Clinicopathological significance of altered Notch signaling in extrahepatic cholangiocarcinoma and gallbladder carcinoma

Yoon, Hyun Ah; Noh, Myung Hwan; Kim, Byung Geun; Han, Ji‐Yeon; Jang, Jin Seok; Choi, Seok Ryeol; Jeong, Jin Sook; Chun, Jin Ho

doi:10.3748/wjg.v17.i35.4023

Cited by 35 publications

(28 citation statements)

References 21 publications

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“…47 Among the various components of the NOTCH pathway, the activation of NOTCH3 was reported in epithelial ovarian cancer, extrahepatic cholangiocarcinoma, gallbladder cancer, and T-acute lymphoblastic leukemia. 23,48,49 We found 50% of colorectal cancer expressed NOTCH3. Compared with non-micropapillary carcinoma, cases with micropapillary carcinoma showed significantly higher levels of NOTCH3 expression (42 vs 69%).…”

Section: Modern Pathology (2013) 26 1123-1131mentioning

confidence: 81%

Colorectal micropapillary carcinomas are associated with poor prognosis and enriched in markers of stem cells

et al. 2013

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Colorectal micropapillary carcinoma has recently been reported as an aggressive variant of adenocarcinoma with a high incidence of lymph node metastasis, but has not been well investigated in terms of survival analysis. This study analyzed the clinicopathological characteristics, including survival data, of the patients with micropapillary carcinoma. We hypothesized that the aggressive features of micropapillary carcinoma might be related to the presence of more tumor cells with stem cell phenotype in colorectal cancer. Fifty-five (10%) micropapillary carcinoma cases were identified among 561 cases of colorectal cancer. We compared the clinicopathological characteristics, including survival data and immunohistochemical profiles of stem cell markers (SOX2, NOTCH3, CD44v6, CD166, ALDH1) of micropapillary carcinomas with those of randomly selected 112 conventional adenocarcinomas lacking micropapillary carcinoma components (non-micropapillary carcinoma) in the colorectum. To exclude the possibility of dilution of control group by patients with microsatellite instability-high carcinomas, we divided non-micropapillary carcinomas into microsatellite instability-high carcinoma and microsatellite stable tumors. Micropapillary carcinomas were characterized by more frequent lymphovascular invasion (Po0.0001) and lymph node metastasis (Po0.0001), higher pathological T and tumor node metastasis stages (P ¼ 0.047 and P ¼ 0.001), and more frequent SOX2 (P ¼ 0.038) and NOTCH3 expressions (P ¼ 0.005). Overall 5-year survival rate for patients with micropapillary carcinoma (37%) was significantly lower than for microsatellite instability-high carcinoma and microsatellite stable carcinoma patients (92 and 72%, Po0.0001). The presence of the micropapillary carcinoma component was shown to be associated with a significantly worse survival rate in univariate (Po0.0001) and multivariate (P ¼ 0.003, Cox hazard ratio 2.402) analyses. In conclusion, recognition of the micropapillary carcinoma component in colonic adenocarcinoma is very important, because the micropapillary carcinoma has been associated with a significantly worse prognosis. We also found a higher expression rate of cancer stem cell markers in micropapillary carcinomas, suggesting their potential contribution to the survival disadvantage of micropapillary carcinoma. Modern Pathology (2013Pathology ( ) 26, 1123Pathology ( -1131 doi:10.1038/modpathol.2012 published online 12 October 2012 Keywords: colorectum; micropapillary carcinoma; prognosis; stem cell marker; TNM stage Colorectal cancer is one of the leading causes of cancer deaths worldwide, and both the prevalence and the incidence rate in South Korea are rapidly rising. 1 For metastatic colorectal cancer, the 5-year survival rate is only about 10%. 2 Micropapillary carcinoma is a relatively uncommon and distinctive tumor characterized by small clusters of tumor cells in the clear lacunar spaces, mimicking lymphatic or vascular channels. 3 Micropapillary carcinoma has high potential to metastasize to the regional l...

