CD44 variant 9 expression in primary early gastric cancer as a predictive marker for recurrence

Hirata, Kenro; Suzuki, Hidekazu; Imaeda, Hiroyuki; Matsuzaki, Juntaro; Tsugawa, Hitoshi; Nagano, Osamu; Asakura, Keiko; Saya, Hideyuki; Hibi, Toshifumi

doi:10.1038/bjc.2013.314

Cited by 118 publications

(110 citation statements)

References 34 publications

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“…CD44v8-10 also seems to promote metastasis in colon, pancreatic, and breast cancer cells (24,40,41), with significant positive correlation to tumor recurrence and mortality (24). Using antibodies directed against the CD44 variant exon 9, CD44v9 expression in primary tumors was significantly and positively associated with tumor recurrence and mortality (35,42). These studies indicate the importance of CD44v9 as a prognostic marker but functional studies that define CD44v9-expressing cells as gastric CSCs are lacking.…”

Section: Discussionmentioning

confidence: 99%

CD44v8-10 Is a Cancer-Specific Marker for Gastric Cancer Stem Cells

et al. 2014

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The surface marker CD44 has been identified as one of several markers associated with cancer stem cells (CSC) in solid tumors, but its ubiquitous expression in many cell types, including hematopoietic cells, has hindered its use in targeting CSCs. In this study, 28 paired primary tumor and adjacent nontumor gastric tissue samples were analyzed for cell surface protein expression. Cells that expressed pan-CD44 were found to occur at significantly higher frequency in gastric tumor tissues. We identified CD44v8-10 as the predominant CD44 variant expressed in gastric cancer cells and verified its role as a gastric CSC marker by limiting dilution and serial transplantation assays. Parallel experiments using CD133 failed to enrich for gastric CSCs. Analyses of another 26 primary samples showed significant CD44v8-10 upregulation in gastric tumor sites. Exogenous expression of CD44v8-10 but not CD44 standard (CD44s) increased the frequency of tumor initiation in immunocompromised mice. Reciprocal silencing of total CD44 resulted in reduced tumor-initiating potential of gastric cancer cells that could be rescued by CD44v8-10 but not CD44s expression. Our findings provide important functional evidence that CD44v8-10

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Section: Discussionmentioning

confidence: 99%

CD44v8-10 Is a Cancer-Specific Marker for Gastric Cancer Stem Cells

et al. 2014

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“…In addition, expression of CD44v9 in tumor tissues has also been associated with tumor recurrence and prognosis in patients with several types of cancer (4,19,20,31,33). Recently, expression levels of CD44v9 in early gastric cancer have also been shown to correlate positively with the risk of recurrence in patients who underwent endoscopic submucosal dissection (21). Furthermore, expression levels of CD44v9 in head and neck cancer cell lines were associated with increased levels of intracellular GSH and resistance to cisplatin (52).…”

Section: Methodsmentioning

confidence: 99%

<b>CD44 variant 9 expression as a predictor for gastric cancer recurrence: immunohistochemical and metabolomic analysis of surgically resected </b><b>tissues </b>

et al. 2017

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CD44 variant 9 (CD44v9) and the heavy chain of 4F2 cell-surface antigen (CD98hc) appear important for regulation of reactive oxygen species defence and tumor growth in gastric cancer. This study examined the roles of CD44v9 and CD98hc as markers of gastric cancer recurrence, and investigated associations with energy metabolism. We applied capillary electrophoresis time-of-flight mass spectrometry to metabolome profiling of gastric cancer specimens from 103 patients who underwent resection with no residual tumor or microscopic residual tumor, and compared metabolite levels to immunohistochemical staining for CD44v9 and CD98hc. Positive expression rates were 40.7% for CD44v9 and 42.7% for CD98hc. Various tumor characteristics were significantly associated with CD44v9 expression. Five-year recurrence-free survival rate was significantly lower for CD44v9-positive tumors (39.1%) than for CD44v9-negative tumors (73.5%; P < 0.0001), but no significant differences in recurrence-free survival were seen according to CD98hc expression. Uniand multivariate analyses identified positive CD44v9 expression as an independent predictor of poorer recurrence-free survival. Metabolome analysis of 110 metabolites found that levels of glutathione disulfide were significantly lower and reduced glutathione (GSH)/ glutathione disulfide (GSSG) ratio was significantly higher in CD44v9-positive tumors than in CD44v9-negative tumors, suggesting that CD44v9 may enhance pentose phosphate pathway flux and maintain GSH levels in cancer cells.Gastric cancer is the fifth most common malignancy (952,000 cases in 2012) and the third leading cause of cancer-related deaths (723,000 deaths in 2012) worldwide (1). Despite the decline in global patient numbers, gastric cancer remains one of the most prevalent cancers in Japan. Although progress in early diagnosis and adjuvant therapy has improved outcomes for gastric cancer patients, radical surgery remains the primary approach for gastric cancer treatment. Outcomes are still unsatisfactory, because gastric cancers relapse with local or distant metastasis even after radical gastrectomy. More specific diagnostic and therapeutic targets are urgently needed to achieve better clinical applications in this field. CD44, a major adhesion molecule for the extracellular matrix, is a single-pass type I transmembrane protein that serves as a cell surface receptor for hyaluronic acid, and has been implicated in vari-

