|
1
|
Chen Y, Fang H, Chen H, Liu X, Zhao J, Stanton C, Ross RP, Chen W, Yang B. Bifidobacterium inhibits the progression of colorectal tumorigenesis in mice through fatty acid isomerization and gut microbiota modulation. Gut Microbes 2025; 17:2464945. [PMID: 39924893 PMCID: PMC11812354 DOI: 10.1080/19490976.2025.2464945] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 01/14/2025] [Accepted: 01/21/2025] [Indexed: 02/11/2025] Open
Abstract
Colorectal cancer (CRC) represents the third most common cancer worldwide. Consequently, there is an urgent need to identify novel preventive and therapeutic strategies for CRC. This study aimed to screen for beneficial bacteria that have a preventive effect on CRC and to elucidate the potential mechanisms. Initially, we compared gut bacteria and bacterial metabolites of healthy volunteers and CRC patients, which demonstrated that intestinal conjugated linoleic acid (CLA), butyric acid, and Bifidobacterium in CRC patients were significantly lower than those in healthy volunteers, and these indicators were significantly negatively correlated with CRC. Next, spontaneous CRC mouse model were conducted to explore the effect of supplemental CLA-producing Bifidobacterium on CRC. Supplementation of mice with CLA-producing Bifidobacterium breve CCFM683 and B. pseudocatenulatum MY40C significantly prevented CRC. Moreover, molecular approaches demonstrated that CLA and the CLA-producing gene, bbi, were the key metabolites and genes for CCFM683 to prevent CRC. Inhibitor intervention results showed that PPAR-γ was the key receptor for preventing CRC. CCFM683 inhibited the NF-κB signaling pathway, up-regulated MUC2, Claudin-1, and ZO-1, and promoted tumor cell apoptosis via the CLA-PPAR-γ axis. Additionally, fecal microbiota transplantation (FMT) and metagenomic analysis showed that CCFM683 up-regulated Odoribacter splanchnicus through CLA production, which then prevented CRC by producing butyric acid, up-regulating TJ proteins, regulating cytokines, and regulating gut microbiota. These results will contribute to the clinical trials of Bifidobacterium and the theoretical research and development of CRC dietary products.
Collapse
Affiliation(s)
- Yang Chen
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu, China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China
| | - Huiting Fang
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu, China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China
| | - Haiqin Chen
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu, China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China
| | - Xiaoming Liu
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu, China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China
| | - Jianxin Zhao
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu, China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China
| | - Catherine Stanton
- International Joint Research Laboratory for Maternal-Infant Microbiota and Health, Jiangnan University, Wuxi, Jiangsu, China
- Teagasc Food Research Centre, Moorepark, Fermoy, Ireland
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - R. Paul Ross
- International Joint Research Laboratory for Maternal-Infant Microbiota and Health, Jiangnan University, Wuxi, Jiangsu, China
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Wei Chen
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu, China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China
| | - Bo Yang
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu, China
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China
- International Joint Research Laboratory for Maternal-Infant Microbiota and Health, Jiangnan University, Wuxi, Jiangsu, China
| |
Collapse
|
|
2
|
Modak S, Aktar T, Majumder D, Singha AK, Maiti D. A systematic review on leptin's role in defining cancer: special emphasis on immunomodulation, inflammation, and therapeutic interventions. Genes Immun 2025:10.1038/s41435-025-00333-7. [PMID: 40374921 DOI: 10.1038/s41435-025-00333-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 04/22/2025] [Accepted: 04/30/2025] [Indexed: 05/18/2025]
Abstract
Leptin, an adipokine related to obesity, is mainly known for its role in regulating energy homeostasis and appetite by working via the leptin receptor. Recently, different groups have demonstrated that apart from adipocytes, specific cell types associated with cancer and tumor microenvironments express leptin and leptin receptors. This tumor microenvironment-associated leptin-leptin receptor signaling contributes to the different hallmarks of cancer, ranging from inflammatory changes to metastasis. Eventually, it has also been reported that high serum level of leptin, a characteristic of obese people, is linked to enhanced tumor growth. On the other hand, leptin can influence both innate as well as adaptive immunity related to cancer. Overall, leptin's role in modulating cancer is controversial. So, in this review, we summarized the role of leptin in shaping different forms of cancer that are influenced by leptin-leptin receptor signaling with special emphasis on immunomodulation and inflammatory events and also discussed the possible therapeutic interventions to date. As this review work, with the collection of different updated knowledge, has summarized the role of leptin on cancer, it would be useful material to have on hand for both beginners as well as pioneers of these and related fields.
