Association of Notch and Hedgehog Pathway Activation With Prognosis in Early-stage Colorectal Cancer

Rallis, Grigorios; Κoletsa, Triantafyllia; Saridaki, Zenia; Manousou, Kyriaki; Koliou, Georgia-Angeliki; Kostopoulos, Ioannis; Kotoula, Vassiliki; Makatsoris, Thomas; Kourea, Helen P.; Raptou, Georgia; Chrisafi, Sofia; Samantas, Epaminontas; Papaparaskeva, Kleo; Pazarli, Elissavet; Papakostas, Pavlos; Kafiri, Georgia; Mauri, Davide; Papoudou‐Bai, Alexandra; Petraki, Kalliopi; Dombros, Nikolaos; Pectasides, Dimitrios; Fountzilas, George

doi:10.21873/anticanres.13326

Cited by 12 publications

(6 citation statements)

References 54 publications

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“…Bernasconi-Elias and colleagues generated Notch3 inhibitory antibodies that exhibited strong antileukemic activity in cell lines as well as tumor xenografts with Notch3 activating mutations [33]. free survival (DFS) and overall survival (OS) [35]. Another study also confirmed a link between high levels of Notch3 and aggressive malignant colorectal cancer cell phenotype [36] and tumor recurrence after surgical resection of CRC [37,38].…”

Section: Discussionmentioning

confidence: 93%

Frequent Activation of Notch Signaling Pathway in Colorectal Cancers and Its Implication in Patient Survival Outcome

Shaik

Alanazi

Pathan

et al. 2020

Journal of Oncology

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Colorectal cancer is a major health concern as it ranks third in incidence and second major cause of cancer-related deaths worldwide. A leading cause of treatment failure has been attributed to cancer stem cells that can invariably resist existing chemotherapeutic regimens. Notch signaling pathway has been involved in the maintenance of stem cells besides being crucial in cell fate decision and embryonic development. This pathway has also been implicated in several human malignancies including colorectal cancer. We investigated mRNA expression of four Notch receptors (Notch1–4), five ligands (Jag1, Jag2, Dll1, Dll3, and Dll4), and four target genes (Hes1, Hes5, Hey1, and Hey2) using highly specific TaqMan gene expression assays in colorectal adenomas and cancers. Upregulated expression of Notch receptors ranged between 29 and 73% in colorectal cancers and between 11 and 56% in adenomas. Expression of Notch3 and Notch4 receptors was significantly higher in colorectal cancers compared to normal and adenoma tissues. The Jagged and Delta-like ligands were overexpressed between 25 and 52% in colorectal cancers, while in adenomas, it ranged between 0 and 33%. Combining the data for upregulation of receptors and ligands suggests that 86% colorectal cancers and 56% adenomas exhibited overexpression of Notch pathway genes in our cohort. Notch target genes were upregulated between 24 and 33% in colorectal cancers and between 11 and 22% in adenomas. Collating upregulation of Notch receptors and ligands with the target genes showed concordance in 58% colorectal tumors. Additionally, we evaluated expression of Notch receptors, ligands, and target genes with prognosis using the TCGA mRNA expression dataset. Patients overexpressing Notch3, Notch4, and Hey1 had significantly poorer overall survival relative to those having lower levels of these genes. Taken together, Notch signaling components are aberrantly overexpressed in colorectal tumors, and development of therapeutics targeting the Notch pathway may prove to be beneficial in the management of colorectal cancers.

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Section: Discussionmentioning

confidence: 93%

Frequent Activation of Notch Signaling Pathway in Colorectal Cancers and Its Implication in Patient Survival Outcome

Shaik

Alanazi

Pathan

et al. 2020

Journal of Oncology

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“… 153 The positive expression of Notch3 protein is an unfavorable prognostic factor of disease-free survival (DFS) and overall survival (OS). 154 However, the functions of notch2 and notch4 are opposite to them, their overexpression can block the proliferation, invasion or migration of cancer cells. 155 , 156 Meanwhile, multiple Notch signaling pathway related mechanisms play a significant role in metastatic CRC(Fig.…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Colorectal liver metastasis: molecular mechanism and interventional therapy

Zhou

Liu

Wang

et al. 2022

Sig Transduct Target Ther

128

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Colorectal cancer (CRC) is one of the most frequently occurring malignancy tumors with a high morbidity additionally, CRC patients may develop liver metastasis, which is the major cause of death. Despite significant advances in diagnostic and therapeutic techniques, the survival rate of colorectal liver metastasis (CRLM) patients remains very low. CRLM, as a complex cascade reaction process involving multiple factors and procedures, has complex and diverse molecular mechanisms. In this review, we summarize the mechanisms/pathophysiology, diagnosis, treatment of CRLM. We also focus on an overview of the recent advances in understanding the molecular basis of CRLM with a special emphasis on tumor microenvironment and promise of newer targeted therapies for CRLM, further improving the prognosis of CRLM patients.

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“…In the intestinal epithelium, Notch signaling plays a crucial role by regulating cell differentiation, determining the lineage fate of TA cells. Activation of the Notch pathway relies on the interaction of five ligands (Jagged1/2 and Delta like-1/3/4) and four receptors (Notch1/2/3/4) (Rallis et al., 2019).…”

Section: Regulation Of Intestinal Homeostasismentioning

confidence: 99%

Diet, Microbiota, and Colorectal Cancer

2019

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The intestinal epithelium is a very dynamic tissue under a high regenerative pressure, which makes it susceptible to malignant transformation. Proper integration of various cell signaling pathways and a balanced cross talk between different cell types composing the organ are required to maintain intestinal homeostasis. Dysregulation of this balance can lead to colorectal cancer (CRC). Here, we review important insights into molecular and cellular mechanisms of CRC. We discuss how perturbation in complex regulatory networks, including the Wnt, Notch, BMP, and Hedgehog pathways; and how variations in inflammatory signaling, nutrients, and microbiota can affect intestinal homeostasis contributing to the malignant transformation of intestinal cells. INTESTINE STRUCTURE AND FUNCTION The intestine is the last part of the gastrointestinal tract, and is divided into two anatomically and functionally different sections: the small intestine and the large intestine, whose main functions are food digestion, stool compaction, and absorption of water, nutrients, and salts. Both the small and large intestines present an outer layer of smooth muscle with enteric nervous system; a middle layer composed of connective tissue, nerves, and lymphatic vessels; and an inner epithelial layer called the mucosa. The small intestine presents epithelial folds resembling finger-like protrusions called villi, which face the lumen and aim to maximize the available absorptive area. Villi are surrounded by epithelial invaginations that form the crypts of Lieberkü hn (Figure 1). In contrast, the colonic epithelium lacks villi and consists of a plane surface with multiple epithelial invaginations forming the crypts (

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Association of Notch and Hedgehog Pathway Activation With Prognosis in Early-stage Colorectal Cancer

Cited by 12 publications

References 54 publications

Frequent Activation of Notch Signaling Pathway in Colorectal Cancers and Its Implication in Patient Survival Outcome

Frequent Activation of Notch Signaling Pathway in Colorectal Cancers and Its Implication in Patient Survival Outcome

Colorectal liver metastasis: molecular mechanism and interventional therapy

Diet, Microbiota, and Colorectal Cancer

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