Cargando…

Targeting IL-23 for the interception of obesity-associated colorectal cancer

Inflammation and obesity are two major factors that promote Colorectal cancer (CRC). Our recent data suggests that interleukin (IL)-23, is significantly elevated in CRC tumors and correlates with patient obesity, tumor grade and survival. Thus, we hypothesize that obesity and CRC may be linked via i...

Descripción completa

Detalles Bibliográficos
Autores principales: Madka, Venkateshwar, Chiliveru, Srikanth, Panneerselvam, Janani, Pathuri, Gopal, Zhang, Yuting, Stratton, Nicole, Kumar, Nandini, Sanghera, Dharambir K., Rao, Chinthalapally V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568285/
https://www.ncbi.nlm.nih.gov/pubmed/37813000
http://dx.doi.org/10.1016/j.neo.2023.100939
_version_ 1785119327442173952
author Madka, Venkateshwar
Chiliveru, Srikanth
Panneerselvam, Janani
Pathuri, Gopal
Zhang, Yuting
Stratton, Nicole
Kumar, Nandini
Sanghera, Dharambir K.
Rao, Chinthalapally V.
author_facet Madka, Venkateshwar
Chiliveru, Srikanth
Panneerselvam, Janani
Pathuri, Gopal
Zhang, Yuting
Stratton, Nicole
Kumar, Nandini
Sanghera, Dharambir K.
Rao, Chinthalapally V.
author_sort Madka, Venkateshwar
collection PubMed
description Inflammation and obesity are two major factors that promote Colorectal cancer (CRC). Our recent data suggests that interleukin (IL)-23, is significantly elevated in CRC tumors and correlates with patient obesity, tumor grade and survival. Thus, we hypothesize that obesity and CRC may be linked via inflammation and IL-23 may be a potential target for intervention in high-risk patients. TCGA dataset and patient sera were evaluated for IL-23A levels. IL-23A [IL-23 p19(−/−)] knockout (KO) mice were crossed to Apc(min/+) mice and progeny were fed low-fat or high-fat diets. At termination intestines were evaluated for tumorigenesis. Tumors, serum, and fecal contents were analyzed for protein biomarkers, cytokines, and microbiome profile respectively. IL-23A levels are elevated in the sera of patients with obesity and colon tumors. Genetic ablation of IL-23A significantly suppressed colonic tumor multiplicity (76–96 %) and incidence (72–95 %) in male and female mice. Similarly, small-intestinal tumor multiplicity and size were also significantly reduced in IL-23A KO mice. IL-23A knockdown in Apc(min/+) mice fed high-fat diet, also resulted in significant suppression of colonic (50–58 %) and SI (41–48 %) tumor multiplicity. Cytokine profiling showed reduction in several circulating pro-inflammatory cytokines including loss of IL-23A. Biomarker analysis suggested reduced tumor cell proliferation and immune modulation with an increase in tumor-infiltrating CD4+ and CD8+ T-lymphocytes in the IL-23A KO mice compared to controls. Fecal microbiome analysis revealed potentially beneficial changes in the bacterial population profile. In summary, our data indicates a tumor promoting role for IL-23 in CRC including diet-induced obesity. With several IL-23 targeted therapies in clinical trials, there is a great potential for targeting this cytokine for CRC prevention and therapy.
format Online
Article
Text
id pubmed-10568285
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Neoplasia Press
record_format MEDLINE/PubMed
spelling pubmed-105682852023-10-13 Targeting IL-23 for the interception of obesity-associated colorectal cancer Madka, Venkateshwar Chiliveru, Srikanth Panneerselvam, Janani Pathuri, Gopal Zhang, Yuting Stratton, Nicole Kumar, Nandini Sanghera, Dharambir K. Rao, Chinthalapally V. Neoplasia Original article Inflammation and obesity are two major factors that promote Colorectal cancer (CRC). Our recent data suggests that interleukin (IL)-23, is significantly elevated in CRC tumors and correlates with patient obesity, tumor grade and survival. Thus, we hypothesize that obesity and CRC may be linked via inflammation and IL-23 may be a potential target for intervention in high-risk patients. TCGA dataset and patient sera were evaluated for IL-23A levels. IL-23A [IL-23 p19(−/−)] knockout (KO) mice were crossed to Apc(min/+) mice and progeny were fed low-fat or high-fat diets. At termination intestines were evaluated for tumorigenesis. Tumors, serum, and fecal contents were analyzed for protein biomarkers, cytokines, and microbiome profile respectively. IL-23A levels are elevated in the sera of patients with obesity and colon tumors. Genetic ablation of IL-23A significantly suppressed colonic tumor multiplicity (76–96 %) and incidence (72–95 %) in male and female mice. Similarly, small-intestinal tumor multiplicity and size were also significantly reduced in IL-23A KO mice. IL-23A knockdown in Apc(min/+) mice fed high-fat diet, also resulted in significant suppression of colonic (50–58 %) and SI (41–48 %) tumor multiplicity. Cytokine profiling showed reduction in several circulating pro-inflammatory cytokines including loss of IL-23A. Biomarker analysis suggested reduced tumor cell proliferation and immune modulation with an increase in tumor-infiltrating CD4+ and CD8+ T-lymphocytes in the IL-23A KO mice compared to controls. Fecal microbiome analysis revealed potentially beneficial changes in the bacterial population profile. In summary, our data indicates a tumor promoting role for IL-23 in CRC including diet-induced obesity. With several IL-23 targeted therapies in clinical trials, there is a great potential for targeting this cytokine for CRC prevention and therapy. Neoplasia Press 2023-10-07 /pmc/articles/PMC10568285/ /pubmed/37813000 http://dx.doi.org/10.1016/j.neo.2023.100939 Text en © 2023 The Authors. Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original article
Madka, Venkateshwar
Chiliveru, Srikanth
Panneerselvam, Janani
Pathuri, Gopal
Zhang, Yuting
Stratton, Nicole
Kumar, Nandini
Sanghera, Dharambir K.
Rao, Chinthalapally V.
Targeting IL-23 for the interception of obesity-associated colorectal cancer
title Targeting IL-23 for the interception of obesity-associated colorectal cancer
title_full Targeting IL-23 for the interception of obesity-associated colorectal cancer
title_fullStr Targeting IL-23 for the interception of obesity-associated colorectal cancer
title_full_unstemmed Targeting IL-23 for the interception of obesity-associated colorectal cancer
title_short Targeting IL-23 for the interception of obesity-associated colorectal cancer
title_sort targeting il-23 for the interception of obesity-associated colorectal cancer
topic Original article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568285/
https://www.ncbi.nlm.nih.gov/pubmed/37813000
http://dx.doi.org/10.1016/j.neo.2023.100939
work_keys_str_mv AT madkavenkateshwar targetingil23fortheinterceptionofobesityassociatedcolorectalcancer
AT chiliverusrikanth targetingil23fortheinterceptionofobesityassociatedcolorectalcancer
AT panneerselvamjanani targetingil23fortheinterceptionofobesityassociatedcolorectalcancer
AT pathurigopal targetingil23fortheinterceptionofobesityassociatedcolorectalcancer
AT zhangyuting targetingil23fortheinterceptionofobesityassociatedcolorectalcancer
AT strattonnicole targetingil23fortheinterceptionofobesityassociatedcolorectalcancer
AT kumarnandini targetingil23fortheinterceptionofobesityassociatedcolorectalcancer
AT sangheradharambirk targetingil23fortheinterceptionofobesityassociatedcolorectalcancer
AT raochinthalapallyv targetingil23fortheinterceptionofobesityassociatedcolorectalcancer