Collapse
Affiliation(s)
- Snehashish Modak
- Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India
| | - Tamanna Aktar
- Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India
| | - Debabrata Majumder
- Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India
- Department of Integrative Immunobiology, Duke University Medical Center, Durham, NC, USA
| | - Ashish Kr Singha
- Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India
- Department of Human Physiology, Holy Cross College, Agartala, West Tripura, India
| | - Debasish Maiti
- Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India.
| |
Collapse
|
|
3
|
Luo Y, Jiang LY, Liao ZZ, Wang YY, Wang YD, Xiao XH. Metabolic Regulation of Inflammation: Exploring the Potential Benefits of Itaconate in Autoimmune Disorders. Immunology 2025; 174:189-202. [PMID: 39542834 DOI: 10.1111/imm.13875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 10/21/2024] [Accepted: 10/22/2024] [Indexed: 11/17/2024] Open
Abstract
Itaconic acid and its metabolites have demonstrated significant therapeutic potential in various immune diseases. Originating from the tricarboxylic acid cycle in immune cells, itaconic acid can modulate immune responses, diminish inflammation, and combat oxidative stress. Recent research has uncovered multiple mechanisms through which itaconic acid exerts its effects, including the inhibition of inflammatory cytokine production, activation of anti-inflammatory pathways, and modulation of immune cell function by regulating cellular metabolism. Cellular actions are influenced by the modulation of metabolic pathways, such as inhibiting succinate dehydrogenase (SDH) activity or glycolysis, activation of nuclear-factor-E2-related factor 2 (Nrf2), boosting cellular defences against oxidative stress, and suppression of immune cell inflammation through the NF-κB pathway. This comprehensive review discusses the initiation, progression, and mechanisms of action of itaconic acid and its metabolites, highlighting their modulatory effects on various immune cell types. Additionally, it examines their involvement in immune disease like rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus, and autoimmune hepatitis, offering greater understanding for creating new therapies for these ailments.
Collapse
Affiliation(s)
- Yin Luo
- The First Affiliated Hospital, Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Li-Yan Jiang
- The First Affiliated Hospital, Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Zhe-Zhen Liao
- The First Affiliated Hospital, Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yuan-Yuan Wang
- The First Affiliated Hospital, Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Ya-Di Wang
- The First Affiliated Hospital, Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Xin-Hua Xiao
- The First Affiliated Hospital, Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| |
Collapse
|
|
4
|
Nguyen L, Shanmugan S. A Review Article: The Relationship Between Obesity and Colorectal Cancer. Curr Diab Rep 2024; 25:8. [PMID: 39621160 PMCID: PMC11611961 DOI: 10.1007/s11892-024-01556-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/17/2024] [Indexed: 12/06/2024]
Abstract
PURPOSE OF REVIEW This article aims to review the recent literature assessing the relationship between obesity and colorectal carcinogenesis, the effect of obesity on the treatment of colorectal cancer (CRC), tools available to help augment the increased risk, and outcomes for patients who are affected by both obesity and colorectal cancer. RECENT FINDINGS The biochemical mechanisms contributing to CRC carcinogenesis are not well understood but are suspected to be related to adipose tissue leading to a pro-inflammatory state and changes in the gut microbiome. Individuals with obesity are at higher risk for CRC development, worse oncologic outcomes, and increased rates of post-operative complications. Bariatric surgery decreases CRC risk but results with GLP-1 agonists are heterogeneous. Prehabilitation is the only weight loss method that has been demonstrated to decrease risks of post-operative morbidity in this population. Obesity augments CRC risk and outcomes. There are persistent knowledge gaps in etiology and epidemiology for the increased CRC risk in obese patients and more research is required to identify the therapeutic advantage of weight loss on CRC risk.
