences (IUMS) (Grant Number #16274).

Author information

Author notes

  1. Leila Moradi and Fatemeh Tajik contributed equally to this manuscript as co-first authors.

Authors and Affiliations

  1. Department of Pathology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Leila Moradi, Mahshid Panahi & Zahra Madjd

  2. Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran

    Fatemeh Tajik, Leili Saeednejad Zanjani, Elmira Gheytanchi, Farideh Hashemi, Masoumeh Dehghan Manshadi & Zahra Madjd

  3. Department of Pathology and Genomic Medicine, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    Leili Saeednejad Zanjani

  4. Faculty of Biological Sciences, Department of Genetics, Tarbiat Modares University, Tehran, Iran

    Zahra Sadat Biabanaki

  5. Faculty of Advanced Technologies in Medicine, Department of Molecular Medicine, Iran University of Medical Sciences, Tehran, Iran

    Golnaz Ensieh Kazemi-Sefat, Farideh Hashemi, Masoumeh Dehghan Manshadi & Zahra Madjd

Authors
  1. Leila Moradi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fatemeh Tajik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leili Saeednejad Zanjani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mahshid Panahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elmira Gheytanchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zahra Sadat Biabanaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Golnaz Ensieh Kazemi-Sefat
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Farideh Hashemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masoumeh Dehghan Manshadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zahra Madjd
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Z.M designed and supervised the project, rechecked and approved all parts of the manuscript and data analysis; L.M., F.T. and E.Gh. wrote the manuscript. L.M., F.T., and Z.S.B. collected the paraffin embedded tissues, collected the patient data and survival data, and performed IHC experiment. L.S.Z. and F.T. analyzed and interpreted the SPSS data. F.H. and M.D.M. helped to prepare the figures and tables and wrote some parts of the manuscript. M.P. marked the most representative areas in different parts of the tumor for the construction of TMAs blocks and scored TMAs slides after IHC staining and helped to prepare the figures. G.E.K.S. interpreted the bioinformatics data and wrote the bioinformatics parts of the manuscript All authors read and approved the final manuscript.

Corresponding author

Correspondence to Zahra Madjd.

Ethics declarations

Conflict of interest

The authors declare no conflict of interests.

Ethical approval

All procedures performed in this study were in line with the ethical standards of the institution at which this study was conducted. Informed consent was individually obtained from all participants. The Research Ethics Committee of Iran University of Medical Sciences issued IR.IUMS.FMD.REC 1398.1130 for this study.

Informed consent

Informed consent was obtained from all individual participants, parents or legally authorized representatives of participants under legal age years old at the time of sample collection with routine consent forms.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moradi, L., Tajik, F., Saeednejad Zanjani, L. et al. Clinical significance of CD166 and HER-2 in different types of gastric cancer. Clin Transl Oncol 26, 664–681 (2024). https://doi.org/10.1007/s12094-023-03297-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-023-03297-0

Keywords

Search

Navigation