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Metabolic pathways in proinflammatory and anti‐inflammatory phenotypes of tumor‐associated macrophages. Simplified model showing the dominating metabolic pathways in both extremes of phenotypes in tumor‐associated macrophages. As macrophages can switch between proinflammatory and anti‐inflammatory phenotypes continuously by changing their cellular metabolism, metabolic pathways can overlap between both types. Proinflammatory macrophages focus on aerobic glycolysis, truncated tricarboxylic acid cycle (TCA cycle) and fatty acid synthesis for energy homeostasis of the cell. Anti‐inflammatory macrophages use the TCA cycle, oxidative phosphorylation and β‐oxidation as their major energy sources. ROS: reactive oxygen species; TCA cycle: tricarboxylic acid cycle
Source publication
Background
The incidence of colorectal cancer (CRC) among patients <50 years of age has increased dramatically over the last decades. At the same time, the growing proportion of obese children and adolescents and the increasing proportion of young and obese patients with CRC suggests an association between metabolic dysfunction and carcinogenesis....
Citations
... Similarly, inflammation is a higher risk factor for CRC in youth rather than in middle-aged and older patients (132). Therefore, obesity-induced inflammation may have a more important role in EOCRC carcinogenesis (135). In one study, obesity-induced lowgrade systemic inflammation in the carcinogenic milieu of CRC, was associated with the generation of inflammatory cytokines through the interaction between infiltrating immune cells and adipocytes (136). ...
Early-onset colorectal cancer (EOCRC) is defined as diagnosed at younger than 50 years of age and indicates a health burden globally. Patients with EOCRC have distinct risk factors, clinical characteristics, and molecular pathogenesis compared with older patients with CRC. Further investigations have identified different roles of obesity between EOCRC and late-onset colorectal cancer (LOCRC). Most studies have focused on the clinical characteristics of obesity in EOCRC, therefore, the mechanism involved in the association between obesity and EOCRC remains inconclusive. This review further states that obesity affects the carcinogenesis of EOCRC as well as its development and progression, which may lead to obesity-related metabolic syndrome, intestinal dysbacteriosis, and intestinal inflammation.
... These TAMs, including both M1 and M2 macrophages, are key regulators of inflammatory signaling that have been found to affect CRC progression and patient survival. Mechanisms for TAM induction of neoplasms includes promoting tumor development by inducing interleukin 10 (IL-10) production in CRC cells through the STAT3 pathway, as well as upregulating production of cytokines such as vascular endothelial growth factor (VEGF) to induce tumor angiogenesis and tumor growth [46]. Advanced tumor stage and decreased overall/progression-free survival have been associated with TAMs, specifically, with a high M2/M1 ratio [41]. ...
... Pro-inflammatory M1 macrophages that produce reactive oxygen and nitrogen species may potentiate this effect, triggering oncogenic mutations in the adjacent epithelial layer [15,41]. Overall, TAMs, adipocytes, and cytokines all seem to play a central role in the development of EOCRC [46]. Leptin, adiponectin, and itaconate are mediators that have been found to either upregulate or downregulate the actions of TAMs via varying pathways. ...
... M1-like macrophages supposedly produce this anti-inflammatory metabolite to self-regulate excessive inflammatory stress responses. However, M2-like macrophages can also produce itaconate under certain conditions [46]. Itaconate is produced during TAM polarization, and it is known to have tumor-promoting effects in ovarian carcinomas and gliomas [15]. ...
Simple Summary
The incidence of colorectal cancer (CRC) in the United States (US) has decreased significantly over the last several decades, but primarily in those 65 years of age and older. However, there has been a dramatic global increase in the incidence of colorectal cancer in patients younger than 50 years old. This cohort is known as early-onset colorectal cancer (EOCRC) and is projected to rise in incidence. This epidemiologic change is poorly understood, but the sharp increase in the incidence of obesity and metabolic dysfunction have been linked to this phenomenon. The aim of our study is to examine the complex inflammatory mechanisms affecting EOCRC, including obesity, hormonal effects, inflammatory processes, and the tumor environment. With an improved understanding of these interactions, new methods to prevent and treat EOCRC could reduce its incidence and prolong survival in affected patients.
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.
... In contrast to M1, M2 macrophages primarily derive energy from oxidative phosphorylation, the tricarboxylic acid (TCA) cycle, and β-oxidation, resulting in the promotion of tumor invasion [122]. Studies confirm that alterations in the metabolism of TAMs regulate their functions and, consequently, the course of the disease [123]. ...