Collapse
Affiliation(s)
- Lily Nguyen
- Department of Surgery, Division of Colon and Rectal Surgery, University of California, 333 The City Blvd West, Suite 1600, Suite 1600, Irvine, CA, USA, 92868-3298
| | - Skandan Shanmugan
- Department of Surgery, Division of Colon and Rectal Surgery, University of California, 333 The City Blvd West, Suite 1600, Suite 1600, Irvine, CA, USA, 92868-3298.
| |
Collapse
|
|
5
|
Fan Q, Fu ZW, Xu M, Lv F, Shi JS, Zeng QQ, Xiong DH. Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer. World J Gastrointest Oncol 2024; 16:4064-4079. [DOI: 10.4251/wjgo.v16.i10.4064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 08/03/2024] [Accepted: 08/16/2024] [Indexed: 09/26/2024] Open
Abstract
The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role-immune checkpoints-and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
Collapse
Affiliation(s)
- Qi Fan
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Zheng-Wei Fu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Ming Xu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Feng Lv
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Jia-Song Shi
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Qi-Qi Zeng
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - De-Hai Xiong
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| |
Collapse
|
|
6
|
He R, Zuo Y, Yi K, Liu B, Song C, Li N, Geng Q. The role and therapeutic potential of itaconate in lung disease. Cell Mol Biol Lett 2024; 29:129. [PMID: 39354366 PMCID: PMC11445945 DOI: 10.1186/s11658-024-00642-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 09/04/2024] [Indexed: 10/03/2024] Open
Abstract
Lung diseases triggered by endogenous or exogenous factors have become a major concern, with high morbidity and mortality rates, especially after the coronavirus disease 2019 (COVID-19) pandemic. Inflammation and an over-activated immune system can lead to a cytokine cascade, resulting in lung dysfunction and injury. Itaconate, a metabolite produced by macrophages, has been reported as an effective anti-inflammatory and anti-oxidative stress agent with significant potential in regulating immunometabolism. As a naturally occurring metabolite in immune cells, itaconate has been identified as a potential therapeutic target in lung diseases through its role in regulating inflammation and immunometabolism. This review focuses on the origin, regulation, and function of itaconate in lung diseases, and briefly discusses its therapeutic potential.
Collapse
Affiliation(s)
- Ruyuan He
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Hubei Province, 99 Zhangzhidong Road, Wuhan, 430060, China
| | - Yifan Zuo
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Hubei Province, 99 Zhangzhidong Road, Wuhan, 430060, China
| | - Ke Yi
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Hubei Province, 99 Zhangzhidong Road, Wuhan, 430060, China
| | - Bohao Liu
- Department of Thoracic Surgery, Jilin University, Changchun, China
| | - Congkuan Song
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Hubei Province, 99 Zhangzhidong Road, Wuhan, 430060, China.
| | - Ning Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Hubei Province, 99 Zhangzhidong Road, Wuhan, 430060, China.
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Hubei Province, 99 Zhangzhidong Road, Wuhan, 430060, China.
| |
Collapse
|
|
7
|
Chen Y, Ma W, Zhao J, Stanton C, Ross RP, Zhang H, Chen W, Yang B. Lactobacillus plantarum Ameliorates Colorectal Cancer by Ameliorating the Intestinal Barrier through the CLA-PPAR-γ Axis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:19766-19785. [PMID: 39186442 DOI: 10.1021/acs.jafc.4c02824] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/28/2024]
Abstract
Colorectal cancer (CRC) is the third-largest cancer worldwide. Lactobacillus can regulate the intestinal barrier and gut microbiota. However, the mechanisms of Lactobacillus that alleviate CRC remained unknown. This study aimed to explore the regulatory effect of Lactobacillus plantarum on CRC and its potential mechanism. CCFM8661 treatment significantly ameliorated CRC compared with phosphate-buffered solution (PBS) treatment in ApcMin/+ mice. In addition, conjugated linoleic acid (CLA) was proved to be the key metabolite for CCFM8661 in ameliorating CRC by molecular biology techniques. Peroxisome proliferator-activated receptor γ (PPAR-γ) was proved to be the key receptor in ameliorating CRC by inhibitor intervention experiments. Moreover, supplementation with CCFM8661 ameliorated CRC by producing CLA to inhibit NF-κB pathway and pro-inflammatory cytokines, up-regulate ZO-1, Claudin-1, and MUC2, and promote tumor cell apoptosis in a PPAR-γ-dependent manner. Metagenomic analysis showed that CCFM8661 treatment significantly increased Odoribacter splanchnicus, which could ameliorate CRC by repairing the intestinal barrier. Clinical results showed that intestinal CLA, butyric acid, PPAR-γ, and Lactobacillus were significantly decreased in CRC patients, and these indicators were significantly negatively correlated with CRC. CCFM8661 alleviated CRC by ameliorating the intestinal barrier through the CLA-PPAR-γ axis. These results will promote the development of dietary probiotic supplements for CRC.