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Section: Modern Pathology (2013) 26 1123-1131mentioning

confidence: 81%

Colorectal micropapillary carcinomas are associated with poor prognosis and enriched in markers of stem cells

et al. 2013

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“…The Notch signaling pathway also plays an important role in the maintenance of hepatic progenitor cells [51]. In a study by Yoon et al [52] that examined 110 resected specimens of biliary ductal cancer, the expression of Notch receptors by immunostaining was identified in more than 80 % of the cases. Moreover, the expression of Notch receptors 1 and 3 was related to cancer progression and poor survival in cholangiocarcinoma [52].…”

Section: Notch Pathwaymentioning

confidence: 99%

“…In a study by Yoon et al [52] that examined 110 resected specimens of biliary ductal cancer, the expression of Notch receptors by immunostaining was identified in more than 80 % of the cases. Moreover, the expression of Notch receptors 1 and 3 was related to cancer progression and poor survival in cholangiocarcinoma [52]. Notch pathways are crucial in a network of transcription factors for cholangiocyte differentiation [53], and blockage of the Notch pathway enhances tumor necrosis factorrelated apoptosis in cholangiocarcinoma [54].…”

Section: Notch Pathwaymentioning

confidence: 99%

Recent advances in cancer stem cell research for cholangiocarcinoma

Kokuryo

Yokoyama

Nagino

2012

J Hepato Biliary Pancreat

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Cancer stem cells have been identified as cells with the capacity to self‐renew and differentiate into multiple lineages of human malignancies. Cholangiocarcinoma is one of the most difficult intra‐abdominal malignancies that can be treated using a surgical approach. Chemotherapy in addition to surgery is necessary to improve patient survival. However, its clinical benefit is limited, and, to date, no other effective anticancer drug is available for this disease. Several reports have shown the existence of cholangiocarcinoma stem cells. Cell surface antigens such as CD133, CD24, EpCAM, CD44, and others have been used to isolate cholangiocarcinoma stem cells. In general, enhanced expression of these markers in resected specimens of cholangiocarcinoma was associated with malignant potential. Distinct and specific pathways are expected to be present in cancer stem cells compared to other cancer cells that have no stem cell properties. To date, reports showing possible signaling pathways in cholangiocarcinoma stem cells are limited. More research is anticipated. Targeting therapies for surface molecular markers or specific signaling pathways of cholangiocarcinoma stem cells may be important in order to change the clinical outcome of patients with this disease. However, no clinical trial has been performed so far. This review will focus on the markers and signaling pathways used to define cholangiocarcinoma stem cells. A novel therapeutic approach of targeting cholangiocarcinoma stem cells will also be discussed.

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“…Mouse models with increased Notch1 expression resulted in the formation of intrahepatic BC, reinforcing its importance in tumor development and growth (82). Notch receptor 1-4 upregulation has been identified in all anatomic subsets of BC, and in up to 80% of intrahepatic BC (83,84). In addition to its role in BC, Notch expression has also been implicated in the development of primary hepatocellular carcinomas (HCC).…”

Section: Notch Pathwaymentioning

confidence: 99%

Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications

Ahn

Bekaii‐Saab

2017

J. Gastrointest. Oncol.

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Biliary cancers (BCs) are a diverse group of tumors that arise from the bile duct epithelium and are divided into cholangiocarcinomas of the intrahepatic and extrahepatic cholangiocarcinoma (EHCC) and cancer of the gallbladder. Despite improvements in treatment and diagnosis, BCs are often diagnosed at an advanced stage and associated with poor prognosis and limited treatment options. Recent discoveries have allowed us to have a better understanding of the genomic diversity in BC, and identify genes that are likely contributing to its pathogenesis, proliferation and treatment resistance. Additionally, these advances have allowed us to reason that each anatomic group within BC behave as distinct diseases, with differences in prognosis and outcomes. Based on this knowledge, recent advances have allowed us to identify actionable mutations that form rational therapeutic targets with novel agents, where their relevance will be better understood through the completion of prospective clinical trials.

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Clinicopathological significance of altered Notch signaling in extrahepatic cholangiocarcinoma and gallbladder carcinoma

Abstract: Aberrant expression of Notch receptors 1 and 3 play a role during cancer progression, and cytoplasmic nuclear coexistence of DLL4 expression correlates with poor survival in extrahepatic CC and gallbladder carcinoma.

Cited by 35 publications

References 21 publications

Colorectal micropapillary carcinomas are associated with poor prognosis and enriched in markers of stem cells

Colorectal micropapillary carcinomas are associated with poor prognosis and enriched in markers of stem cells

Recent advances in cancer stem cell research for cholangiocarcinoma

Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications

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