|
1
|
Huang J, Meng P, Liang Y, Li X, Zhou S, Li J, Wang X, Miao J, Shen W, Zhou L. Tubular CD44 plays a key role in aggravating AKI through NF-κB p65-mediated mitochondrial dysfunction. Cell Death Dis 2025; 16:119. [PMID: 39979265 PMCID: PMC11842857 DOI: 10.1038/s41419-025-07438-x] [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: 01/10/2024] [Revised: 01/26/2025] [Accepted: 02/10/2025] [Indexed: 02/22/2025]
Abstract
Acute kidney injury (AKI) is in rapid prevalence nowadays. Of note, the underlying mechanisms have not been clarified. Several reports showed a cluster of differentiation-44 (CD44), a cell-surface glycoprotein, might be involved in AKI. However, its role in AKI has not been clearly clarified. Herein, we found CD44 increased in renal tubules in AKI mice. Gene ablation of CD44 improved mitochondrial biogenesis and fatty acid oxidation (FAO) function, further protecting against tubular cell death and kidney injury. Conversely, ectopic CD44 impaired mitochondrial homeostasis and exacerbated tubular cell apoptosis to aggravate AKI progression. From transcriptome sequencing, we found that CD44 induces mitogen-activated protein kinase (MAPK) and NF-κB p65 signaling. Lipidomics also showed that CD44 interfered with multiple aspects of lipid metabolism. We deeply investigated NF-κB p65 inhibited the transcription of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), resulting in mitochondrial dysfunction and cell apoptosis. CD44 also facilitated iron intake to assist cell ferroptosis. Hence, our study provided a new mechanism for AKI, and demonstrated that targeted inhibition on CD44 could be a promising therapeutic strategy to resist AKI.
Collapse
Affiliation(s)
- Jiewu Huang
- Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Ping Meng
- Department of Central Laboratory, Huadu District People's Hospital of Guangzhou, Guangzhou, China
| | - Ye Liang
- Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Xiaolong Li
- Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Shan Zhou
- Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Jiemei Li
- Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Xiaoxu Wang
- Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Jinhua Miao
- Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Weiwei Shen
- Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China
| | - Lili Zhou
- Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China.
| |
Collapse
|
|
2
|
Hua Y, Ma X, Zhao X, Wei X, Mu X, Zhang X. Characterization of metastasis-specific macrophages in colorectal cancer for prognosis prediction and immunometabolic remodeling. Sci Rep 2024; 14:26361. [PMID: 39487182 PMCID: PMC11530676 DOI: 10.1038/s41598-024-77248-2] [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: 05/21/2024] [Accepted: 10/21/2024] [Indexed: 11/04/2024] Open
Abstract
This study develops a prognostic model to predict metastasis and prognosis in colorectal cancer liver metastases by identifying distinct macrophage subsets. Using scRNA-seq data from primary colorectal cancer and liver metastases, we dissected the cellular landscape to find unique macrophage subpopulations, particularly EEF1G + macrophages, which were prevalent in liver metastases. The study leveraged data from GSE231559, TCGA, and GEO databases to construct an 8-gene risk model named EMGS, based on the EEF1G + macrophage gene signature. Patients were divided into high-risk and low-risk groups using the median EMGS score, with the high-risk group showing significantly worse survival. This group also demonstrated upregulated pathways associated with tumor progression, such as epithelial-mesenchymal transition and angiogenesis, and downregulated metabolic pathways. Moreover, the high-risk group presented an immunosuppressive microenvironment, with a higher TIDE score indicating lower effectiveness of immunotherapy. The study identifies potential drugs targeting the high-risk group, suggesting therapeutic avenues to improve survival. Conclusively, the EMGS score identifies colorectal cancer patients at high risk of liver metastases, highlighting the role of specific macrophage subsets in tumor progression and providing a basis for personalized treatment strategies.
Collapse
Affiliation(s)
- Yang Hua
- Department of colorectal surgery, Tianjin Union Medical Center, Tianjin, 300122, China.
- Tianjin Institute of Coloproctology, Tianjin, 300122, China.
| | - Xiukun Ma
- Department of surgery, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, 300120, China
| | - Xinyu Zhao
- Department of colorectal surgery, Tianjin Union Medical Center, Tianjin, 300122, China
- Tianjin Institute of Coloproctology, Tianjin, 300122, China
| | - Xiaomeng Wei
- Infection Management Division, Tianjin Union Medical Center, Tianjin, 300122, China
| | - Xiaojing Mu
- Department of colorectal surgery, Tianjin Union Medical Center, Tianjin, 300122, China
- Tianjin Institute of Coloproctology, Tianjin, 300122, China
| | - XiPeng Zhang
- Department of colorectal surgery, Tianjin Union Medical Center, Tianjin, 300122, China
- Tianjin Institute of Coloproctology, Tianjin, 300122, China
| |
Collapse
|
|
3
|
Cai WJ, Chen RR, Liu ZB, Lai J, Hou LJ, Zhang R. Prognostic Prediction and Immune Microenvironment Characterization in Uveal Melanoma: A Novel Mitochondrial Metabolism-Related Gene Signature. ACS OMEGA 2024; 9:43034-43045. [PMID: 39464480 PMCID: PMC11500162 DOI: 10.1021/acsomega.4c06294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 09/25/2024] [Accepted: 09/30/2024] [Indexed: 10/29/2024]
Abstract
Uveal Melanoma (UM), a highly aggressive and metastatic intraocular cancer with a strong propensity for liver metastasis, presents limited therapeutic alternatives and unfavorable survival outcomes. Despite its low incidence, the underlying mechanisms of UM pathogenesis and the precise role of mitochondrial metabolism in UM remain inadequately understood. Utilizing Cox proportional hazards regression analysis was used to assess prognostic relevance, and consensus clustering was employed for molecular subtyping. A risk signature was constructed using Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression. We further conducted comparative analyses on clinicopathological characteristics, somatic mutation profiles, drug sensitivity, gene expression patterns, and tumor microenvironment features across different molecular subtypes. Moreover, a nomogram was developed and evaluated. Among 1234 mitochondria metabolism-related genes (MMRGs), 343 were identified as significantly associated with the prognosis of UM. These prognosis-associated MMRGs facilitated the classification of UM into two distinct molecular subtypes, which displayed notable differences in prognosis and pathological staging. Furthermore, an index termed the MMRGs-derived index (MMI) was derived from eight MMRGs, serving as a quantitative measure for poor prognosis risk in UM. MMI demonstrated significant associations with clinicopathological characteristics, somatic mutations, drug responsiveness, and the tumor microenvironment, where higher MMI levels corresponded to worse prognosis, advanced pathological stages, and increased immune cell infiltration. The nomogram built upon MMI provided a potential tool for clinical prognosis assessment in UM patients. This study demonstrated the potential value of MMRGs in predicting prognosis and molecular stratification within UM; however, additional clinical and basic research is warranted to validate their applicability and elucidate the related mechanisms.