Collapse
Affiliation(s)
- Yang Chen
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, Jiangsu, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, Jiangsu, China
- Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Hubei University of Technology, Wuhan 430068, Hubei, China
| | - Weiwei Ma
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin 150000, China
| | - Jianxin Zhao
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, Jiangsu, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, Jiangsu, China
| | - Catherine Stanton
- International Joint Research Laboratory for Maternal-Infant Microbiota and Health, Jiangnan University, Wuxi 214122, Jiangsu, China
- Teagasc Food Research Centre, Moorepark, Fermoy, Cork P61 C996, Ireland
- APC Microbiome Ireland, University College Cork, Cork T12 K8AF, Ireland
| | - R Paul Ross
- International Joint Research Laboratory for Maternal-Infant Microbiota and Health, Jiangnan University, Wuxi 214122, Jiangsu, China
- Teagasc Food Research Centre, Moorepark, Fermoy, Cork P61 C996, Ireland
- APC Microbiome Ireland, University College Cork, Cork T12 K8AF, Ireland
| | - Hao Zhang
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, Jiangsu, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, Jiangsu, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, Jiangsu, China
| | - Wei Chen
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, Jiangsu, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, Jiangsu, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, Jiangsu, China
| | - Bo Yang
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, Jiangsu, China
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, Jiangsu, China
- International Joint Research Laboratory for Maternal-Infant Microbiota and Health, Jiangnan University, Wuxi 214122, Jiangsu, China
| |
Collapse
|
|
8
|
Jones AN, Scheurlen KM, Macleod A, Simon HL, Galandiuk S. Obesity and Inflammatory Factors in the Progression of Early-Onset Colorectal Cancer. Cancers (Basel) 2024; 16:1403. [PMID: 38611081 PMCID: PMC11010915 DOI: 10.3390/cancers16071403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 03/27/2024] [Accepted: 04/01/2024] [Indexed: 04/14/2024] Open
Abstract
Metabolic dysfunction associated with obesity leads to a chronic pro-inflammatory state with systemic effects, including the alteration of macrophage metabolism. Tumor-associated macrophages have been linked to the formation of cancer through the production of metabolites such as itaconate. Itaconate downregulates peroxisome proliferator-activated receptor gamma as a tumor-suppressing factor and upregulates anti-inflammatory cytokines in M2-like macrophages. Similarly, leptin and adiponectin also influence macrophage cytokine expression and contribute to the progression of colorectal cancer via changes in gene expression within the PI3K/AKT pathway. This pathway influences cell proliferation, differentiation, and tumorigenesis. This work provides a review of obesity-related hormones and inflammatory mechanisms leading to the development and progression of early-onset colorectal cancer (EOCRC). A literature search was performed using the PubMed and Cochrane databases to identify studies related to obesity and EOCRC, with keywords including 'EOCRC', 'obesity', 'obesity-related hormones', 'itaconate', 'adiponectin', 'leptin', 'M2a macrophage', and 'microbiome'. With this concept of pro-inflammatory markers contributing to EOCRC, increased use of chemo-preventative agents such as aspirin may have a protective effect. Elucidating this association between obesity-related, hormone/cytokine-driven inflammatory effects with EOCRC may help lead to new therapeutic targets in preventing and treating EOCRC.
