Comparison of human epidermal growth factor receptor 2 and cancer stem cell markers like CD44 and CD133 expressions with clinicopathological parameters in gastric cancer

Yıl 2023, Cilt: 9 Sayı: 5 - September 2023, 1015 - 1026, 04.09.2023

Melin Gecer , Nur Büyükpınarbaşılı , Seval Turna , Mehmet Beşiroğlu , Zuhal Gucın

https://doi.org/10.18621/eurj.1296567

Öz

Objectives: Gastric carcinoma (GC) is the fourth most common cause of cancer-related tumor deaths worldwide. The prognostic significance of CD44, CD133 and human epidermal growth factor receptor 2 (HER2) expression in GC remains controversial. Therefore, we aimed to investigate the relationship of CD44, CD133 and HER2 expression with clinicopathological features in metastatic and non-metastatic GC patients.

Methods: A total of 139 patients with GC (68 with metastasis, 71 without metastasis) diagnosed were retrospectively analyzed. CD44 and CD133 expression were determined by immunohistochemical method in all cases. In addition, HER2 overexpression of the tumor was evaluated in patients with metastatic GC.

Results: The CD133 positivity rate was 90.6% (n = 126) when all cases were considered, and that for CD44 was 84.9% (n = 118). There was no difference in CD133 and CD44 positivity (intensity or density) rates and between the total scores of metastatic and non-metastatic patients with GC (p > 0.05). HER2 positivity in metastatic cases was detected in 49 (70.1%) patients by immunohistochemical method. No correlation was found between CD133 total score and age, tumor size or depth, and HER2 scores in metastatic or non-metastatic cases (p > 0.05). In the correlation analyzes performed with CD44 scores, only a borderline significant correlation was found between CD44 scores and tumor size (r:0.175; p = 0.047) in non-metastatic cases.

Conclusions: We demonstrated associations between CD44/CD133 expression and histological grade in all patients, between CD44 and tumor size in non-metastatic patients, and between HER2 and intestinal type (Lauren) in metastatic patients. The results of this study need to be confirmed by multicenter studies including large case series.