Collapse
Affiliation(s)
- Wei-Jun Cai
- National
Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Ru-Ru Chen
- National
Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Zi-Bin Liu
- Department
of Ophthalmology, Hangzhou TCM Hospital
Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310007, China
| | - Jian Lai
- Department
of Ophthalmology, Hangzhou TCM Hospital
Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310007, China
| | - Li-Jie Hou
- National
Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Rui Zhang
- Department
of Ophthalmology, Hangzhou TCM Hospital
Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310007, China
| |
Collapse
|
|
4
|
Chen J, Shen L, Wu T, Yang Y. Unraveling the significance of AGPAT4 for the pathogenesis of endometriosis via a multi-omics approach. Hum Genet 2024; 143:1163-1174. [PMID: 38850428 PMCID: PMC11485110 DOI: 10.1007/s00439-024-02681-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 05/26/2024] [Indexed: 06/10/2024]
Abstract
Endometriosis is characterized by the ectopic proliferation of endometrial cells, posing considerable diagnostic and therapeutic challenges. Our study investigates AGPAT4's involvement in endometriosis pathogenesis, aiming to unveil new therapeutic targets. Our investigation by analyzing eQTL data from GWAS for preliminary screening. Subsequently, within the GEO dataset, we utilized four machine learning algorithms to precisely identify risk-associated genes. Gene validity was confirmed through five Mendelian Randomization methods. AGPAT4 expression was measured by Single-Cell Analysis, ELISA and immunohistochemistry. We investigated AGPAT4's effect on endometrial stromal cells using RNA interference, assessing cell proliferation, invasion, and migration with CCK8, wound-healing, and transwell assays. Protein expression was analyzed by western blot, and AGPAT4 interactions were explored using AutoDock. Our investigation identified 11 genes associated with endometriosis risk, with AGPAT4 and COMT emerging as pivotal biomarkers through machine learning analysis. AGPAT4 exhibited significant upregulation in both ectopic tissues and serum samples from patients with endometriosis. Reduced expression of AGPAT4 was observed to detrimentally impact the proliferation, invasion, and migration capabilities of endometrial stromal cells, concomitant with diminished expression of key signaling molecules such as Wnt3a, β-Catenin, MMP-9, and SNAI2. Molecular docking analyses further underscored a substantive interaction between AGPAT4 and Wnt3a.Our study highlights AGPAT4's key role in endometriosis, influencing endometrial stromal cell behavior, and identifies AGPAT4 pathways as promising therapeutic targets for this condition.
Collapse
Affiliation(s)
- Jun Chen
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Licong Shen
- Department of Gynecology, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Tingting Wu
- Department of Cardiovasology, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yongwen Yang
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha, 410008, China.
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
| |
Collapse
|
|
5
|
Yun CC, Han Y, McConnell B. Lysophosphatidic Acid Signaling in the Gastrointestinal System. Cell Mol Gastroenterol Hepatol 2024; 18:101398. [PMID: 39233124 PMCID: PMC11532463 DOI: 10.1016/j.jcmgh.2024.101398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 09/06/2024]
Abstract
The intestinal epithelium undergoes continuous homeostatic renewal to conduct the digestion and absorption of nutrients. At the same time, the intestinal epithelial barrier separates the host from the intestinal lumen, preventing systemic infection from enteric pathogens. To maintain homeostasis and epithelial functionality, stem cells, which reside in the base of intestinal crypts, generate progenitor cells that ultimately differentiate to produce an array of secretory and absorptive cells. Intestinal regeneration is regulated by niche signaling pathways, specifically, Wnt, bone morphogenetic protein, Notch, and epidermal growth factor. In addition, growth factors and other peptides have emerged as potential modulators of intestinal repair and inflammation through their roles in cellular proliferation, differentiation, migration, and survival. Lysophosphatidic acid (LPA) is such a factor that modulates the proliferation, survival, and migration of epithelial cells while also regulating trafficking of immune cells, both of which are important for tissue homeostasis. Perturbation of LPA signaling, however, has been shown to promote cancer and inflammation. This review focuses on the recent advances in LPA-mediated signaling that contribute to physiological and pathophysiological regulation of the gastrointestinal system.
Collapse
Affiliation(s)
- C Chris Yun
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Gastroenterology Research, Atlanta Veterans Administration Medical Center, Decatur, Georgia.
| | - Yiran Han
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Beth McConnell
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| |
Collapse
|
|
6
|
Tatsuno R, Komohara Y, Pan C, Kawasaki T, Enomoto A, Jubashi T, Kono H, Wako M, Ashizawa T, Haro H, Ichikawa J. Surface Markers and Chemokines/Cytokines of Tumor-Associated Macrophages in Osteosarcoma and Other Carcinoma Microenviornments-Contradictions and Comparisons. Cancers (Basel) 2024; 16:2801. [PMID: 39199574 PMCID: PMC11353089 DOI: 10.3390/cancers16162801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/01/2024] [Accepted: 08/07/2024] [Indexed: 09/01/2024] Open
Abstract
Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Prognosis is improving with advances in multidisciplinary treatment strategies, but the development of new anticancer agents has not, and improvement in prognosis for patients with pulmonary metastases has stalled. In recent years, the tumor microenvironment (TME) has gained attention as a therapeutic target for cancer. The immune component of OS TME consists mainly of tumor-associated macrophages (TAMs). They exhibit remarkable plasticity, and their phenotype is influenced by the TME. In general, surface markers such as CD68 and CD80 show anti-tumor effects, while CD163 and CD204 show tumor-promoting effects. Surface markers have potential value as diagnostic and prognostic biomarkers. The cytokines and chemokines produced by TAMs promote tumor growth and metastasis. However, the role of TAMs in OS remains unclear to date. In this review, we describe the role of TAMs in OS by focusing on TAM surface markers and the TAM-produced cytokines and chemokines in the TME, and by comparing their behaviors in other carcinomas. We found contrary results from different studies. These findings highlight the urgency for further research in this field to improve the stalled OS prognosis percentages.
Collapse
Affiliation(s)
- Rikito Tatsuno
- Department of Orthopaedic Surgery, University of Yamanashi, Yamanashi 400-0016, Japan; (R.T.); (T.J.); (H.K.); (M.W.); (T.A.); (H.H.)
| | - Yoshihiro Komohara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8555, Japan; (Y.K.); (C.P.)
| | - Cheng Pan
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8555, Japan; (Y.K.); (C.P.)
| | - Tomonori Kawasaki
- Department of Pathology, Saitama Medical University International Medical Center, Saitama 350-1298, Japan;
| | - Atsushi Enomoto
- Department of Pathology, Graduate School of Medicine, Nagoya University, Nagoya 464-8601, Japan;
| | - Takahiro Jubashi
- Department of Orthopaedic Surgery, University of Yamanashi, Yamanashi 400-0016, Japan; (R.T.); (T.J.); (H.K.); (M.W.); (T.A.); (H.H.)
| | - Hiroyuki Kono
- Department of Orthopaedic Surgery, University of Yamanashi, Yamanashi 400-0016, Japan; (R.T.); (T.J.); (H.K.); (M.W.); (T.A.); (H.H.)
| | - Masanori Wako
- Department of Orthopaedic Surgery, University of Yamanashi, Yamanashi 400-0016, Japan; (R.T.); (T.J.); (H.K.); (M.W.); (T.A.); (H.H.)
| | - Tomoyuki Ashizawa
- Department of Orthopaedic Surgery, University of Yamanashi, Yamanashi 400-0016, Japan; (R.T.); (T.J.); (H.K.); (M.W.); (T.A.); (H.H.)
| | - Hirotaka Haro
- Department of Orthopaedic Surgery, University of Yamanashi, Yamanashi 400-0016, Japan; (R.T.); (T.J.); (H.K.); (M.W.); (T.A.); (H.H.)
| | - Jiro Ichikawa
- Department of Orthopaedic Surgery, University of Yamanashi, Yamanashi 400-0016, Japan; (R.T.); (T.J.); (H.K.); (M.W.); (T.A.); (H.H.)
| |
Collapse
|
|
7
|
Liu W, Kuang T, Liu L, Deng W. The role of innate immune cells in the colorectal cancer tumor microenvironment and advances in anti-tumor therapy research. Front Immunol 2024; 15:1407449. [PMID: 39100676 PMCID: PMC11294098 DOI: 10.3389/fimmu.2024.1407449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 06/25/2024] [Indexed: 08/06/2024] Open
Abstract
Innate immune cells in the colorectal cancer microenvironment mainly include macrophages, neutrophils, natural killer cells, dendritic cells and bone marrow-derived suppressor cells. They play a pivotal role in tumor initiation and progression through the secretion of diverse cytokines, chemokines, and other factors that govern these processes. Colorectal cancer is a common malignancy of the gastrointestinal tract, and understanding the role of innate immune cells in the microenvironment of CRC may help to improve therapeutic approaches to CRC and increase the good prognosis. In this review, we comprehensively explore the pivotal role of innate immune cells in the initiation and progression of colorectal cancer (CRC), alongside an extensive evaluation of the current landscape of innate immune cell-based immunotherapies, thereby offering valuable insights for future research strategies and clinical trials.