Collapse
Affiliation(s)
- Alexandra N. Jones
- Price Institute of Surgical Research, University of Louisville, Louisville, KY 40202, USA; (A.N.J.); (A.M.); (H.L.S.)
| | - Katharina M. Scheurlen
- Price Institute of Surgical Research, University of Louisville, Louisville, KY 40202, USA; (A.N.J.); (A.M.); (H.L.S.)
| | - Anne Macleod
- Price Institute of Surgical Research, University of Louisville, Louisville, KY 40202, USA; (A.N.J.); (A.M.); (H.L.S.)
| | - Hillary L. Simon
- Price Institute of Surgical Research, University of Louisville, Louisville, KY 40202, USA; (A.N.J.); (A.M.); (H.L.S.)
- Division of Colon and Rectal Surgery, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville, Louisville, KY 40202, USA
| | - Susan Galandiuk
- Price Institute of Surgical Research, University of Louisville, Louisville, KY 40202, USA; (A.N.J.); (A.M.); (H.L.S.)
- Division of Colon and Rectal Surgery, Hiram C. Polk Jr. MD Department of Surgery, University of Louisville, Louisville, KY 40202, USA
| |
Collapse
|
|
9
|
Zhang J, Chen C, Yan W, Fu Y. New sights of immunometabolism and agent progress in colitis associated colorectal cancer. Front Pharmacol 2024; 14:1303913. [PMID: 38273841 PMCID: PMC10808433 DOI: 10.3389/fphar.2023.1303913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 12/19/2023] [Indexed: 01/27/2024] Open
Abstract
Colitis associated colorectal cancer is a disease with a high incidence and complex course that develops from chronic inflammation and deteriorates after various immune responses and inflammation-induced attacks. Colitis associated colorectal cancer has the characteristics of both immune diseases and cancer, and the similarity of treatment models contributes to the similar treatment dilemma. Immunometabolism contributes to the basis of life and is the core of many immune diseases. Manipulating metabolic signal transduction can be an effective way to control the immune process, which is expected to become a new target for colitis associated colorectal cancer therapy. Immune cells participate in the whole process of colitis associated colorectal cancer development by transforming their functional condition via changing their metabolic ways, such as glucose, lipid, and amino acid metabolism. The same immune and metabolic processes may play different roles in inflammation, dysplasia, and carcinoma, so anti-inflammation agents, immunomodulators, and agents targeting special metabolism should be used in combination to prevent and inhibit the development of colitis associated colorectal cancer.
Collapse
Affiliation(s)
- Jingyue Zhang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chaoyue Chen
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Fu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
10
|
Bocian-Jastrzębska A, Malczewska-Herman A, Kos-Kudła B. Role of Leptin and Adiponectin in Carcinogenesis. Cancers (Basel) 2023; 15:4250. [PMID: 37686525 PMCID: PMC10486522 DOI: 10.3390/cancers15174250] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/18/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
Hormones produced by adipocytes, leptin and adiponectin, are associated with the process of carcinogenesis. Both of these adipokines have well-proven oncologic potential and can affect many aspects of tumorigenesis, from initiation and primary tumor growth to metastatic progression. Involvement in the formation of cancer includes interactions with the tumor microenvironment and its components, such as tumor-associated macrophages, cancer-associated fibroblasts, extracellular matrix and matrix metalloproteinases. Furthermore, these adipokines participate in the epithelial-mesenchymal transition and connect to angiogenesis, which is critical for cancer invasiveness and cancer cell migration. In addition, an enormous amount of evidence has demonstrated that altered concentrations of these adipocyte-derived hormones and the expression of their receptors in tumors are associated with poor prognosis in various types of cancer. Therefore, leptin and adiponectin dysfunction play a prominent role in cancer and impact tumor invasion and metastasis in different ways. This review clearly and comprehensively summarizes the recent findings and presents the role of leptin and adiponectin in cancer initiation, promotion and progression, focusing on associations with the tumor microenvironment and its components as well as roles in the epithelial-mesenchymal transition and angiogenesis.
