267 INTESTINAL STEM CELL MARKERS AND ITS POTENTIAL USE IN THE CLINICOPATHOLOGICAL SETTING OF ESOPHAGEAL ADENOCARCINOMA

Abstract Barrett’s esophagus (BE) is the primary precursor lesion of esophageal adenocarcinoma (EAC), which not only resembles the intestinal mucosa morphologically but also expresses various intestinal stem cell (ISC) markers. We hypothesized that ISC markers, Lgr5 (also a cancer stem cell marker), Ascl2 (fate determinator of ISC),Bmi1 (quiescent counterpart of Lgr5) and Cdx2 (primary regulator of ISC gene expression) have clinicopathological significance and could potentially be a predictor for survival in EAC. Methods Tissue microarray consisted of 64 EAC and 22 BE, and the expressions of Lgr5, Ascl2, Bmi1 and Cdx2 were analyzed using immunohistochemistry and scored independently by two pathologists. Clinicopathological factors (age, pathological grade and stage, affected lymph nodes, neoadjuvant therapy) were confounding factors, and univariable analysis using Fisher's exact tests as well as survival analysis using the Kaplan–Meier (KM) method and Cox proportional hazards regression (Cox PH) were performed to investigate its statistical significance. We performed a bioinformatic analysis of the TCGA dataset to validate the immunohistochemical findings. Results Among EAC, 69%, 88%, 64% and 70% expressed high Ascl2, Lgr5, Bmi1 and Cdx2, respectively. High Ascl2 and low Lgr5 expression significantly correlated to a higher number of involved lymph nodes; high Bmi1 expression significantly correlated to the pathological stage. Cdx2 was not correlated to any markers. KM analysis showed a negative impact of high Ascl2 expression on overall survival (OS; p = 0.0276) as well as progression-free survival (PFS; p = 0.0466), but not Lgr5, Bmi1 nor Cdx2. Cox PH analysis revealed Ascl2 (p = 0.011), and Cdx2 (p = 0.015) expression are independent prognostic factors for EAC. Conclusion Our results suggest that among the four ISC markers, Ascl2 and Cdx2 protein holds potential to be utilized as a prognostic biomarker. TCGA dataset revealed the association of ASCL2 mRNA expression with the number of positive lymph nodes but not overall survival, which implies further research is needed to explain the mechanism of Ascl2 overexpression in EAC carcinogenesis via ISC regulation.

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Intestinal Stem Cell Marker, ASCL2 Is a Novel Prognostic Predictor in Esophageal Adenocarcinoma

10.21203/rs.3.rs-297726/v1 ◽

2021 ◽

Author(s):

Yukiko Shibahara ◽

Osvaldo Espin-Garcia ◽

James Conner ◽

Jessica Weiss ◽

Mathieu Derouet ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Prognostic Factor ◽

Esophageal Adenocarcinoma ◽

Independent Prognostic Factor ◽

Nodal Status ◽

Stem Cell Marker ◽

Intestinal Stem Cell ◽

Cell Marker ◽

Lgr5 Expression

Abstract Purpose: Stem cell markers play a significant role in esophageal adenocarcinoma carcinogenesis via Barrett’s esophagus; however, its utility as a prognostic biomarker has not been established. Methods: We analyzed the immunohistochemical expression of Ascl2 and Lgr5 utilizing whole slides (WS; 35 cases) and tissue microarray (TMA; 64 cases of esophageal adenocarcinoma with adjacent normal squamous epithelium, Barrett's esophagus, and dysplasia). Two pathologists semi-quantitatively scored stained slides independently/blindly, and the results were correlated with clinicopathologic factors and outcomes. Results: In WS, 51% and 57% expressed high Ascl2 and high Lgr5; in TMA, 69% and 88% expressed high Ascl2 and high Lgr5, respectively. In TMA, high Ascl2 and low Lgr5 expression significantly correlated to a higher number of involved lymph nodes (p=0.027 and p=0.0039), and Lgr5 expression significantly correlated to the pathological stage (p=0.0032). Kaplan-Meier analysis showed a negative impact of high Ascl2 expression on overall survival (OS; WS p=0.0168, TMA p=0.0276) as well as progression-free survival (PFS; WS p=0.000638, TMA p=0.0466), but not Lgr5. Multivariate Cox regression analysis revealed that Ascl2 expression is an independent prognostic factor for esophageal adenocarcinoma (OS; WS p=0.25, TMA p=0.011. PFS; WS p=0.012, TMA p=0.038). Analysis of the TCGA dataset showed that ASCL2 mRNA levels were correlated to nodal status but not overall survival.Conclusion: Intestinal stem cell marker, Ascl2 is an independent prognostic factor in esophageal adenocarcinoma. High Ascl2 levels were associated with nodal status in both immunohistochemical and mRNA expression. These findings may contribute to the development of prognosis-based subclassification of esophageal adenocarcinoma.