Anahtar Kelimeler

Stem cell, CD44, CD133, gastric cancer, HER2

Kaynakça

• 1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49.
• 2. Guner A. Recent trends of gastric cancer treatment in Turkey. Transl Gastroenterol Hepatol 2017;2:31.
• 3. Yalcin S. Gastric cancer in Turkey-a bridge between west and east. Gastrointest Cancer Res 2009;3:29-32.
• 4.Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, Maciejewski R, Polkowski WP. Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res 2018;10:239-48.
• 5. Skierucha M, Milne AN, Offerhaus GJ, Polkowski WP, Maciejewski R, Sitarz R. Molecular alterations in gastric cancer with special reference to the early-onset subtype. World J Gastroenterol 2016;22:2460-74.
• 6. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 1965;64:31-49.
• 7. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al.; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11-20.
• 8. Yu Z, Pestell TG, Lisanti MP, Pestell RG. Cancer stem cells. Int J Biochem Cell Biol 2012;44:2144-51.
• 9. Lu L, Wu M, Sun L, Li W, Fu W, Zhang X et al. Clinicopathological and prognostic significance of cancer stem cell markers CD44 and CD133 in patients with gastric cancer: A comprehensive meta-analysis with 4729 patients involved. Medicine (Baltimore) 2016;95:e5163.
• 10. Takaishi S, Okumura T, Tu S, Wang SS, Shibata W, Vigneshwaran R, et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 2009;27:1006-20.
• 11. Wakamatsu Y, Sakamoto N, Oo HZ, Naito Y, Uraoka N, Anami K, et al. Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer. Pathol Int 2012;62:112-9.
• 12. Chen S, Hou JH, Feng XY, Zhang XS, Zhou ZW, Yun JP, et al. Clinicopathologic significance of putative stem cell marker, CD44 and CD133, in human gastric carcinoma. J Surg Oncol 2013;107:799-806.
• 13. Nosrati A, Naghshvar F, Khanari S. Cancer stem cell markers CD44, CD133 in primary gastric adenocarcinoma. Int J Mol Cell Med 2014;3:279-86.
• 14. 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;23:1586-97.
• 15. Duzcu SE, Astarci HM, Tunc N, Boran C. Expressions of putative cancer stem cell markers, CD44 and CD133, are correlated with pathological tumour stage in gastric adenocarcinoma. J Coll Physicians Surg Pak 2021;30:553-8.
• 16. 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;24:368-81.
• 17. Wang W, Dong LP, Zhang N, Zhao CH. Role of cancer stem cell marker CD44 in gastric cancer: a meta-analysis. Int J Clin Exp Med 2014;7:5059-66.
• 18. Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B. CD44 is the principal cell surface receptor for hyaluronate. Cell 1990;61:1303-13.
• 19. Attia S, Atwan N, Arafa M, Shahin RA. Expression of CD133 as a cancer stem cell marker in invasive gastric carcinoma. Pathologica 2019;111:18-23.
• 20. Ishigami S, Ueno S, Arigami T, Uchikado Y, Setoyama T, Arima H, et al. Prognostic impact of CD133 expression in gastric carcinoma. Anticancer Res 2010;30:2453-7.
• 21. Saricanbaz I, Karahacioglu E, Ekinci O, Bora H, Kilic D, Akmansu M. Prognostic significance of expression of CD133 and Ki-67 in gastric cancer. Asian Pac J Cancer Prev 2014;15:8215-9.
• 22. Hashimoto K, Aoyagi K, Isobe T, Kouhuji K, Shirouzu K. Expression of CD133 in the cytoplasm is associated with cancer progression and poor prognosis in gastric cancer. Gastric Cancer 2014;17:97-106.
• 23. Abrahao-Machado LF, Scapulatempo-Neto C. HER2 testing in gastric cancer: an update. World J Gastroenterol 2016;22:4619-25.
• 24. Jørgensen JT, Hersom M. HER2 as a prognostic marker in gastric cancer - A systematic analysis of data from the literature. J Cancer 2012;3:137-44.
• 25. Ryu HS, Park DJ, Kim HH, Kim WH, Lee HS. Combination of epithelial-mesenchymal transition and cancer stem cell-like phenotypes has independent prognostic value in gastric cancer. Hum Pathol 2012;43:520-8.
• 26. Zhao Q, Zhou H, Liu Q, Cao Y, Wang G, Hu A, et al. Prognostic value of the expression of cancer stem cell-related markers CD133 and CD44 in hepatocellular carcinoma: From patients to patient-derived tumor xenograft models. Oncotarget 2016;7:47431-43.
• 27. Doventas A, Bilici A, Demirel F, Ersoy G, Turna H, Doventas Y. Prognostic significance of CD44 and c-erb-B2 protein overexpression in patients with gastric cancer. Hepatogastroenterology 2012;59:2196-201.
• 28. He C, Bian XY, Ni XZ, Shen DP, Shen YY, Liu H, et al. Correlation of human epidermal growth factor receptor 2 expression with clinicopathological characteristics and prognosis in gastric cancer. World J Gastroenterol 2013;19:2171-8.
