Co-expression of CD24 and CD44 in gastric carcinoma and its influence on clinicopathological parameters and prognosis

doi:10.3969/j.issn.2095-4344.0998

Abstract

Abstract:

BACKGROUND: Studies have shown that the expression of CD24 and CD44 may be closely related to the disease progression, clinicopathological parameters and prognosis of gastric carcinoma.
OBJECTIVE: To investigate the expression of CD24 and CD44 in gastric carcinoma and its influence on clinicopathological parameters and prognosis.
METHODS: The clinical data of patients undergoing surgical resection of gastric carcinoma in Heze Municipal Hospital from April 2006 to April 2012 were collected. The expression of CD24 and CD44 protein in cancer tissues, paracancerous tissues and normal tissues from resected specimens was detected by immunohistochemistry. The relationship between the expressions of CD24 and CD44, clinicopathological parameters and prognosis of the patients was analyzed.
RESULTS AND CONCLUSION: (1) Among 180 patients, the positive rate of CD24 was 57.5% (92/180), which was lowly expressed in 54 cases and highly expressed in 38 cases; the positive rate of CD44 was 49.3% (79/180), which was lowly expressed in 48 cases and highly expressed in 31 cases. The co-expression rate was 24.3% (39/180) and the double negative rate was 30.0% (48/180). (2) Compared with cancer tissues, the positive rates of CD24 and CD44 in normal gastric tissues and paracancerous tissues were significantly lower (P < 0.001). (3) Univariate analysis showed that the co-expression of CD24 and CD44 in gastric cancer tissues was related to the size of gastric carcinoma, T staging, N staging, vascular invasion (P < 0.05), but not related to age, sex, tumor site, WHO pathological classification, Lauren classification and M staging (P > 0.05). Multivariate analysis showed that T staging and N staging were independent risk factors affecting the expression of CD24 and CD44 in gastric cancer tissues. (4) Spearman rank correlation analysis showed no correlation between the expression intensity of CD24 and CD44 (r=0.020, P=0.795). (5) Seventeen of 180 cases were lost to follow-up, and the loss rate was 9.4%. Eighty-seven patients died within 5 years. Twenty-one of 53 patients in CD24 single-positive group died, and 23 of 40 patients in CD44 single-positive group died. Thirteen of 48 patients in double-negative group died, and 30 of 39 patients in double positive group died. Log-rank test results showed that the survival rate of the four groups was significantly different (χ²=21.72, P < 0.001), and the CD24(+) CD44(+) group had the worst prognosis. To conclude, CD24 and CD44 have higher positive rates in gastric carcinoma, which are closely related with the staging of patients. Moreover, the co-expression of CD24 and CD44 strongly indicates a poor prognosis.

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

Key words: Stomach Neoplasms, Antigens, CD24, Antigens, CD44, Neoplastic Stem Cells, Tissue Engineering

CLC Number:

R394.2

Han Fang-zheng, Zhang Xiao-lin, Dong Wei-yi, Xie Yun-ting. Co-expression of CD24 and CD44 in gastric carcinoma and its influence on clinicopathological parameters and prognosis[J]. Chinese Journal of Tissue Engineering Research, 2018, 22(29): 4625-4630.

Figures/Tables 2

2.1 CD24、CD44在胃癌组织中的表达免疫组化检测发现，CD24主要表达于肿瘤细胞的细胞膜及细胞质，沿腺管基底侧或共壁腺体的共壁侧分布。在180例患者标本中，CD24的阳性表达率为57.5%(92/180)，其中低表达54例，高表达38例。CD44主要表达于肿瘤细胞的细胞膜，胞浆内也可见少量表达。在180例患者标本中，CD44的阳性表达率为49.3%(79/180)，其中低表达48例，高表达31例。二者的共表达率为24.3%(39/180)，双阴率为30.0%(48/180)，见图1。 2.2 CD24、CD44在正常胃组织、癌旁组织、癌组织中的阳性率比较与癌组织相比，正常胃组织和癌旁组织CD24、CD44的阳性率均显著较低，且差异有显著性意义(P均< 0.001)；但癌旁组织与正常胃组织相比，CD24、CD44表达阳性率差异无显著性意义(P均> 0.05)，见表1。 2.3 胃癌组织中CD24、CD44双阳性表达与患者临床病理参数关系的单因素分析单因素分析结果显示，CD24、CD44在胃癌组织中的共表达与胃癌组织大小、T分期、N分期、脉管浸润相关(P < 0.05)，但与患者年龄、性别、肿瘤部位、WHO病理分型、Lauren分型、M分期无关(P > 0.05)，见表2。 2.4 胃癌组织中CD24、CD44双阳性表达与患者临床病理参数关系的多因素分析将上述单因素分析中有意义的指标纳入logistic回归模型进行多因素分析，结果发现T分期、N分期是影响CD24、CD44在胃癌组织中共表达的独立影响因素，见表3。 2.5 CD24、CD44表达强度的相关性分析 Spearman等级相关分析结果显示，CD24和CD44的表达强度之间不存在相关关系(r=0.020，P=0.795)，见表4。 2.6 CD24、CD44表达对患者预后的影响 180例患者，失访17例，失访率为9.4%。5年内死亡87例，CD24单阳组53例患者，死亡21例；CD44单阳组40例患者，死亡23例；双阴组48例患者，死亡13例；双阳组39例患者，死亡30例。Log-rank统计检验显示，4组患者的生存率差异有显著性意义(χ2=21.72，P < 0.001)。生存分析结果显示，CD24(+)CD44(+)患者预后最差，CD24(-)CD44(-)患者预后最好，见图2。"