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Intestinal Stem Cell Marker ASCL2 is a Novel Prognostic Predictor in Esophageal Adenocarcinoma

Cureus ◽

10.7759/cureus.21021 ◽

2022 ◽

Author(s):

Yukiko Shibahara ◽

Osvaldo Espin-Garcia ◽

James Conner ◽

Jessica Weiss ◽

Mathieu Derouet ◽

...

Keyword(s):

Stem Cell ◽

Esophageal Adenocarcinoma ◽

Stem Cell Marker ◽

Intestinal Stem Cell ◽

Cell Marker ◽

Prognostic Predictor

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Slug overexpression and association with clinicopathological features in gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.426 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 426-426

Author(s):

Joori Kim ◽

In-Ho Kim ◽

Han Hee Lee ◽

Sung Hak Lee ◽

Jae Myung PARK

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Stem Cell ◽

Adjuvant Chemotherapy ◽

Cancer Stem Cell ◽

Stem Cell Marker ◽

Stem Cell Markers ◽

Slug Expression ◽

Disease Free ◽

E Cadherin

426 Background: Slug is a suppressive transcriptional factor of E-cadherin, acting as an activator of epithelial-mesenchymal transition(EMT). Its clinical relevance in gastric cancer(GC) is not fully known. Methods: Our study evaluated the expression patterns of EMT and cancer stem cell markers in GC patients who had clinical stage 2-3, underwent gastrectomy, D2 lymph node dissection (LND), adjuvant chemotherapy. Immunohistochemistry of E-cadherin, vimentin, CD133, ABCG2, NEDD9, SMAD4, XB130, Slug, Snail were investigated from 210 gastric cancer samples using tissue microarrays. The correlation between each markers expressed and the association with clinicopathological factors were analyzed. Results: Slug expression was more frequent in stage 3 than stage 2 (p=0.000), advanced T (p=0.007) and N stage (p=0.001), while histologic type did not make difference. Slug expression correlated with the expression of cancer stem cell marker CD133 (r=0.180, p=0.015) and CD133 expression was also related with ABCG2 (r=0.412, p=0.000). High Slug group showed shorter overall survival, compared to low Slug group (median OS 134 vs 124 months, p=0.044). The 2-year and 5-year disease-free (DF) rate for patients with high Slug and low Slug was 87.1% and 79.8%, 68.1% and 79.8%, respectively(p=0.038). The DFS curve reached an earlier plateau at 11-month in low Slug group, while in high Slug group took as long as 99 months. A multivariate analysis using the Cox proportional hazards regression model demonstrated Slug to be an independent prognostic factor for overall survival; hazard ratio 0.504 [95% CI 0.278-0.916] (p=0.025). Conclusions: In stage 2-3 GC patients who underwent gastrectomy with D2 LND and adjuvant chemotherapy, high Slug expression is associated with better disease-free and overall survival. Patients may benefit by testing Slug immunohistochemistry to predict prognosis after gastrectomy.