Collapse
Affiliation(s)
| | | | | | - Wenhong Deng
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| |
Collapse
|
|
8
|
Xie Q, Zeng Y, Zhang X, Yu F. The significance of lipid metabolism reprogramming of tumor-associated macrophages in hepatocellular carcinoma. Cancer Immunol Immunother 2024; 73:171. [PMID: 38954021 PMCID: PMC11220057 DOI: 10.1007/s00262-024-03748-9] [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: 02/15/2024] [Accepted: 05/28/2024] [Indexed: 07/04/2024]
Abstract
In the intricate landscape of the tumor microenvironment, tumor-associated macrophages (TAMs) emerge as a ubiquitous cellular component that profoundly affects the oncogenic process. The microenvironment of hepatocellular carcinoma (HCC) is characterized by a pronounced infiltration of TAMs, underscoring their pivotal role in modulating the trajectory of the disease. Amidst the evolving therapeutic paradigms for HCC, the strategic reprogramming of metabolic pathways presents a promising avenue for intervention, garnering escalating interest within the scientific community. Previous investigations have predominantly focused on elucidating the mechanisms of metabolic reprogramming in cancer cells without paying sufficient attention to understanding how TAM metabolic reprogramming, particularly lipid metabolism, affects the progression of HCC. In this review article, we intend to elucidate how TAMs exert their regulatory effects via diverse pathways such as E2F1-E2F2-CPT2, LKB1-AMPK, and mTORC1-SREBP, and discuss correlations of TAMs with these processes and the characteristics of relevant pathways in HCC progression by consolidating various studies on TAM lipid uptake, storage, synthesis, and catabolism. It is our hope that our summary could delineate the impact of specific mechanisms underlying TAM lipid metabolic reprogramming on HCC progression and provide useful information for future research on HCC and the development of new treatment strategies.
Collapse
Affiliation(s)
- Qingjian Xie
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yuan Zeng
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiangting Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Fujun Yu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
| |
Collapse
|
|
9
|
Korbecki J, Bosiacki M, Pilarczyk M, Gąssowska-Dobrowolska M, Jarmużek P, Szućko-Kociuba I, Kulik-Sajewicz J, Chlubek D, Baranowska-Bosiacka I. Phospholipid Acyltransferases: Characterization and Involvement of the Enzymes in Metabolic and Cancer Diseases. Cancers (Basel) 2024; 16:2115. [PMID: 38893234 PMCID: PMC11171337 DOI: 10.3390/cancers16112115] [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: 04/15/2024] [Revised: 05/23/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
This review delves into the enzymatic processes governing the initial stages of glycerophospholipid (phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine) and triacylglycerol synthesis. The key enzymes under scrutiny include GPAT and AGPAT. Additionally, as most AGPATs exhibit LPLAT activity, enzymes participating in the Lands cycle with similar functions are also covered. The review begins by discussing the properties of these enzymes, emphasizing their specificity in enzymatic reactions, notably the incorporation of polyunsaturated fatty acids (PUFAs) such as arachidonic acid and docosahexaenoic acid (DHA) into phospholipids. The paper sheds light on the intricate involvement of these enzymes in various diseases, including obesity, insulin resistance, and cancer. To underscore the relevance of these enzymes in cancer processes, a bioinformatics analysis was conducted. The expression levels of the described enzymes were correlated with the overall survival of patients across 33 different types of cancer using the GEPIA portal. This review further explores the potential therapeutic implications of inhibiting these enzymes in the treatment of metabolic diseases and cancer. By elucidating the intricate enzymatic pathways involved in lipid synthesis and their impact on various pathological conditions, this paper contributes to a comprehensive understanding of these processes and their potential as therapeutic targets.
Collapse
Affiliation(s)
- Jan Korbecki
- Department of Anatomy and Histology, Collegium Medicum, University of Zielona Góra, Zyty 28, 65-046 Zielona Góra, Poland;
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (M.B.); (D.C.)
| | - Mateusz Bosiacki
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (M.B.); (D.C.)
| | - Maciej Pilarczyk
- Department of Nervous System Diseases, Neurosurgery Center University Hospital in Zielona Góra, Collegium Medicum, University of Zielona Gora, 65-417 Zielona Góra, Poland; (M.P.); (P.J.)
| | - Magdalena Gąssowska-Dobrowolska
- Department of Cellular Signalling, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland;
| | - Paweł Jarmużek
- Department of Nervous System Diseases, Neurosurgery Center University Hospital in Zielona Góra, Collegium Medicum, University of Zielona Gora, 65-417 Zielona Góra, Poland; (M.P.); (P.J.)
| | | | - Justyna Kulik-Sajewicz
- Department of Conservative Dentistry and Endodontics, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland;
| | - Dariusz Chlubek
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (M.B.); (D.C.)
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland; (M.B.); (D.C.)
| |
Collapse
|
|
10
|
Dietze R, Szymanski W, Ojasalu K, Finkernagel F, Nist A, Stiewe T, Graumann J, Müller R. Phosphoproteomics Reveals Selective Regulation of Signaling Pathways by Lysophosphatidic Acid Species in Macrophages. Cells 2024; 13:810. [PMID: 38786034 PMCID: PMC11119170 DOI: 10.3390/cells13100810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 05/06/2024] [Accepted: 05/08/2024] [Indexed: 05/25/2024] Open
Abstract
Lysophosphatidic acid (LPA) species, prevalent in the tumor microenvironment (TME), adversely impact various cancers. In ovarian cancer, the 18:0 and 20:4 LPA species are selectively associated with shorter relapse-free survival, indicating distinct effects on cellular signaling networks. Macrophages represent a cell type of high relevance in the TME, but the impact of LPA on these cells remains obscure. Here, we uncovered distinct LPA-species-specific responses in human monocyte-derived macrophages through unbiased phosphoproteomics, with 87 and 161 phosphosites upregulated by 20:4 and 18:0 LPA, respectively, and only 24 shared sites. Specificity was even more pronounced for downregulated phosphosites (163 versus 5 sites). Considering the high levels 20:4 LPA in the TME and its selective association with poor survival, this finding may hold significant implications. Pathway analysis pinpointed RHO/RAC1 GTPase signaling as the predominantly impacted target, including AHRGEF and DOCK guanine exchange factors, ARHGAP GTPase activating proteins, and regulatory protein kinases. Consistent with these findings, exposure to 20:4 resulted in strong alterations to the actin filament network and a consequent enhancement of macrophage migration. Moreover, 20:4 LPA induced p38 phosphorylation, a response not mirrored by 18:0 LPA, whereas the pattern for AKT was reversed. Furthermore, RNA profiling identified genes involved in cholesterol/lipid metabolism as selective targets of 20:4 LPA. These findings imply that the two LPA species cooperatively regulate different pathways to support functions essential for pro-tumorigenic macrophages within the TME. These include cellular survival via AKT activation and migration through RHO/RAC1 and p38 signaling.
Collapse
Affiliation(s)
- Raimund Dietze
- Department of Translational Oncology, Center for Tumor Biology and Immunology, Philipps University, 35043 Marburg, Germany; (R.D.); (K.O.); (F.F.)
| | - Witold Szymanski
- Institute of Translational Proteomics, Biochemical Pharmacological Centre, Philipps University, 35043 Marburg, Germany
- Core Facility Translational Proteomics, Philipps University, 35043 Marburg, Germany
| | - Kaire Ojasalu
- Department of Translational Oncology, Center for Tumor Biology and Immunology, Philipps University, 35043 Marburg, Germany; (R.D.); (K.O.); (F.F.)
| | - Florian Finkernagel
- Department of Translational Oncology, Center for Tumor Biology and Immunology, Philipps University, 35043 Marburg, Germany; (R.D.); (K.O.); (F.F.)