Collapse
Affiliation(s)
- Agnes Bocian-Jastrzębska
- Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinogy, Medical University of Silesia, 40-514 Katowice, Poland; (A.M.-H.); (B.K.-K.)
| | | | | |
Collapse
|
|
11
|
Li M, Yang Y, Xiong L, Jiang P, Wang J, Li C. Metabolism, metabolites, and macrophages in cancer. J Hematol Oncol 2023; 16:80. [PMID: 37491279 PMCID: PMC10367370 DOI: 10.1186/s13045-023-01478-6] [Citation(s) in RCA: 152] [Impact Index Per Article: 76.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 07/13/2023] [Indexed: 07/27/2023] Open
Abstract
Tumour-associated macrophages (TAMs) are crucial components of the tumour microenvironment and play a significant role in tumour development and drug resistance by creating an immunosuppressive microenvironment. Macrophages are essential components of both the innate and adaptive immune systems and contribute to pathogen resistance and the regulation of organism homeostasis. Macrophage function and polarization are closely linked to altered metabolism. Generally, M1 macrophages rely primarily on aerobic glycolysis, whereas M2 macrophages depend on oxidative metabolism. Metabolic studies have revealed that the metabolic signature of TAMs and metabolites in the tumour microenvironment regulate the function and polarization of TAMs. However, the precise effects of metabolic reprogramming on tumours and TAMs remain incompletely understood. In this review, we discuss the impact of metabolic pathways on macrophage function and polarization as well as potential strategies for reprogramming macrophage metabolism in cancer treatment.
Collapse
Affiliation(s)
- Mengyuan Li
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China
| | - Yuhan Yang
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China
| | - Liting Xiong
- Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, China
| | - Ping Jiang
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China.
| | - Junjie Wang
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China.
- Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, China.
| | - Chunxiao Li
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China.
| |
Collapse
|
|
12
|
Scheurlen KM, Snook DL, Alfieri T, Littlefield AB, George JB, Seraphine C, Cook CN, Rochet A, Gaskins JT, Galandiuk S. Obesity hormones and itaconate mediating inflammation in human colon cancer cells - Another lead to early-onset colon cancer? Heliyon 2023; 9:e13132. [PMID: 36825172 PMCID: PMC9941943 DOI: 10.1016/j.heliyon.2023.e13132] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/09/2023] [Accepted: 01/18/2023] [Indexed: 01/22/2023] Open
Abstract
Background Chronic inflammation is a key feature of obesity and a hallmark of colon cancer (CC). The obesity-related hormones leptin and adiponectin alter inflammatory gene profiles in cancer, but their specific role in CC is unclear. We have previously studied the effects of leptin and the macrophage-specific mediator itaconate on M2-like macrophages. This current study evaluates their effects on CC cells. Methods HT-29 CC cells (derived from a young patient, stage III CC) were treated with either leptin, adiponectin, 4-octyl itaconate (OI) or dimethyl itaconate (DI). Gene expression after treatment was analyzed at four time points (3, 6, 18, and 24 h). Results CCL22 was upregulated after treatment with adiponectin (at 18 h [FC 16.3, p < 0.001]). IL-8 expression increased following both adiponectin (at 3 h [FC 68.1, p < 0.001]) and leptin treatments (at 6 h [FC 7.3, p < 0.001]), while OI induced downregulation of IL-8 (at 24 h [FC -5.0, p < 0.001]). CXCL10 was upregulated after adiponectin treatment (at 6 h [FC 3.0, p = 0.025]) and downregulated by both OI and DI at 24 h, respectively (OI [FC -10.0, p < 0.001]; DI [FC -10.0, p < 0.001]). IL-1β was upregulated after adiponectin treatment (at 3 h [FC 10.6, p < 0.001]) and downregulated by DI (at 24 h [FC -5.0, p < 0.001]). TNF-α expression was induced following adiponectin (at 6 h [FC 110.7, p < 0.001]), leptin (at 18 h [FC 5.8, p = 0.027]) and OI (at 3 h [FC 91.1, p = 0.001]). PPARγ was affected by both OI (at 3 h [FC 10.1, p = 0.031], at 24 h [FC -10.0, p = 0.031]) and DI (at 18 h [FC -1.7, p = 0.033]). Conclusions Obesity hormones directly affect inflammatory gene expression in HT29 CC cells, potentially enhancing cancer progression. Itaconate affects the prognostic marker PPARγ in HT29 CC cells. Leptin, adiponectin and itaconate may represent a link between obesity and CC.
