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Review
. 2022 Oct:67:25-34.
doi: 10.1016/j.cytogfr.2022.06.002. Epub 2022 Jun 30.

The NOTCH4-GATA4-IRG1 axis as a novel target in early-onset colorectal cancer

Katharina M Scheurlen  1 , Julia H Chariker  2 , Ziad Kanaan  3 , Andrew B Littlefield  1 , Joan B George  1 , Caden Seraphine  1 , Andre Rochet  1 , Eric C Rouchka  2 , Susan Galandiuk  4
Affiliations
Review

The NOTCH4-GATA4-IRG1 axis as a novel target in early-onset colorectal cancer

Katharina M Scheurlen et al. Cytokine Growth Factor Rev. 2022 Oct.

Abstract

The early onset of colorectal cancer (CRC) in individuals younger than 50 years is an emerging phenomenon, and obesity is a strong risk factor. Inflammatory mechanisms are mediated by immune cells, with macrophages and their phenotypical changes playing a significant role in CRC. Obesity-related hormones, such as leptin and adiponectin, affect macrophage polarization and cytokine expression. Macrophage metabolism, and therefore polarization, directly affects tumor progression and survival in patients with CRC. Altered obesity-related hormone levels induce phosphoinositide kinase-3 (PI3K)/serine-threonine-protein kinase (AKT) activation in colon cancer, causing increased cell survival, hyperplasia, and proliferation. Investigating the effects of obesity-related mechanisms on PI3K/Akt signaling can provide new insights for targeting mechanisms in CRC and obesity among the young. Central molecules for the control of cell proliferation, differentiation, and tumorigenesis within the gastrointestinal tract include downstream targets of the PI3K/AKT pathway, such as Neurogenic locus notch homolog 4 (Notch4) and GATA binding proteins (GATA). Leptin and adiponectin both alter gene expression within this pathway, thereby affecting TAM-mediated CRC progression. Our goal is to introduce the NOTCH4-GATA4-IRG1 axis as a link between inflammation and sporadic CRC and to discuss this pathway as a new potential immunotherapeutic target in individuals affected with obesity and early-onset CRC.

Keywords: Adiposity; Colonic neoplasms; Colorectal neoplasms; Early-onset colorectal cancer; Obesity; Tumor-associated macrophages.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1. Structure of the NOTCH4-GATA4-IRG1 axis
Pathway network showing gene interactions of the NOTCH4-GATA4-IRG1 axis (blue shapes) and their relation to the obesity-related hormones leptin and adiponectin (yellow shapes). Red arrows demonstrate activation, while blue dotted arrows show inhibitory effects. Major gene interactions are in bold.
Fig. 2
Fig. 2. The effects of obesity-related hormones on itaconate in CRC progression
Leptin and adiponectin are produced by white subcutaneous adipocytes and regulated energy homeostasis by triggering the hypothalamus to lower the appetite. In obese individuals, the functions of these hormone levels are dysbalanced, leading to high leptin and low adiponectin levels. Both hormones can affect cellular metabolism and therefore itaconate production in colorectal macrophages. This suggests a potential role of leptin and adiponectin in CRC development. CRC = colorectal cancer; TCA = tricarboxylic acid cycle; IRG1 = immune-responsive gene 1
Fig. 3
Fig. 3. Cellular mechanisms of Notch signaling between cells within the tumor microenvironment.
The Notch receptor (red and green) of a signaling cell is modified undergoing two proteolytic cleavages after binding to its ligands on an adjacent cell (purple). The Notch intracellular domain (NICD, green) is released, transferred to the nucleus, binds to the DNA-binding CSL (CBF1, Su(H) and LAG-1) protein and induces gene transcription. NOTCH = Neurogenic locus notch homolog 4; ECD = extracellular domain; ICD = intracellular domain; MAML = mastermind-like protein 1; CoA = coenzyme A; CSL protein = CBF1, Su(H) and LAG-1 protein; HEY = Hairy and Enhancer of split-related with YRPW motif protein; HES = Hairy and Enhancer of split
See this image and copyright information in PMC

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