- Bioinformatics Core Facility, Philipps University, 35043 Marburg, Germany
| | - Andrea Nist
- Genomics Core Facility, Philipps University, 35043 Marburg, Germany; (A.N.); (T.S.)
| | - Thorsten Stiewe
- Genomics Core Facility, Philipps University, 35043 Marburg, Germany; (A.N.); (T.S.)
| | - Johannes Graumann
- Institute of Translational Proteomics, Biochemical Pharmacological Centre, Philipps University, 35043 Marburg, Germany
- Core Facility Translational Proteomics, Philipps University, 35043 Marburg, Germany
| | - Rolf Müller
- Department of Translational Oncology, Center for Tumor Biology and Immunology, Philipps University, 35043 Marburg, Germany; (R.D.); (K.O.); (F.F.)
| |
Collapse
|
|
11
|
Safi R, Menéndez P, Pol A. Lipid droplets provide metabolic flexibility for cancer progression. FEBS Lett 2024; 598:1301-1327. [PMID: 38325881 DOI: 10.1002/1873-3468.14820] [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: 09/04/2023] [Revised: 01/08/2024] [Accepted: 01/10/2024] [Indexed: 02/09/2024]
Abstract
A hallmark of cancer cells is their remarkable ability to efficiently adapt to favorable and hostile environments. Due to a unique metabolic flexibility, tumor cells can grow even in the absence of extracellular nutrients or in stressful scenarios. To achieve this, cancer cells need large amounts of lipids to build membranes, synthesize lipid-derived molecules, and generate metabolic energy in the absence of other nutrients. Tumor cells potentiate strategies to obtain lipids from other cells, metabolic pathways to synthesize new lipids, and mechanisms for efficient storage, mobilization, and utilization of these lipids. Lipid droplets (LDs) are the organelles that collect and supply lipids in eukaryotes and it is increasingly recognized that the accumulation of LDs is a new hallmark of cancer cells. Furthermore, an active role of LD proteins in processes underlying tumorigenesis has been proposed. Here, by focusing on three major classes of LD-resident proteins (perilipins, lipases, and acyl-CoA synthetases), we provide an overview of the contribution of LDs to cancer progression and discuss the role of LD proteins during the proliferation, invasion, metastasis, apoptosis, and stemness of cancer cells.
Collapse
Affiliation(s)
- Rémi Safi
- Josep Carreras Leukemia Research Institute, Barcelona, Spain
- Lipid Trafficking and Disease Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
| | - Pablo Menéndez
- Josep Carreras Leukemia Research Institute, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- Department of Biomedical Sciences, Faculty of Medicine, Universitat de Barcelona, Spain
- Consorcio Investigación Biomédica en Red de Cancer, CIBER-ONC, ISCIII, Barcelona, Spain
- Spanish Network for Advanced Cell Therapies (TERAV), Barcelona, Spain
| | - Albert Pol
- Lipid Trafficking and Disease Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- Department of Biomedical Sciences, Faculty of Medicine, Universitat de Barcelona, Spain
| |
Collapse
|
|
12
|
Liu J, Wang T, Zhang W, Huang Y, Wang X, Li Q. Association between Metabolic Reprogramming and Immune Regulation in Digestive Tract Tumors. Oncol Res Treat 2024; 47:273-286. [PMID: 38636467 DOI: 10.1159/000538659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 03/28/2024] [Indexed: 04/20/2024]
Abstract
BACKGROUND The cancers of the digestive tract, including colorectal cancer (CRC), gastric cancer, and esophageal cancer, are part of the most common cancers as well as one of the most important leading causes of cancer death worldwide. SUMMARY Despite the emergence of immune checkpoint inhibitors (e.g., anti-CTLA-4 and anti-PD-1/PD-L1) in the past decade, offering renewed optimism in cancer treatment, only a fraction of patients derive benefit from these therapies. This limited efficacy may stem from tumor heterogeneity and the impact of metabolic reprogramming on both tumor cells and immune cells within the tumor microenvironment (TME). The metabolic reprogramming of glucose, lipids, amino acids, and other nutrients represents a pivotal hallmark of cancer, serving to generate energy, reducing equivalent and biological macromolecule, thereby fostering tumor proliferation and invasion. Significantly, the metabolic reprogramming of tumor cells can orchestrate changes within the TME, rendering patients unresponsive to immunotherapy. KEY MESSAGES In this review, we predominantly encapsulate recent strides on metabolic reprogramming among digestive tract cancer, especially CRC, in the TME with a focus on how these alterations influence anti-tumor immunity. Additionally, we deliberate on potential strategies to address these abnormities in metabolic pathways and the viability of combined therapy within the realm of anti-cancer immunotherapy.
Collapse
Affiliation(s)
- Jiafeng Liu
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Tianxiao Wang
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Wenxin Zhang
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuxin Huang
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Xinhai Wang
- Department of Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Qunyi Li
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
13
|
Gao Y, Zhao K, Huang Y, Zhang D, Luo N, Peng X, Yang F, Xiao W, Wang M, Shi R, Miao H. Lanosterol synthase deficiency promotes tumor progression by orchestrating PDL1-dependent tumor immunosuppressive microenvironment. MedComm (Beijing) 2024; 5:e528. [PMID: 38606362 PMCID: PMC11006713 DOI: 10.1002/mco2.528] [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: 09/15/2023] [Revised: 02/26/2024] [Accepted: 03/04/2024] [Indexed: 04/13/2024] Open
Abstract
Lipid metabolic reprogramming is closely related to tumor progression with the mechanism not fully elucidated. Here, we report the immune-regulated role of lanosterol synthase (LSS), an essential enzyme in cholesterol synthesis. Database analysis and clinical sample experiments suggest that LSS was lowly expressed in colon and breast cancer tissues, which indicates poor prognosis. The biological activity of tumor cell lines and tumor progression in NOD scid gamma (NSG) mice were not affected after LSS knockdown, whereas LSS deficiency obviously aggravated tumor burden in fully immunized mice. Flow cytometry analysis showed that LSS knockdown significantly promoted the formation of tumor immunosuppressive microenvironment, characterized by the increase in M2 macrophages and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), as well as the decrease in anti-tumoral T lymphocytes. With the inhibition of myeloid infiltration or loss function of T lymphocytes, the propulsive effect of LSS knockdown on tumor progression disappeared. Mechanistically, LSS knockdown increased programmed death ligand 1 (PDL1) protein stability by 2,3-oxidosqualene (OS) binding to PDL1 protein. Anti-PDL1 therapy abolished LSS deficiency-induced immunosuppressive microenvironment and cancer progression. In conclusion, our results show that LSS deficiency promotes tumor progression by establishing an OS-PDL1 axis-dependent immunosuppressive microenvironment, indicative of LSS or OS as a potential hallmark of response to immune checkpoint blockade.