References

[1] Takaishi S, Okumura T, Tu S, et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells. 2009; 27(5):1006-1020.

[2] Plentz RR, Barat S, Chen X, et al. Notch and wnt-beta catenin pathways as targets of γ-secretase inhibitor IX (GSI) mediated therapy in CD44+ gastric cancer (GC) cells. J Clin Oncol. 2016; 34(4) :99.

[3] Chen W, Zhang X, Chu C, et al. Identification of CD44+ cancer stem cells in human gastric cancer. Hepatogastroenterology. 2013;60(124):949-954.

[4] Park JW, Um H, Yang H, et al. Proteogenomic analysis of NCC-S1M, a gastric cancer stem cell-like cell line that responds to anti-PD-1. Biochem Biophys Res Commun. 2017;484(3):631-635.

[5] Miao ZF, Xu H, Xu HM, et al. DLL4 overexpression increases gastric cancer stem/progenitor cell self-renewal ability and correlates with poor clinical outcome via Notch-1 signaling pathway activation. Cancer Med. 2017;6(1):245-257.

[6] Sun M, Zhou W, Zhang YY, et al. CD44+ gastric cancer cells with stemness properties are chemoradioresistant and highly invasive. Oncol Lett. 2013;5(6):1793-1798.

[7] Shitara K, Doi T, Nagano O, et al. Dose-escalation study for the targeting of CD44v+ cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205). Gastric Cancer. 2017;20(2):341-349.

[8] Li K, Dan Z, Nie YQ. Gastric cancer stem cells in gastric carcinogenesis, progression, prevention and treatment. World J Gastroenterol. 2014;20(18):5420-5426.

[9] 李禄椿. Notch1信号转导通路对CD44+胃癌细胞生物学特性的影响[D]. 重庆:重庆医科大学, 2014.

[10] 李威,姜波健,俞继卫. CD44与CD133蛋白在胃癌组织中的表达及其临床意义[J].中国普外基础与临床杂志,2014,21(1):21-28.

[11] 许峰峰,杨世斌,肖隆斌,等.上皮细胞黏附分子、CD24在胃癌组织的表达及临床意义[J].中华实验外科杂志,2012,29(9):1831-1833.

[12] Mao J, Fan S, Ma W, et al. Roles of Wnt/β-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment. Cell Death Dis. 2014;5:e1039.

[13] Nishikawa S, Konno M, Hamabe A, et al. Aldehyde dehydrogenase high gastric cancer stem cells are resistant to chemotherapy. Int J Oncol. 2013;42(4):1437-1442.

[14] Yao HJ, Zhang YG, Sun L, et al. The effect of hyaluronic acid functionalized carbon nanotubes loaded with salinomycin on gastric cancer stem cells. Biomaterials.2014;35(33): 9208-9223.

[15] Izumiya M, Kabashima A, Higuchi H, et al. Chemoresistance is associated with cancer stem cell-like properties and epithelial-to- mesenchymal transition in pancreatic cancer cells. Anticancer Res. 2012;32(9):3847-3853.

[16] 周志华,张建东,徐桂芳,等. 基于克隆形态分选胃癌干细胞及其对氟尿嘧啶敏感性的检测[J].中华胃肠外科杂志,2013,16(4) : 376-380.

[17] 陈军. 胃癌干细胞干性特性及化疗药物对其影响的初步研究[D]. 重庆:第三军医大学, 2013.