Colorectal cancer (CRC) is one of the most common and deadliest cancers worldwide. According to the GLOBOCAN (WHO) report in 2020, nearly 2 million patients were diagnosed globally. Despite the advances in cancer diagnosis and therapy, CRC remains a global challenge. Recently, attention has been paid to the tumor microenvironment (TME), which constitutes a significant part of the tumor and mainly includes various immune cells, fibroblasts, vascular cells, and extracellular elements, such as the extracellular matrix (ECM). Many components of the stroma initially exert an anti-tumor effect, but over time, they undergo functional transformation into elements that promote tumor growth. As a result, conditions conducive to further cancer development, invasion into local tissues, and distant metastasis arise. The microenvironment of colorectal cancer (CRC) may be an important direction in the search for therapeutic targets, but it requires further understanding. The main purpose of our review is to explain the role of the complex CRC microenvironment in the progression of this cancer and highlight the potential of targeted therapy directed at the TME. Therefore, continued research into its components and typical biomarkers is necessary to improve therapy and enhance the quality of life for patients.
... 30 In the tumor microenvironment, TAMs predominately have anti-inflammatory M2-like attributes that are particularly associated with tumor progression and poor overall patient survival. [31][32][33] In colon cancer, the M2a subtype with a STAT6-stimulated pathway plays a particular role. 34,35 In order to investigate the mechanisms mediated by anti-inflammatory TAMs in a cell culture model, a distinct TAM-like M2 macrophage subtype is required. ...
Aims
Macrophages play an essential role in cancer development. Tumor‐associated macrophages (TAMs) have predominantly M2‐like attributes that are associated with tumor progression and poor patient survival. Numerous methods have been reported for differentiating and polarizing macrophages in vitro, but there is no standardized and validated model for creating TAMs. Primary cells show varying cytokine responses depending on their origin and functional studies utilizing these cells may lack generalization and validity. A distinct cell line‐derived TAM‐like M2 subtype is required to investigate the mechanisms mediated by anti‐inflammatory TAMs in vitro. Our previous work demonstrated a standardized protocol for creating an M2 subtype derived from a human THP‐1 cell line. The cell expression profile, however, has not been validated. The aim of this study was to characterize and validate the TAM‐like M2 subtype macrophage created based on our protocol to introduce them as a standardized model for cancer research.
Methods and results
Using qRT‐PCR and ELISA, we demonstrated that proinflammatory, anti‐inflammatory, and tumor‐associated marker expression changed during THP‐1‐derived marcrophage development in vitro, mimicking a TAM‐related profile (e.g., TNFα, IL‐1β). The anti‐inflammatory marker IL‐8/CXCL8, however, is most highly expressed in young M0 macrophages. Flow cytometry showed increased expression of CD206 in the final TAM‐like M2 macrophage. Single‐cell RNA‐sequencing analysis of primary human monocytes and colon cancer tissue macrophages demonstrated that cell line‐derived M2 macrophages resembled a TAM‐related gene profile.
Conclusions
The THP‐1‐derived M2 macrophage based on a standardized cell line model represents a distinct anti‐inflammatory TAM‐like phenotype with an M2a subtype profile. This model may provide a basis for in vitro investigation of functional mechanisms in a variety of anti‐inflammatory settings, particularly colon cancer development.
... Monocytes can migrate into tumors and differentiate into macrophages which can play a role in the progression of cancer and have been found to express CD206 [24,25]. Studies have shown that the presence of CD206-positive monocytes in the blood of colorectal cancer patients is associated with poor prognosis and poor response to therapy [26]. Therefore, targeting CD206 on monocytes has also been proposed as a potential strategy for treating CRCLM. ...
... BD in San Jose, CA, USA). It is important to note that all results were obtained using the correct compensation controls, following the recommendations specified by the EuroFlow consortium [26]. For data analysis, the Infinicyt™ software (V.1.8; ...
... Cytognos SL Salamanca, Spain) was used. The gating strategy, to allow the identification of the various cell populations described in this study, is shown in Figure 2. results were obtained using the correct compensation controls, following the recommendations specified by the EuroFlow consortium [26]. For data analysis, the Infinicyt™ software (V.1.8; ...