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Lgr5, an intestinal stem cell marker, is abnormally expressed in Barrett's esophagus and esophageal adenocarcinoma

Diseases of the Esophagus ◽

10.1111/j.1442-2050.2009.00979.x ◽

2010 ◽

Vol 23 (2) ◽

pp. 168-174 ◽

Cited By ~ 54

Author(s):

L. Becker ◽

Q. Huang ◽

H. Mashimo

Keyword(s):

Stem Cell ◽

Barrett’S Esophagus ◽

Esophageal Adenocarcinoma ◽

Barrett's Esophagus ◽

Stem Cell Marker ◽

Intestinal Stem Cell ◽

Cell Marker

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The potential prognostic value of expression of stem cell marker of CD44s, EpCAM, and OVA66 in patients with gastric adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15562 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15562-e15562

Author(s):

Ning Yan ◽

Ying chun Xu ◽

Fengchun Zhang ◽

Siyu Chen

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Differential Expression ◽

Gastric Adenocarcinoma ◽

Univariate Analysis ◽

Stem Cell Marker ◽

Stem Cell Markers ◽

Immunohistochemistry Analysis ◽

Significant Difference ◽

Cancer Tissues

e15562 Background: The present study aimed to (i) examine the expression pattern of putative stem cell markers, CD44s, EpCAM, and new tumor specific antigen OVA66, in gastric adenocarcinoma (GA) and normal para-cancer tissues; (ii) determine if the expression of these proteins is associated with overall survival of GA. Methods: 84 GA patients confirmed by histopathology were examined the expressions of CD44s, EpCAM and OVA66 using tissue microarray technique. The immunohistochemistry analysis were carried out to explore the differential expression CD44s , EpCAM and OVA66 in GA compared to normal para-cancer tissues (p = 0.001). Next, Kaplan-Meier analysis was conducted to investigate their effect in overall survival(OS). Results: The immunohistochemistry analysis demonstrated the differential expression CD44s and EpCAM in GA compared to normal para-cancer tissues (p = 0.001), while there was no significant difference of OVA66 expression between cancer and normal specimens (p = 0.366). The upregulated expression of CD44s was well correlated with lymph node metastasis (p = 0.018), however the expression of OVA66 was only associated with gender of the patients (p = 0.025) and age at presentation (p = 0.018). The univariate analysis demonstrated that patients with blood and lymphatic vessel invasion, pT category 3 to 4, pN positive, with faraway metastasis, and stage Ⅲ to Ⅳ had a significantly shorter OS. Both increased expressions of the CD44s and EpCAM was shown in patients with poor OS (p = 0.037) and was confirmed by multivariate analysis. Conclusions: Our study suggested EpCAM is a potential diagnostic marker for gastric cancer and combined with CD44+/EpCAM+ can be regarded as an independent prognostic marker for patients with GA.

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Identification of the putative intestinal stem cell marker doublecortin and CaM kinase-like-1 in Barrett's esophagus and esophageal adenocarcinoma

Journal of Gastroenterology and Hepatology ◽

10.1111/j.1440-1746.2011.06928.x ◽

2012 ◽

Vol 27 (4) ◽

pp. 773-780 ◽

Cited By ~ 37

Author(s):

Kenneth J Vega ◽

Randal May ◽

Sripathi M Sureban ◽

Stan A Lightfoot ◽

Dongfeng Qu ◽

...

Keyword(s):

Stem Cell ◽

Barrett’S Esophagus ◽

Esophageal Adenocarcinoma ◽

Barrett's Esophagus ◽

Stem Cell Marker ◽

Intestinal Stem Cell ◽

Cell Marker ◽

Cam Kinase

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Expression of Intestinal Stem Cell and Cancer Stem Cell Markers in Submucosal Invasion and Its Prognostic Significance in Gastric Cancers

10.20944/preprints202007.0484.v1 ◽

2020 ◽

Author(s):

Hye Sung Kim ◽

Hyun Joo Song ◽

In Ho Jeong ◽

Bo Gun Jang

Keyword(s):