[18] 王佳佳,孙立新,孙力超,等. 人胃癌CD90+干细胞可能影响胃癌的转移和患者的预后[J]. 中国肿瘤生物治疗杂志,2013, 20(2): 230-236.

[19] Samadani AA, Akhavan-Niaki H. Interaction of sonic hedgehog (SHH) pathway with cancer stem cell genes in gastric cancer. Med Oncol. 2015;32(3):48.

[20] 恽艳. 肿瘤干细胞标志Lgr5和CD44在胃癌中的表达及临床病理意义[D]. 苏州:苏州大学,2014.

[21] Soave A, John LM, Dahlem R, et al. The Impact of Tumor Diameter and Tumor Necrosis on Oncologic Outcomes in Patients With Urothelial Carcinoma of the Bladder Treated With Radical Cystectomy. Urology. 2015;86(1):92-98.

[22] 池桢,黄昌明,郑朝辉,等. 肿瘤大小对T3期胃癌患者预后的影响[J]. 中华胃肠外科杂志, 2011, 14(2) :114-116.

[23] 陆俊,黄昌明,郑朝辉,等. 肿瘤大小对早期胃癌病人预后的影响[J]. 中国实用外科杂志, 2012,32(9):758-761.

[24] Stokes GN, Shelton JB Jr, Zahn CM, et al. Association of CD44 isoform immunohistochemical expression with myometrial and vascular invasion in endometrioid endometrial carcinoma. Gynecol Oncol. 2002;84(1):58-61.

[25] Yildiz E, Gokce G, Kilicarslan H, et al. Prognostic value of the expression of Ki-67, CD44 and vascular endothelial growth factor, and microvessel invasion, in renal cell carcinoma. BJU Int. 2004; 93(7):1087-1093.

[26] Wakamatsu Y, Sakamoto N, Oo HZ, 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(2): 112-119.

[27] Nishikawa S, Konno M, Hamabe A, et al. Surgically resected human tumors reveal the biological significance of the gastric cancer stem cell markers CD44 and CD26. Oncol Lett. 2015; 9(5):2361-2367.

[28] Watanabe T, Okumura T, Hirano K, et al. Circulating tumor cells expressing cancer stem cell marker CD44 as a diagnostic biomarker in patients with gastric cancer. Oncol Lett. 2017; 13(1):281-288.

[29] Arima S, Kunimura T, Date H, et al. Expression of Standard CD44 in Advanced Gastric Cancer: Relationship with Metastasis to Lymph Nodes. Journal of Physical Chemistry. 2011; 22(3): 163-169.

[30] Eom BW, Joo J, Park B, et al. Nomogram Incorporating CD44v6 and Clinicopathological Factors to Predict Lymph Node Metastasis for Early Gastric Cancer. PLoS One. 2016; 11(8): e0159424.

[31] Zhou C, Ji J, Cai Q, et al. MTA2 enhances colony formation and tumor growth of gastric cancer cells through IL-11. BMC Cancer. 2015;15:343.

[32] Müller W, Schneiders A, Heider KH, et al. Expression and prognostic value of the CD44 splicing variants v5 and v6 in gastric cancer. J Pathol. 1997;183(2):222-227.

[33] Lee ES, Kim SH, Lee JY, et al. Radiologist performance in differentiating polypoid early from advanced gastric cancer using specific CT criteria: emphasis on dimpling sign. AJR Am J Roentgenol. 2009;193(6):1546-1555.

[34] Yoon C, Park DJ, Schmidt B, et al. CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance. Clin Cancer Res. 2014; 20(15):3974-3988.

[35] Nishikawa S, Konno M, Hamabe A, et al. Surgically resected human tumors reveal the biological significance of the gastric cancer stem cell markers CD44 and CD26. Oncol Lett. 2015; 9(5): 2361-2367.

[36] 陈仕才,宋新明,陈志辉,等.CD133 和 CD44 在结直肠癌细胞中的表达及其与患者5年生存率的相关性分析[J].中国病理生理杂志, 2011,27(5):883-889.

[37] 金可可,蒋仲荪,陈少贤,等.非小细胞肺癌患者 CD44及其变异体 V6 的测定[J].中国病理生理杂志,2001,17(11):1008-1092.

[38] 杨世斌,肖隆斌,许峰峰,等. EPCAM、CD44和CD24在胃癌组织中的表达及其临床意义[J].中国病理生理杂志,2012,28(7): 1224-1229.

[39] Bektas S, Bahadir B, Ucan BH, et al. CD24 and galectin-1 expressions in gastric adenocarcinoma and clinicopathologic significance. Pathol Oncol Res. 2010;16(4):569-577.