• 29. Janjigian YY, Werner D, Pauligk C, Steinmetz K, Kelsen DP, Jäger E, et al. Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA International collaborative analysis. Ann Oncol 2012;23:2656-62.
• 30. Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al. The eighth edition AJCC Cancer Staging Manual: continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging. CA Cancer J Clin 2017;67:93-99.
• 31. Wang T, Ong CW, Shi J, Srivastava S, Yan B, Cheng CL, et al. Sequential expression of putative stem cell markers in gastric carcinogenesis. Br J Cancer 2011;105:658-65.
• 32. Hofmann M, Stoss O, Shi D, Büttner R, van de Vijver M, Kim W, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 2008;52:797-805.
• 33. Ogitani Y, Aida T, Hagihara K, Yamaguchi J, Ishii C, Harada N, et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res 2016;22:5097-108.
• 34. Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu MH, Sakai D, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med 2020;382:2419-30.
• 35. Mayer B, Jauch KW, Günthert U, Figdor CG, Schildberg FW, Funke I, et al. De-novo expression of CD44 and survival in gastric cancer. Lancet 1993;342:1019-22.
• 36. Ghaffarzadehgan K, Jafarzadeh M, Raziee HR, Sima HR, Esmaili-Shandiz E, Hosseinnezhad H, et al. Expression of cell adhesion molecule CD44 in gastric adenocarcinoma and its prognostic importance. World J Gastroenterol 2008;14):6376-81.
• 37. Jung WY, Kang Y, Lee H, Mok YJ, Kim HK, Kim A, et al. Expression of moesin and CD44 is associated with poor prognosis in gastric adenocarcinoma. Histopathology 2013;63:474-81.
• 38. Xia P, Xu XY. Prognostic significance of CD44 in human colon cancer and gastric cancer: Evidence from bioinformatic analyses. Oncotarget 2016;7:45538-46.
• 39. Ibrahim HM, AbdElbary AM, Mohamed SY, Elwan A, Abdelhamid MI, Ibrahim A. Prognostic value of cyclin D1 and CD44 expression in gastric adenocarcinoma. J Gastrointest Cancer 2019;50:370-9.
• 40. Wu Y, Li Z, Zhang C, Yu K, Teng Z, Zheng G, et al. CD44 family proteins in gastric cancer: a meta-analysis and narrative review. Int J Clin Exp Med 2015;8:3595-606.
• 41. Fang M, Wu J, Lai X, Ai H, Tao Y, Zhu B, et al. CD44 and CD44v6 are correlated with gastric cancer progression and poor patient prognosis: evidence from 42 studies. Cell Physiol Biochem 2016;40:567-578.
• 42. Razmi M, Ghods R, Vafaei S, Sahlolbei M, Saeednejad Zanjani L, Madjd Z. Clinical and prognostic significances of cancer stem cell markers in gastric cancer patients: a systematic review and meta-analysis. Cancer Cell Int 2021;21:139.
• 43. Ryu MS, Hee JP, Moon CM, Kim SE, Jung HK, Shim KN, et al. Expression of CD44 according to clinicopathologic characteristics of gastric cancer. Ewha Med J 2018;41. 63-74.
• 44. Otaegi-Ugartemendia M, Matheu A, Carrasco-Garcia E. Impact of cancer stem cells on therapy resistance in gastric cancer. Cancers (Basel) 2022;14:1457.
• 45. Smith LM, Nesterova A, Ryan MC, Duniho S, Jonas M, Anderson M, et al. CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers. Br J Cancer 2008;99:100-9.
• 46. Zhao P, Li Y, Lu Y. Aberrant expression of CD133 protein correlates with Ki-67 expression and is a prognostic marker in gastric adenocarcinoma. BMC Cancer 2010;10:218.
• 47. Gu G, Dustin D, Fuqua SA. Targeted therapy for breast cancer and molecular mechanisms of resistance to treatment. Curr Opin Pharmacol 2016;31:97-103.
• 48. 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;51:1371-9.
• 49. 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;53:75-9.
• 50. Hsu JT, Chen TC, Tseng JH, Chiu CT, Liu KH, Yeh CN, et al. Impact of HER-2 overexpression/amplification on the prognosis of gastric cancer patients undergoing resection: a single-center study of 1,036 patients. Oncologist 2011;16:1706-13.
• 51. Gülten G, Yilmaz B, Demirkan NÇ. Comparing human epidermal growth factor receptor 2 amplification and expression using immunohistochemistry and silver in situ hybridisation in gastric carcinoma and lymph node metastasis. Oncol Lett 2020;20:1897-905.
• 52. Lei YY, Huang JY, Zhao QR, Jiang N, Xu HM, Wang ZN, et al. The clinicopathological parameters and prognostic significance of HER2 expression in gastric cancer patients: a meta-analysis of literature. World J Surg Oncol 2017;15:68.
• 53. 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;72:2083-8.
• 54. Tanner M, Hollmén M, Junttila TT, Kapanen AI, Tommola S, Soini Y, et al. Amplification of HER-2 in gastric carcinoma: association with Topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol 2005;16:273-8.
• 55. 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;32:57-65.
• 56. 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 2010;376:687-97.