Colorectal cancer (CRC) is the third most prevalent type of cancer, and liver metastasis is the most common site of metastatic development. In the tumor microenvironment (TME), various innate immune cells are known to influence cancer progression and metastasis occurrence. CD274 (PD-L1) and CD206 (MRC1) are proteins that have been associated with poor prognosis and disease progression. We conducted a study on tumoral and non-tumoral biopsies from 47 patients with CRC liver metastasis, using flow cytometry to phenotypically characterize innate immune cells. Our findings showed an increase in the expression of CD274 on classical, intermediate, and non-classical monocytes when comparing tumor with non-tumor samples. Furthermore, tumor samples with a desmoplastic growth pattern exhibited a significantly decreased percentage of CD274- and CD206-positive cells in all monocyte populations compared to non-desmoplastic samples. We found a correlation between a lower expression of CD206 or CD274 on classical, intermediate, and non-classical monocytes and increased disease-free survival, which points to a better prognosis for these patients. In conclusion, our study has identified potential new targets and biomarkers that could be incorporated into a personalized medicine approach to enhance the outcome for colorectal cancer patients.
... However, itaconate does not always exert a beneficial side to the organism. For example, it was found that itaconate is one of the metabolites produced by proinflammatory subtypes of tumor-associated macrophages and can promote tumor development [101]. Itaconate can also competitively inhibit erythroid-specific 5-aminolevulinate synthase, the first and rate-limiting step in heme synthesis, thereby inhibiting erythropoietic heme synthesis and promoting anemia during an inflammatory response in the erythroid compartment [102]. ...
With advances in immunometabolic studies, more and more evidence has shown that metabolic changes profoundly affect the immune function of macrophages. The tricarboxylic acid cycle is a central metabolic pathway of cells. Itaconate, a byproduct of the tricarboxylic acid cycle, is an emerging metabolic small molecule that regulates macrophage inflammation and has received much attention for its potent anti-inflammatory effects in recent years. Itaconate regulates macrophage function through multiple mechanisms and has demonstrated promising therapeutic potential in a variety of immune and inflammatory diseases. New progress in the mechanism of itaconate continues to be made, but it also implies complexity in its action and a need for a more comprehensive understanding of its role in macrophages. In this article, we review the primary mechanisms and current research progress of itaconate in regulating macrophage immune metabolism, hoping to provide new insights and directions for future research and disease treatment.
... The obesity-related hormones leptin and adiponectin can alter cytokine profiles in cancer cells and, thereby, either inhibit or promote carcinogenic mechanisms [2]. These effects have been discussed as a potential link between metabolic dysfunction and early-onset CC (EOCC) in young patients less than 50 years old [4,5]. A protective function of adiponectin has been postulated for several types of cancers, inhibiting genes that promote apoptosis and cell migration [2,6]. ...
... CC cells have been shown to secrete mediators that modify TAM polarization and cytokine expression, further enhancing tumor growth and progression through IL-6 [4,8]. ...
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.
... Inflammation in TME makes TAMs produce itaconate which is known to have tumor-promoting effects. Itaconate can regulate glycolysis and the activation of several transcription factors, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), hypoxia-inducible factor 1α (HIF1α), signal transducer and activator of transcription 3 (STAT3), and activator protein 1 (AP-1) [16]. Chronic inflammation during long-term inflammatory bowel disease (IBD) can reprogram colorectal cell metabolism via activation of the STAT3/c-Myc pathway [17]. ...
Colorectal cancer (CRC) is one of the most prevalent cancers globally. Despite recent progress in identifying etiologies and molecular genetics as well as new therapeutic approaches, the clinical outcome of current CRC therapies remains poor. This fact highlights the importance of further understanding underlying mechanisms involved in colorectal tumor initiation and progression. Abnormal metabolic alterations offer an evolutional advantage for CRC tumor cells and enhance their aggressive phenotype. Therefore, dysregulation of cellular metabolism is intricately associated with colorectal tumorigenesis. This review summarizes recent findings regarding the CRC-related changes in cellular metabolic pathways such as glycolysis, tricarboxylic acid cycle, fatty acid oxidation, and mitochondrial metabolism. We describe the oncogenic signaling pathways associated with metabolic dysregulation during malignant transformation and tumor progression. Given the crucial role of metabolic pathway alterations in the pathogenesis of CRC, we provide an overview of novel pharmacological strategies for the treatment of CRC by targeting metabolic and signaling pathways.
... [19][20][21] Patterns of diet and lifestyle are closely linked with metabolic alterations, which can be demonstrated by biochemical characteristics and BMI. 5 Biochemical markers, such as uric acid and triglycerides, represent the status of metabolism, which triggers carcinogenic mechanisms. 22 Regular CRC screenings are recommended for vulnerable patients over the age of 50 years because early detection can identify early-stage lesions or precancerous lesions. 23 To put these factors into perspective, as a screening method, there is a question as to whether serology markers are distinct between early-onset and late-onset patients. ...