Collapse
Affiliation(s)
- Yuan Gao
- Department of PathophysiologyCollege of High Altitude Military MedicineThird Military Medical University (Army Medical University)ChongqingChina
| | - Kun Zhao
- Department of PathophysiologyCollege of High Altitude Military MedicineThird Military Medical University (Army Medical University)ChongqingChina
| | - Yulan Huang
- Department of PathophysiologyCollege of High Altitude Military MedicineThird Military Medical University (Army Medical University)ChongqingChina
| | - Dapeng Zhang
- Department of PathophysiologyCollege of High Altitude Military MedicineThird Military Medical University (Army Medical University)ChongqingChina
| | - Na Luo
- Department of PathophysiologyCollege of High Altitude Military MedicineThird Military Medical University (Army Medical University)ChongqingChina
| | - Xiaoqing Peng
- Department of OncologyFuling HospitalChongqing UniversityChongqingChina
| | - Feng Yang
- Department of General SurgeryXinqiao HospitalThird Military Medical University (Army Medical University)ChongqingChina
| | - Weidong Xiao
- Department of General SurgeryXinqiao HospitalThird Military Medical University (Army Medical University)ChongqingChina
| | - Meng Wang
- Department of PathophysiologyCollege of High Altitude Military MedicineThird Military Medical University (Army Medical University)ChongqingChina
| | - Rongchen Shi
- Frontier Medical Training BrigadeThird Military Medical University (Army Medical University)XinjiangChina
| | - Hongming Miao
- Department of PathophysiologyCollege of High Altitude Military MedicineThird Military Medical University (Army Medical University)ChongqingChina
- Jinfeng LaboratoryChongqingChina
| |
Collapse
|
|
14
|
Chen X, Ma Z, Yi Z, Wu E, Shang Z, Tuo B, Li T, Liu X. The effects of metabolism on the immune microenvironment in colorectal cancer. Cell Death Discov 2024; 10:118. [PMID: 38453888 PMCID: PMC10920911 DOI: 10.1038/s41420-024-01865-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 02/07/2024] [Accepted: 02/12/2024] [Indexed: 03/09/2024] Open
Abstract
Colorectal cancer (CRC) is a malignancy that is widely prevalent worldwide. Due to its unsatisfactory treatment outcome and extremely poor prognosis, many studies on the molecular mechanisms and pathological mechanisms of CRC have been published in recent years. The tumor microenvironment (TME) is an extremely important feature of tumorigenesis and one of the hallmarks of tumor development. Metabolic reprogramming is currently a hot topic in tumor research, and studies on this topic have provided important insights into CRC development. In particular, metabolic reprogramming in cancer causes changes in the composition of energy and nutrients in the TME. Furthermore, it can alter the complex crosstalk between immune cells and associated immune factors, such as associated macrophages and T cells, which play important immune roles in the TME, in turn affecting the immune escape of tumors by altering immune surveillance. In this review, we summarize several metabolism-related processes affecting the immune microenvironment of CRC tumors. Our results showed that the immune microenvironment is regulated by metabolic reprogramming and influences the development of CRC.
Collapse
Affiliation(s)
- Xingzhao Chen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Zhiyuan Ma
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Zhiqiang Yi
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Enqin Wu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Zhengye Shang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Taolang Li
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Dalian Road 149, Zunyi, 563000, China.
| | - Xuemei Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China.
| |
Collapse
|
|
15
|
Wang Y, Xu C, Yang X, Liu X, Guo Z, Lin X, Li L, Huang Z. Glycerol-3-phosphate acyltransferase 3-mediated lipid droplets accumulation confers chemoresistance of colorectal cancer. MedComm (Beijing) 2024; 5:e486. [PMID: 38344398 PMCID: PMC10857777 DOI: 10.1002/mco2.486] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 12/18/2023] [Accepted: 12/25/2023] [Indexed: 10/23/2024] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy worldwide. It is well known that lipid metabolism reprogramming contributes to the tumor progression. However, the lipid metabolic alterations and potential remodeling mechanism underlying the chemoresistance of CRC remain largely unclear. In this study, we compared the gene expression profiles of chemoresistant versus control CRC cells from the GEO database and identified a key factor, Glycerol-3-phosphate acyltransferase 3 (GPAT3), that promotes lipid droplet (LD) production and confers chemoresistance of CRC. With applying of HPLC-MS and molecular dynamics simulation, we also demonstrated that the activity of lysophosphatidic acid synthesis by GPAT3 was dependent on its acetylation at K316 site. In particular, GPAT3-mediated LD accumulation inhibited immunogenic cell death of tumor, and thus facilitated CD8+ T-cell exhaustion and malignant progression in mouse xenografts and hepatic-metastasis tumors in CRC patients. High GPAT3 expression turned CRC cells into nonimmunogenic cells after (Oxaliplatin) Oxa treatment, which was supported by a decrease in cytotoxic IFN-γ release and CD8+ T-cell exhaustion. In conclusion, these findings revealed the role of GPAT3-associated LD accumulation, which conferred a malignant phenotype (chemoresistance) and regulated the tumor microenvironment of CRC. These results suggest that GPAT3 is a potential target to enhance CRC chemosensitivity and develop novel therapeutic interventions.
Collapse
Affiliation(s)
- Ying Wang
- Wuxi Cancer InstituteAffiliated Hospital of Jiangnan UniversityWuxiJiangsuChina
| | - Caihua Xu
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Xianfeng Yang
- Department of RadiologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Xiaofei Liu
- Department of thyroid breast surgery, First Clinical CollegeShandong University of Traditional Chinese MedicineJinanShandongChina
| | - Zijian Guo
- Department of Oncological SurgeryAffiliated Hospital of Jiangnan UniversityWuxiJiangsuChina
| | - Xinyu Lin
- Wuxi Cancer InstituteAffiliated Hospital of Jiangnan UniversityWuxiJiangsuChina
| | - Lihua Li
- Wuxi Cancer InstituteAffiliated Hospital of Jiangnan UniversityWuxiJiangsuChina
| | - Zhaohui Huang
- Wuxi Cancer InstituteAffiliated Hospital of Jiangnan UniversityWuxiJiangsuChina
| |
Collapse
|
|
16
|
Chen H, Ma R, Zhou B, Yang X, Duan F, Wang G. Integrated immunological analysis of single-cell and bulky tissue transcriptomes reveals the role of interactions between M0 macrophages and naïve CD4 + T cells in the immunosuppressive microenvironment of cervical cancer. Comput Biol Med 2023; 163:107151. [PMID: 37348264 DOI: 10.1016/j.compbiomed.2023.107151] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/27/2023] [Accepted: 06/07/2023] [Indexed: 06/24/2023]
Abstract
In recent decades, the incidence and mortality of cervical cancer have declined in developed countries due to the implementation of screening and vaccination programs. However, cervical cancer remains one of the major culprits of cancer-related deaths in young women. Current studies have found that immune cell-related intercellular communication in the tumor microenvironment has a large impact on the construction of the immunosuppressive microenvironment. In this study, we performed a comprehensive immune analysis on bulk RNA-seq and scRNA-seq data obtained from cervical cancer and revealed that two highly plastic cell populations, M0 macrophages and naïve CD4+ T cells, were significantly correlated with prognosis and clinical phenotypes. Notably, signaling between M0 macrophages and naïve CD4+ T cells as well as intracellular transcription factor activity were significantly altered in the tumor state. Furthermore, we identified overlapping genes between the transcription factor target genes of M0 macrophages or naïve CD4+ T cells and the differentially expressed genes in each type of cell, and these overlapping genes were subsequently subjected to an analysis using the LASSO regression model. Finally, we generated a score index that was significantly associated with the clinical prognosis of cervical cancer. In conclusion, interventions to improve the communication between M0 macrophages and naïve CD4+ T cells may help to improve the immunosuppressive microenvironment of cervical cancer and prevent immune evasion. The relevant molecular mechanisms need to be further validated by experimental and cohort studies.