Collapse
Affiliation(s)
- Katharina M. Scheurlen
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Dylan L. Snook
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Toriana Alfieri
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Andrew B. Littlefield
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Joan B. George
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Caden Seraphine
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Cheyenne N. Cook
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Andre Rochet
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Jeremy T. Gaskins
- Department of Bioinformatics & Biostatistics, University of Louisville, 485 E. Gray Street, Louisville, KY, 40202, USA
| | - Susan Galandiuk
- Price Institute of Surgical Research, The Hiram C. Polk, Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA,Corresponding author. @UofLDeptofSurg
| |
Collapse
|
|
13
|
Kim HW, Yu AR, Lee JW, Yoon HS, Lee BS, Park HW, Lee SK, Lee YI, Whang J, Kim JS. Aconitate Decarboxylase 1 Deficiency Exacerbates Mouse Colitis Induced by Dextran Sodium Sulfate. Int J Mol Sci 2022; 23:ijms23084392. [PMID: 35457208 PMCID: PMC9025264 DOI: 10.3390/ijms23084392] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 04/10/2022] [Accepted: 04/13/2022] [Indexed: 01/01/2023] Open
Abstract
Ulcerative colitis is a complex inflammatory bowel disorder disease that can induce rectal and colonic dysfunction. Although the prevalence of IBD in Western countries is almost 0.5% of the general population, genetic causes are still not fully understood. In a recent discovery, itaconate was found to function as an immune-modulating metabolite in mammalian immune cells, wherein it is synthesized as an antimicrobial compound from the citric acid cycle intermediate cis-aconitic acid. However, the association between the Acod1 (Aconitate decarboxylase 1)-itaconate axis and ulcerative colitis has rarely been studied. To elucidate this, we established a DSS-induced colitis model with Acod1-deficient mice and then measured the mouse body weights, colon lengths, histological changes, and cytokines/chemokines in the colon. We first confirmed the upregulation of Acod1 RNA and protein expression levels in DSS-induced colitis. Then, we found that colitis symptoms, including weight loss, the disease activity index, and colon shortening, were worsened by the depletion of Acod1. In addition, the extent of intestinal epithelial barrier breakdown, the extent of immune cell infiltration, and the expression of proinflammatory cytokines and chemokines in Acod1-deficient mice were higher than those in wild-type mice. Finally, we confirmed that 4-octyl itaconate (4-OI) alleviated DSS-induced colitis in Acod1-deficient mice and decreased the expression of inflammatory cytokines and chemokines. To our knowledge, this study is the first to elucidate the role of the Acod1-itaconate axis in colitis. Our data clearly showed that Acod1 deletion resulted in severe DSS-induced colitis and substantial increases in inflammatory cytokine and chemokine levels. Our results suggest that Acod1 may normally play an important regulatory role in the pathogenesis of colitis, demonstrating the potential for novel therapies using 4-OI.
Collapse
Affiliation(s)
- Ho Won Kim
- Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Korea; (H.W.K.); (A.-R.Y.); (J.W.L.); (H.S.Y.)
| | - A-Reum Yu
- Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Korea; (H.W.K.); (A.-R.Y.); (J.W.L.); (H.S.Y.)
| | - Ji Won Lee
- Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Korea; (H.W.K.); (A.-R.Y.); (J.W.L.); (H.S.Y.)
| | - Hoe Sun Yoon
- Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Korea; (H.W.K.); (A.-R.Y.); (J.W.L.); (H.S.Y.)
| | - Byung Soo Lee
- Department of Ophthalmology, Konyang University Hospital and College of Medicine, Daejeon 35365, Korea;
| | - Hwan-Woo Park
- Department of Cell Biology, Konyang University College of Medicine, Daejeon 35365, Korea;
| | - Sung Ki Lee
- Department of Obstetrics and Gynecology, Konyang University Hospital, Daejeon 35365, Korea;
| | - Young Ik Lee
- Lee’s Biotech Co., 415, C Dong, 17 Techno 4-ro, Yuseong-gu, Daejeon 34013, Korea;
| | - Jake Whang
- Korea Mycobacterium Resource Center (KMRC), Department of Research and Development, The Korean Institute of Tuberculosis, Osong 28158, Korea;
| | - Jong-Seok Kim
- Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Korea; (H.W.K.); (A.-R.Y.); (J.W.L.); (H.S.Y.)
- Correspondence: ; Tel.: +82-42-600-8648
| |
Collapse
|