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“…Little is known regarding the biology or behavior of CD44, CD44V9, ABCG2, CD24, BMI-1, ALDH1 of stage I and II OSCC. We would choose those CSC marker among many reports considered important for survival rates including esophageal, lung, gastric, colorectal, and head and neck cancer (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)21,22). And the significance of expression of those markers in stage I and II OSCC remains to be determined.…”

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confidence: 99%

Expression of CD44, CD44v9, ABCG2, CD24, Bmi‑1 and ALDH1 in stage I and II oral squamous cell carcinoma and their association with clinicopathological factors

et al. 2018

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Abstract. Cancer stem cells (CSCs) exhibit self-replication, self-differentiation, drug resistance and immune evasion activities. In recent years CSCs have become increasingly important for the treatment of malignant tumors. CSCs express specific markers, including cluster of differentiation (CD)44, CD44 variant 9 (CD44v9), ATP-binding cassette sub-family G member 2 (ABCG2), CD24, B lymphoma Mo-MLV insertion region 1 homolog (BMI-1) and aldehyde dehydrogenase 1 (ALDH1). However, the prognostic value of their expression in patients with oral squamous cell carcinoma (OSCC) are not well known. The present study evaluated these markers in stage I and II patients with OSCC and examined the association between T classification, histological differentiation, classification of invasion mode, lymph node metastasis and disease-free survival rate. Tissue specimens were obtained from 70 patients with stage I or II OSCC following either surgery or biopsy. Immunohistochemistry was performed and positive staining was defiend as 10% positive cells. CD44 and CD44v9 expressions were strongly detected in all OSCC tissues compared with normal epithelial cells. A total of 22 (31.4%) cases expressed ABCG2 and there was a significant association between ABCG2 expression and invasion. A total of 41 cases (59.0%) expressed CD24 and there was a significant association between CD24 expression and invasion. A total of 33 cases (47.1%) expressed BMI-1 and there was a significant association between BMI-1 expression and the disease-free survival rate. A total of 18 cases (25.7%) expressed ALDH1.Although there was no association between ALDH1 expression and T classification, there were significant associations between ALDH1 expression and histological differentiation, invasion mode, metastasis and the disease-free survival rate. Multivariate analysis revealed that ALDH1 expression was the only prognostic factor for disease-free survival rate. The results of the present study suggest that the positivity of ALDH1 detected in patients with OSCC correlates with the number of cells undergoing epithelial mesenchymal transition and metastasis. These findings indicated that the expression of ALDH1 may be an effective prognostic marker indicating the survival of patients with stage I and II OSCC. IntroductionCancer stem cells (CSCs) are functionally defined by their extensive self-renewal capacity. CSC confers increased radioand chemoresistance in tumors, resulting in tumor recurrence and metastatic spread. Therefore, identification of the regulators that control the tumorigenic potential of CSCs might provide new therapeutic strategies against CSCs to improve cancer treatment. The CSC theory suggests that only a few cancer cells with a capacity for high tumorigenicity, self-renewal, and differentiation are responsible for the maintenance and growth of tumors. Similar to normal tissue stem cells, CSCs can also exist within a supportive niche (1).Oral squamous cell carcinoma (OSCC) patients in stage I and II are mainly treated by surgery and almost all...

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CD44 variant 9 expression in primary early gastric cancer as a predictive marker for recurrence

Cited by 118 publications

References 34 publications

CD44v8-10 Is a Cancer-Specific Marker for Gastric Cancer Stem Cells

CD44v8-10 Is a Cancer-Specific Marker for Gastric Cancer Stem Cells

<b>CD44 variant 9 expression as a predictor for gastric cancer recurrence: immunohistochemical and metabolomic analysis of surgically resected </b><b>tissues </b>

Expression of CD44, CD44v9, ABCG2, CD24, Bmi‑1 and ALDH1 in stage I and II oral squamous cell carcinoma and their association with clinicopathological factors

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