Collapse
Affiliation(s)
- Huaqiu Chen
- Center of Genetic Testing, The First Affiliated Hospital of Dali University, Dali, Yunnan Province, 671000, China; Department of Laboratory, Xichang People's Hospital, Sichuan, 615000, China
| | - Rong Ma
- Center of Genetic Testing, The First Affiliated Hospital of Dali University, Dali, Yunnan Province, 671000, China; Department of Laboratory, The First People's Hospital of Qujing, Yunnan Province, 655000, China
| | - Bingjie Zhou
- Center of Genetic Testing, The First Affiliated Hospital of Dali University, Dali, Yunnan Province, 671000, China; Maternity and Obstetrics Department of Fangshan District Maternity and Child Health Hospital of Beijing, Fangshan District of Beijing, 102488, China
| | - Xitong Yang
- Center of Genetic Testing, The First Affiliated Hospital of Dali University, Dali, Yunnan Province, 671000, China
| | - Fuhui Duan
- Center of Genetic Testing, The First Affiliated Hospital of Dali University, Dali, Yunnan Province, 671000, China
| | - Guangming Wang
- Center of Genetic Testing, The First Affiliated Hospital of Dali University, Dali, Yunnan Province, 671000, China.
| |
Collapse
|
|
17
|
Jiang S, Yang H, Li M. Emerging Roles of Lysophosphatidic Acid in Macrophages and Inflammatory Diseases. Int J Mol Sci 2023; 24:12524. [PMID: 37569902 PMCID: PMC10419859 DOI: 10.3390/ijms241512524] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/02/2023] [Accepted: 08/04/2023] [Indexed: 08/13/2023] Open
Abstract
Lysophosphatidic acid (LPA) is a bioactive phospholipid that regulates physiological and pathological processes in numerous cell biological functions, including cell migration, apoptosis, and proliferation. Macrophages are found in most human tissues and have multiple physiological and pathological functions. There is growing evidence that LPA signaling plays a significant role in the physiological function of macrophages and accelerates the development of diseases caused by macrophage dysfunction and inflammation, such as inflammation-related diseases, cancer, atherosclerosis, and fibrosis. In this review, we summarize the roles of LPA in macrophages, analyze numerous macrophage- and inflammation-associated diseases triggered by LPA, and discuss LPA-targeting therapeutic strategies.
Collapse
Affiliation(s)
- Shufan Jiang
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China;
- Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Huili Yang
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China;
| | - Mingqing Li
- Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China;
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China
| |
Collapse
|
|
18
|
Tsamchoe M, Lazaris A, Kim D, Krzywon L, Bloom J, Mayer T, Petrillo SK, Dejgaard K, Gao ZH, Rak J, Metrakos P. Circulating extracellular vesicles containing S100A9 reflect histopathology, immunophenotype and therapeutic responses of liver metastasis in colorectal cancer patients. BJC REPORTS 2023; 1:8. [PMID: 39516397 PMCID: PMC11524068 DOI: 10.1038/s44276-023-00007-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/20/2023] [Accepted: 06/28/2023] [Indexed: 11/16/2024]
Abstract
BACKGROUND Metastasis is the principal cause of cancer treatment failure and an area of dire diagnostic needs. Colorectal cancer metastases to the liver (CRCLMs) are predominantly classified into desmoplastic and replacement based on their histological growth patterns (HGPs). Desmoplastic responds well to current treatments, while replacement HGP has a poor prognosis with low overall survival rates. METHODS We hypothesised that complex cellular response underlying HGPs may be reflected in the proteome of circulating extracellular vesicles (EVs). EV proteomics data was generated through LC-MS/MS and analysed with Maxquant and Perseus. To validate the S100A9 signature, ELISA was performed, and IHC and IF were conducted on tissue for marker detection and colocalization study. RESULTS Plasma EV proteome signature distinguished desmoplastic from the replacement in patients with 22 differentially expressed proteins, including immune related markers. Unsupervised PCA analysis revealed clear separation of the two lesions. The marker with the highest confidence level to stratify the two HGPs was S100A9, which was traced in CRCLM lesions and found to colocalize with macrophages and neutrophils. EV-associated S100A9 in plasma may reflect the innate immunity status of metastatic lesions and their differential therapeutic responses. CONCLUSION Plasma EV-derived S100A9 could be useful in personalising therapy in patients with CRCLM.
Collapse
Affiliation(s)
- Migmar Tsamchoe
- Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada
- Research Institute of McGill University Health Center, Cancer Research Program, Montreal, QC, Canada
| | - Anthoula Lazaris
- Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada.
- Research Institute of McGill University Health Center, Cancer Research Program, Montreal, QC, Canada.
| | - Diane Kim
- Research Institute of McGill University Health Center, Cancer Research Program, Montreal, QC, Canada
| | - Lucyna Krzywon
- Research Institute of McGill University Health Center, Cancer Research Program, Montreal, QC, Canada
| | - Jessica Bloom
- Research Institute of McGill University Health Center, Cancer Research Program, Montreal, QC, Canada
| | - Thomas Mayer
- Research Institute of McGill University Health Center, Cancer Research Program, Montreal, QC, Canada
| | - Stephanie K Petrillo
- Research Institute of McGill University Health Center, Cancer Research Program, Montreal, QC, Canada
| | - Kurt Dejgaard
- Department of Biochemistry, McGill University, Montreal, QC, Canada
| | - Zu-Hua Gao
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Janusz Rak
- McGill University, Montreal Children's Hospital, RI MUHC, Montreal, QC, Canada
| | - Peter Metrakos
- Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada.
- Research Institute of McGill University Health Center, Cancer Research Program, Montreal, QC, Canada.
- Department of Surgery, McGill University Health Center, Montreal, QC, Canada.
| |
Collapse
|
|
19
|
Liu S, Shen YY, Yin LY, Liu J, Zu X. Lipid Metabolic Regulatory Crosstalk Between Cancer Cells and Tumor-Associated Macrophages. DNA Cell Biol 2023; 42:445-455. [PMID: 37535386 DOI: 10.1089/dna.2023.0071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2023] Open
Abstract
In the tumor microenvironment, tumor-associated macrophages (TAMs) are one of the most abundant cell populations, playing key roles in tumorigenesis, chemoresistance, immune evasion, and metastasis. There is an important interaction between TAMs and cancer cells: on the one hand, tumors control the function of infiltrating macrophages, contributing to reprogramming of TAMs, and on the other hand, TAMs affect the growth of cancer cells. This review focuses on lipid metabolism changes in the complex relationship between cancer cells and TAMs. We discuss how lipid metabolism in cancer cells affects macrophage phenotypic and metabolic changes and, subsequently, how altered lipid metabolism of TAMs influences tumor progression. Identifying the metabolic changes that influence the complex interaction between tumor cells and TAMs is also an important step in exploring new therapeutic approaches that target metabolic reprogramming of immune cells to enhance their tumoricidal potential and bypass therapy resistance. Our work may provide new targets for antitumor therapies.
Collapse
Affiliation(s)
- Shu Liu
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Ying Ying Shen
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Li Yang Yin
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jianghua Liu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Xuyu Zu
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| |
Collapse
|
|
20
|
Han J, Dong L, Wu M, Ma F. Dynamic polarization of tumor-associated macrophages and their interaction with intratumoral T cells in an inflamed tumor microenvironment: from mechanistic insights to therapeutic opportunities. Front Immunol 2023; 14:1160340. [PMID: 37251409 PMCID: PMC10219223 DOI: 10.3389/fimmu.2023.1160340] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 04/20/2023] [Indexed: 05/31/2023] Open
Abstract
Immunotherapy has brought a paradigm shift in the treatment of tumors in recent decades. However, a significant proportion of patients remain unresponsive, largely due to the immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play crucial roles in shaping the TME by exhibiting dual identities as both mediators and responders of inflammation. TAMs closely interact with intratumoral T cells, regulating their infiltration, activation, expansion, effector function, and exhaustion through multiple secretory and surface factors. Nevertheless, the heterogeneous and plastic nature of TAMs renders the targeting of any of these factors alone inadequate and poses significant challenges for mechanistic studies and clinical translation of corresponding therapies. In this review, we present a comprehensive summary of the mechanisms by which TAMs dynamically polarize to influence intratumoral T cells, with a focus on their interaction with other TME cells and metabolic competition. For each mechanism, we also discuss relevant therapeutic opportunities, including non-specific and targeted approaches in combination with checkpoint inhibitors and cellular therapies. Our ultimate goal is to develop macrophage-centered therapies that can fine-tune tumor inflammation and empower immunotherapy.