Stem Cell ◽

Cancer Stem Cell ◽

Prognostic Significance ◽

Submucosal Invasion ◽

Intestinal Type ◽

Stem Cell Marker ◽

Intestinal Stem Cell ◽

Stem Cell Markers ◽

Muscularis Mucosa ◽

Submucosal Cancer

Submucosal invasion is a critical step in gastric cancer (GC) progression, which greatly enhances metastasis risk. Cancer stem cells are responsible for invasion, metastasis, and tumor growth. To identify stem cell-related markers associated with submucosal invasion in GCs, we investigated the expression of candidate cancer stem cell (CSC) markers (CD133, CD44, and ALDH1A) and intestinal stem cell (ISC) markers (EPHB2, OLFM4, and LGR5) in early GCs with submucosal invasion. Remarkably, expression of all ISC markers and CD133 was frequently confined to the basal area of the lamina propria (basal pattern) in mucosal cancer. The proportion of stem cell marker-positive cells substantially increased during submucosal invasion. Given that ISC markers are restricted to the crypt base of the normal intestinal mucosa, these findings suggest that many early GCs may retain hierarchical characteristics. CD44 expression showed a focal pattern, ALDH1A was predominantly expressed diffusely, and there was no expansion of CD44 or ALDH1A expression in the submucosal cancer cells. RSPO2 from muscularis mucosa seem to be partly responsible for the increased expression of ISC markers in GC cells at the basal areas. We also found that ISC markers were correlated with CDX2 expression in GCs, indicating that ISC markers are involved in the intestinal differentiation in GCs. Interestingly, ISC markers (EPHB2 and OLFM4) and CD133 showed a positive impact on clinical outcomes. In particular, the prognostic value of EPHB2 was significant for intestinal-type GCs in a multivariate analysis. In summary, ISC markers and CD133 showed a basal distribution pattern along with enhanced expression in submucosal invading cells in early GCs. EPHB2 was an independent prognostic marker in intestinal-type GCs.

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ARE STEM CELL MARKER EXPRESSION AND CD133 ANALYSIS RELEVANT TO DIFFERENTIATE COLORECTAL CANCER?

ABCD Arquivos Brasileiros de Cirurgia Digestiva (São Paulo) ◽

10.1590/0102-672020200004e1568 ◽

2020 ◽

Vol 33 (4) ◽

Author(s):

Leticia Elizabeth Augustin CZECZKO ◽

Carmen Australia Paredes Marcondes RIBAS ◽

Nicolau Gregori CZECZKO ◽

Thelma Larocca SKARE ◽

Camila Kienen YAMAKAWA ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Stem Cell ◽

Univariate Analysis ◽

Stem Cell Marker ◽

Stem Cell Markers ◽

Poor Overall Survival ◽

Clinicopathologic Characteristics ◽

Primary Tumors ◽

Cd133 Expression

ABSTRACT Background: CD133 and AXL have been described as cancer stem cell markers, and c-MYC as a key regulatory cellular mechanism in colorectal cancer (CRC). Aim: Evaluate the prognostic role of the biomarkers CD133, AXL and c-MYC and their association with clinicopathologic characteristics in colorectal adenocarcinomas and adenomas. Methods: A total of 156 patients with UICC stage I-IV adenocarcinomas (n=122) and adenomas (n=34) were analyzed. Tissue microarrays (TMA) from primary tumors and polyps for CD133, c-MYC and AXL expression were performed and analyzed for their significance with clinicopathologic characteristics. Results: Poorly differentiated adenocarcinomas and disease progression were independent risk factors for poor overall survival. The median overall survival time was 30 months. Positive CD133 expression (35.9% of all cases), particularly of right-sided CRCs (44.8% of the CD133+ cases), was negatively correlated with death in the univariate analysis, which did not reach significance in the multivariate analysis. c-MYC (15.4% of all cases) was predominantly expressed in advanced-stage patients with distant (non-pulmonary/non-hepatic) metastasis. AXL expression was found only occasionally, and predominantly dominated in adenomas, with less penetrance in high-grade dysplasia. Conclusions: CD133 expression was not associated with inferior overall survival in CRC. While AXL showed inconclusive results, c-MYC expression in primary CRCs was associated with distant metastasis.

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