Objective
Given that the onset of diseases including colorectal cancer precursors is affecting younger individuals and that obesity is an important risk factor for early‐onset, we conducted a study to explore the biochemical profile of differences in serum between early‐onset patients and late‐onset colorectal precancerous lesions.
Methods
A total of 1447 patients, including 469 early‐onset patients and 978 late‐onset patients, were enrolled from the First Affiliated Hospital of Nanchang University (FAHNU), of which there were 311 sessile serrated adenoma/polyps (SSA/P) and 1136 normal adenomas. The distribution of the included categorical variables was compared via Pearson's chi‐squared test, whereas continuous variables were compared by using the nonparametric Kruskal–Wallis test and anova.
Results
Compared with late‐onset patients, the levels of total bilirubin and HDL‐C were lower (p < 0.05), whereas triglyceride and uric acid levels were higher, in early‐onset patients. Interestingly, in the subgroup analysis, triglyceride and uric acid levels remained at higher levels, whereas HDL‐C remained at lower levels, in early‐onset patients than in late‐onset patients. Other characteristics, such as LDL‐C, drinking, γ‐GT, and the N/L ratio, were similar between the two groups. An additional analysis of the association of tumor size with markers showed that lower levels of HDL‐C and higher levels of uric acid were associated with increased tumor size (p < 0.05).
Conclusions
Early‐onset CRC precursor cases exhibit higher levels of triglycerides and lower levels of HDL‐C than late‐onset cases. Additionally, levels of HDL‐C are negatively associated with tumor size, whereas uric acid was positively correlated with tumor size.
... Tumor-associated macrophages (TAMs) are critical cellular components of the mucosal immune system in CRC, which serve as a bridge between intestinal tumor-promoting metabolites and the onset and progression of CRC through inflammatory pathways. 8,9 TAMs can influence resistance to anti-cancer treatments, such as chemotherapy and anti-PD-1/ PD-L1 therapy, and abundance of TAMs is associated with poor prognosis in various tumors. 10,11 TAMs express PD-L1, and PD-L1-expressing TAM levels in tumors may be used as predictive markers for the efficacy of anti-PD-1/PD-L1 therapies. ...
Background & Aims
Although cancer immunotherapies are effective for advanced-stage cancers, there are no clinically approved immunotherapies for colon cancers (CRCs). Therefore, there is a high demand for the development of novel therapies. Extracellular adenosine-mediated signaling is considered a promising target for advanced-stage cancers that are non-responsive to programmed death 1 (PD-1)-/programmed death-ligand 1 (PD-L1)-targeted immunotherapies. In this study, we aimed to elucidate novel tumorigenic mechanisms of extracellular adenosine.
Methods
To investigate the effects of extracellular adenosine on tumor-associated macrophages (TAMs), peripheral blood-derived human macrophages were treated with adenosine and analyzed using flow cytometry and western blot. Changes in adenosine-treated macrophages were further assessed using multi-omics analysis, including total RNA sequencing and proteomics. Colon cancer mouse models were used to measure the therapeutic efficacy of AB680 and palbociclib. We also used tissue microarrays of patients with CRC, to evaluate their clinical relevance.
Results
Extracellular adenosine-mediated reduction of cyclin D1 (CCND1) was found to be critical for the regulation of immune checkpoint molecules and PD-L1 levels in human macrophages, indicating that post-translational modification of PD-L1 is affected by adenosine. A potent CD73 selective inhibitor, AB680, reversed the effects of adenosine on CCND1 and PD-L1. This result strongly suggests that AB680 is a combinatory therapeutic option to overcome the undesired side effects of the cyclin-dependent kinase 4/6 inhibitor, palbociclib, which increases PD-L1 expression in tumors. Because palbociclib is undergoing clinical trials for metastatic CRC in combination with cetuximab (clinical trial number: NCT03446157), we validated that the combination of AB680 and palbociclib significantly improved anti-tumor efficacy in CRC animal models, thereby highlighting it as a novel immunotherapeutic strategy. We further assessed whether the level of CCND1 in TAMs was indeed reduced in tumor sections obtained from CRC patients, for evaluating the clinical relevance of this strategy.
Conclusions
In this study, we demonstrated that a novel combination therapy of AB680 and palbociclib may be advantageous for the treatment of CRC.