Collapse
Affiliation(s)
- Jiashu Han
- 4+4 Medical Doctor Program, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng, Beijing, China
| | - Luochu Dong
- 4+4 Medical Doctor Program, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng, Beijing, China
| | - Mengwei Wu
- Department of General Surgery, Peking Union Medical College Hospital (CAMS), Beijing, China
| | - Fei Ma
- Center for National Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| |
Collapse
|
|
21
|
ZHONG JIATENG, GUO JINGYU, ZHANG XINYU, FENG SHUANG, DI WENYU, WANG YANLING, ZHU HUIFANG. The remodeling roles of lipid metabolism in colorectal cancer cells and immune microenvironment. Oncol Res 2023; 30:231-242. [PMID: 37305350 PMCID: PMC10207963 DOI: 10.32604/or.2022.027900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 01/18/2023] [Indexed: 02/05/2023] Open
Abstract
Lipid is a key component of plasma membrane, which plays an important role in the regulation of various cell biological behaviors, including cell proliferation, growth, differentiation and intracellular signal transduction. Studies have shown that abnormal lipid metabolism is involved in many malignant processes, including colorectal cancer (CRC). Lipid metabolism in CRC cells can be regulated not only by intracellular signals, but also by various components in the tumor microenvironment, including various cells, cytokines, DNA, RNA, and nutrients including lipids. In contrast, abnormal lipid metabolism provides energy and nutrition support for abnormal malignant growth and distal metastasis of CRC cells. In this review, we highlight the remodeling roles of lipid metabolism crosstalk between the CRC cells and the components of tumor microenvironment.
Collapse
Affiliation(s)
- JIATENG ZHONG
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453100, China
| | - JINGYU GUO
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China
| | - XINYU ZHANG
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China
| | - SHUANG FENG
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China
| | - WENYU DI
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453100, China
| | - YANLING WANG
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - HUIFANG ZHU
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China
| |
Collapse
|
|
22
|
Zang J, Sun J, Xiu W, Liu X, Chai Y, Zhou Y. Low Expression of AGPAT5 Is Associated With Clinical Stage and Poor
Prognosis in Colorectal Cancer and Contributes to Tumour
Progression. Clin Med Insights Oncol 2022; 16:11795549221137399. [PMCID: PMC9716453 DOI: 10.1177/11795549221137399] [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: 05/16/2022] [Accepted: 10/20/2022] [Indexed: 12/05/2022] Open
Abstract
Background: Colorectal cancer (CRC) has a high prevalence and poor prognosis. This study
aimed to identify biomarkers related to the clinical stage (I-IV) of
CRC. Methods: The LinkedOmics database was used as the discovery cohort, and two Gene
Expression Omnibus (GEO) databases (GSE41258 and GSE422848) served as
validation cohorts. The trend test of genes related to clinical stage (I-IV)
of CRC patients was identified by the Jonckheere-Terpstra test. The
cBioPortal database, Gene Expression Profiling Interactive Analysis (GEPIA)
and PrognoScan databases were used to explore the expression change and
prognostic value of clinical stage-related genes in CRC patients. CRC cells
overexpressed AGPAT5 were constructed and used for cell counting kit-8
(CCK-8), flow cytometric, and wound healing assays in vitro. Results: We identified four clinical stage-related genes, GSR, AGPAT5, CRLF1, and
NPR3, in CRC. The CNA frequencies of GSR, CRLF1, AGPAT5, and NPR3 occurred
in 11%, 2.4%, 13%, and 3% of patients, respectively. The expression of GSR
and AGPAT5 tended to decrease with CRC stage (I-IV) progression, and the
expression of CRLF1 and NPR3 tended to increase with CRC stage (I-IV)
progression. Compared with the normal group, AGPAT5 expression was markedly
decreased in stage IV CRC. Higher GSR and AGPAT5 expression levels were
associated with better overall survival (OS) and disease-free survival (DFS)
in CRC patients. Lower CRLF1 and NPR3 expression levels were associated with
better OS and DFS in CRC. GSR, CRLF1, AGPAT5, and NPR3 expression were
related to CRC progression, microsatellite instability, and tumour purity in
CRC. Furthermore, AGPAT5 was downregulated in CRC cell lines, and
overexpression of AGPAT5 inhibited cell proliferation and migration and
promoted cell apoptosis in CRC cells. Conclusion: Low AGPAT5 expression may serve as a poor prognostic factor and clinical
stage biomarker in CRC. In addition, AGPAT5 acts as a tumour suppressor in
CRC progression.
Collapse
Affiliation(s)
- Jia Zang
- Department of Colorectal Surgery,
Shanghai Changzheng Hospital, Shanghai, P.R. China
| | - Juanjuan Sun
- Department of Colorectal Surgery,
Shanghai Changzheng Hospital, Shanghai, P.R. China
| | - WenChao Xiu
- The Second Ward of Anorectal
Department, Qilu Hospital of Shandong University (Qingdao), China
| | - Xiaoshuang Liu
- Department of General Surgery, Shuguang
Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R.
China
| | - Yunsheng Chai
- Department of Colorectal Surgery,
Shanghai Changzheng Hospital, Shanghai, P.R. China,Yunsheng Chai, Department of Colorectal
Surgery, Shanghai Changzheng Hospital, No. 415, FengYang Road, Shanghai 200003,
P.R. China.
| | - Yanyan Zhou
- Department of Colorectal Surgery,
Shanghai Changzheng Hospital, Shanghai, P.R. China
| |
Collapse
|
|
23
|
Song T, He K, Ning J, Li W, Xu T, Yu W, Rao T, Cheng F. Evaluation of aliphatic acid metabolism in bladder cancer with the goal of guiding therapeutic treatment. Front Oncol 2022; 12:930038. [PMID: 36059672 PMCID: PMC9433665 DOI: 10.3389/fonc.2022.930038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 07/28/2022] [Indexed: 11/13/2022] Open
Abstract
Urothelial bladder cancer (BLCA) is a common internal malignancy with a poor prognosis. The re-programming of lipid metabolism is necessary for cancer cell growth, proliferation, angiogenesis and invasion. However, the role of aliphatic acid metabolism genes in bladder cancer patients has not been explored. The samples’ gene expression and clinicopathological data were obtained from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Univariate, multivariate, and LASSO Cox regression were used to develop a BLCA prognostic model. GSVA was used to assess function, whereas pRRophetic was used to assess chemotherapeutic drug sensitivity. The twelve-gene signature may define the tumor immune milieu, according to the risk score model. We compared the expression of aliphatic acid metabolism genes in malignant and non-cancerous tissues and chose 90 with a false discovery rate of 0.05 for The Cancer Genome Atlas cohort. The prognostic risk score model can effectively predict BLCA OS. A nomogram including age, clinical T stage, gender, grade, pathological stage, and clinical M stage was developed as an independent BLCA prognostic predictor. The halfmaximal inhibitory concentration (IC50) was used to assess chemotherapeutic medication response. Sorafenib and Pyrimethamine were used to treat patients with low risk scores more sensitively than patients with high risk scores. Immunotherapy candidates with CMS1 exhibited higher risk ratings. The aliphatic acid prognostic risk score model can assess metabolic trends. Clinical stage and molecular subtype may be used to categorize individuals using the risk score.With this new paradigm, future cancer treatment and immunotherapy may be tailored to the patient’s exact requirements.
