The NOTCH4-GATA4-IRG1 axis as a novel target in early-onset colorectal cancer |
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| Institution: | 1. Digestive Surgery Research Laboratory, Price Institute of Surgical Research, Department of Surgery, University of Louisville, Louisville, KY, USA;2. Kentucky IDeA Networks of Biomedical Research Excellence (KY INBRE), Bioinformatics Core, University of Louisville, Louisville, KY, USA;3. Gastroenterology, Rochester, MI, John D. Dingell VAMC, Department of Medicine, Division of Gastroenterology, Wayne State University, MI, USA;1. Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Turin, Italy;2. Oncology Unit, ASST Bergamo Ovest, Treviglio, Bergamo, Italy;3. Department of Radiology, University of Cagliari, Cagliari, Italy;4. Harvard Premedical Program, Harvard University, Cambridge, MA, USA;5. Medical Oncology, Hospital of Nuoro, ASSL Nuoro, Nuoro, Italy;6. Department of Medical Oncology, Azienda Ospedaliera Universitaria Di Cagliari, Cagliari, Italy;1. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea;2. College of Pharmacy, Hanyang University, Ansan 15588, Republic of Korea;3. Department of Pathology, College of Medicine, Chosun University, Gwangju 61452, Republic of Korea;4. College of Veterinary Medicine, Chonbuk National University, Iksan 54596, Republic of Korea;1. Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China;2. Department of Laboratory Medicine, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China;3. Department of Laboratory Medicine, The Affiliated People’s Hospital, Jiangsu University, Zhenjiang, China;4. Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China;1. Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, Beijing 100053, China;2. Beijing Geriatric Medical Research Center, Beijing 100053, China;3. Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China |
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| 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. |
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| Keywords: | Early-onset colorectal cancer Colorectal neoplasms Colonic neoplasms Tumor-associated macrophages Obesity Adiposity |
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