Inflammation and Notch signaling: a crosstalk with opposite effects on tumorigenesis

Abstract

The Notch cascade is a fundamental and highly conserved pathway able to control cell-fate. The Notch pathway arises from the interaction of one of the Notch receptors (Notch1–4) with different types of ligands; in particular, the Notch pathway can be activated canonically (through the ligands Jagged1, Jagged2, DLL1, DLL3 or DLL4) or non-canonically (through various molecules shared by other pathways). In the context of tumor biology, the deregulation of Notch signaling is found to be crucial, but it is still not clear if the activation of this pathway exerts a tumor-promoting or a tumor suppressing function in different cancer settings. Untill now, it is well known that the inflammatory compartment is critically involved in tumor progression; however, inflammation, which occurs as a physiological response to damage, can also drive protective processes toward carcinogenesis. Therefore, the role of inflammation in cancer is still controversial and needs to be further clarified. Interestingly, recent literature reports that some of the signaling molecules modulated by the cells of the immune system also belong to or interact with the canonical and non-canonical Notch pathways, delineating a possible link between Notch activation and inflammatory environment. In this review we analyze the hypothesis that specific inflammatory conditions can control the activation of the Notch pathway in terms of biological effect, partially explaining the dichotomy of both phenomena. For this purpose, we detail the molecular links reported in the literature connecting inflammation and Notch signaling in different types of tumor, with a particular focus on colorectal carcinogenesis, which represents a perfect example of context-dependent interaction between malignant transformation and immune response.

Biliary reflux as a causal factor in hypopharyngeal carcinoma: New clinical evidence and implications

“…34,43 Bile(+) HSCC produces higher transcriptional levels of PIK3CA, TP53, NOTCH1, NOTCH2, and NOTCH3 compared with their ANTs or bile(-) tumors. 46,47 The data from the current study do not fully support a strong association between the NOTCH family and bile(+) HSCC. Because PI3K activation may lead to downstream NF-κB activation, 35 its role in bile-induced NF-κB activation requires further exploration.…”

Mutational landscape of penile squamous cell carcinoma in a Chinese population

“…47 Moreover, both the Notch and Hippo pathways play potential roles in inflammation. 48,49 Alterations in the top three highest ranked pathways accounted for over 50% of cases in our sample. The frequently mutated genes (>10%) in these pathways were proven to be expressed in penile tumors.…”

“…It has been linked to tumorigenesis, as well as tumor invasion and metastasis . Moreover, both the Notch and Hippo pathways play potential roles in inflammation . Alterations in the top three highest ranked pathways accounted for over 50% of cases in our sample.…”

Jagged1‐expressing adenovirus‐infected dendritic cells induce expansion of Foxp3+ regulatory T cells and alleviate T helper type 2‐mediated allergic asthma in mice

“…Recent findings have revealed the important roles of the Notch signaling pathway in T‐cell differentiation . This signaling is mediated by Notch ligand–receptor interactions between neighboring cells.…”

“…Recent findings have revealed the important roles of the Notch signaling pathway in T-cell differentiation. 18,19 This signaling is mediated by Notch ligand-receptor interactions between neighboring cells. In mammals, Notch receptors contain four members (Notch1-4), and Notch ligands include members of the Delta-like (Dll) family (Dll1, Dll3, and Dll4) and Jagged (Jag) family (Jag1 and Jag2).…”