Collapse
Affiliation(s)
- Tianbao Song
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Kaixiang He
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jinzhuo Ning
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wei Li
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Tao Xu
- Department of Urology, Huanggang Central Hospital, Huanggang, China
| | - Weimin Yu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ting Rao
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Fan Cheng, ; Ting Rao,
| | - Fan Cheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Fan Cheng, ; Ting Rao,
| |
Collapse
|
|
24
|
Du K, Zou J, Wang B, Liu C, Khan M, Xie T, Huang X, Shen P, Tian Y, Yuan Y. A Metabolism-Related Gene Prognostic Index Bridging Metabolic Signatures and Antitumor Immune Cycling in Head and Neck Squamous Cell Carcinoma. Front Immunol 2022; 13:857934. [PMID: 35844514 PMCID: PMC9282908 DOI: 10.3389/fimmu.2022.857934] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 05/18/2022] [Indexed: 12/26/2022] Open
Abstract
Background In the era of immunotherapy, predictive or prognostic biomarkers for head and neck squamous cell carcinoma (HNSCC) are urgently needed. Metabolic reprogramming in the tumor microenvironment (TME) is a non-negligible reason for the low therapeutic response to immune checkpoint inhibitor (ICI) therapy. We aimed to construct a metabolism-related gene prognostic index (MRGPI) for HNSCC bridging metabolic characteristics and antitumor immune cycling and identified the immunophenotype, genetic alternations, potential targeted inhibitors, and the benefit of immunotherapy in MRGPI-defined subgroups of HNSCC. Methods Based on The Cancer Genome Atlas (TCGA) HNSCC dataset (n = 502), metabolism-related hub genes were identified by the weighted gene co-expression network analysis (WGCNA). Seven genes were identified to construct the MRGPI by using the Cox regression method and validated with an HNSCC dataset (n = 270) from the Gene Expression Omnibus (GEO) database. Afterward, the prognostic value, metabolic activities, genetic alternations, gene set enrichment analysis (GSEA), immunophenotype, Connectivity map (cMAP), and benefit of immunotherapy in MRGPI-defined subgroups were analyzed. Results The MRGPI was constructed based on HPRT1, AGPAT4, AMY2B, ACADL, CKM, PLA2G2D, and ADA. Patients in the low-MRGPI group had better overall survival than those in the high-MRGPI group, consistent with the results in the GEO cohort (cutoff value = 1.01). Patients with a low MRGPI score display lower metabolic activities and an active antitumor immunity status and more benefit from immunotherapy. In contrast, a higher MRGPI score was correlated with higher metabolic activities, more TP53 mutation rate, lower antitumor immunity ability, an immunosuppressive TME, and less benefit from immunotherapy. Conclusion The MRGPI is a promising indicator to distinguish the prognosis, the metabolic, molecular, and immune phenotype, and the benefit from immunotherapy in HNSCC.
Collapse
Affiliation(s)
- Kunpeng Du
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Jingwen Zou
- Department of Liver Surgery of the Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Baiyao Wang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Chunshan Liu
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Muhammad Khan
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Tao Xie
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Xiaoting Huang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Piao Shen
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Yunhong Tian
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
- *Correspondence: Yunhong Tian, ; Yawei Yuan,
| | - Yawei Yuan
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
- *Correspondence: Yunhong Tian, ; Yawei Yuan,
| |
Collapse
|
|
25
|
Li S, Lu Z, Huang Y, Wang Y, Jin Q, Shentu X, Ye J, Ji J, Yao K, Han H. Anti-Oxidative and Anti-Inflammatory Micelles: Break the Dry Eye Vicious Cycle. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2200435. [PMID: 35435328 PMCID: PMC9189644 DOI: 10.1002/advs.202200435] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 03/13/2022] [Indexed: 05/15/2023]
Abstract
Dry eye disease (DED) impacts ≈30% of the world's population and causes serious ocular discomfort and even visual impairment. Inflammation is one core cause of the DED vicious cycle, a multifactorial deterioration in DED process. However, there are also reactive oxygen species (ROS) regulating inflammation and other points in the cycle from the upstream, leading to treatment failure of current therapies merely targeting inflammation. Accordingly, the authors develop micelle-based eye drops (more specifically p38 mitogen-activated protein kinases (MAPK) inhibitor Losmapimod (Los)-loaded and ROS scavenger Tempo (Tem)-conjugated cationic polypeptide micelles, designated as MTem/Los) for safe and efficient DED management. Cationic MTem/Los improve ocular retention of conjugated water-soluble Tem and loaded water-insoluble Los via electrostatic interaction with negatively charged mucin on the cornea, enabling an increase in therapeutic efficiency and a decrease in dosing frequency. Mechanistically, MTem/Los effectively decrease ROS over-production, reduce the expression of proinflammatory cytokines and chemokines, restrain macrophage proinflammatory phenotypic transformation, and inhibit cell apoptosis. Therapeutically, the dual-functional MTem/Los suppress the inflammatory response, reverse corneal epithelial defect, save goblet cell dysfunction, and recover tear secretion, thus breaking the vicious cycle and alleviating the DED. Moreover, MTem/Los exhibit excellent biocompatibility and tolerability for potential application as a simple and rapid treatment of oxidative stress- and inflammation-induced disorders, including DED.
Collapse
Affiliation(s)
- Su Li
- Eye CenterThe Second Affiliated HospitalSchool of MedicineZhejiang University88 Jiefang RoadHangzhou310009P. R. China
| | - Zhouyu Lu
- Eye CenterThe Second Affiliated HospitalSchool of MedicineZhejiang University88 Jiefang RoadHangzhou310009P. R. China
| | - Yue Huang
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of EducationDepartment of Polymer Science and EngineeringZhejiang UniversityHangzhou310027P. R. China
| | - Yin Wang
- School of PharmacyShanghai Jiao Tong University800 Dongchuan RoadShanghai200240P. R. China
| | - Qiao Jin
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of EducationDepartment of Polymer Science and EngineeringZhejiang UniversityHangzhou310027P. R. China
| | - Xingchao Shentu
- Eye CenterThe Second Affiliated HospitalSchool of MedicineZhejiang University88 Jiefang RoadHangzhou310009P. R. China
- Zhejiang Provincial Key Lab of OphthalmologyZhejiang University88 Jiefang RoadHangzhou310009P. R. China
| | - Juan Ye
- Eye CenterThe Second Affiliated HospitalSchool of MedicineZhejiang University88 Jiefang RoadHangzhou310009P. R. China
- Zhejiang Provincial Key Lab of OphthalmologyZhejiang University88 Jiefang RoadHangzhou310009P. R. China
| | - Jian Ji
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of EducationDepartment of Polymer Science and EngineeringZhejiang UniversityHangzhou310027P. R. China
| | - Ke Yao
- Eye CenterThe Second Affiliated HospitalSchool of MedicineZhejiang University88 Jiefang RoadHangzhou310009P. R. China
- Zhejiang Provincial Key Lab of OphthalmologyZhejiang University88 Jiefang RoadHangzhou310009P. R. China
| | - Haijie Han
- Eye CenterThe Second Affiliated HospitalSchool of MedicineZhejiang University88 Jiefang RoadHangzhou310009P. R. China
- Zhejiang Provincial Key Lab of OphthalmologyZhejiang University88 Jiefang RoadHangzhou310009P. R. China
| |
Collapse
|
|
26
|
Xu S, Guo Y, Luo T, Jiang P, Yan Z, He Y, Fu L, Liu H, Gao Z, Wang D, Sun Z, Yang X, Pan W, Sun F. Transcriptomic Profiles of Splenic CD19 + B Cells in Mice Chronically Infected With the Larval Echinococcus granulosus. Front Vet Sci 2022; 9:848458. [PMID: 35548052 PMCID: PMC9082817 DOI: 10.3389/fvets.2022.848458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 03/28/2022] [Indexed: 11/26/2022] Open
Abstract
Background We previously reported that the larval Echinococcus granulosus (E. granulosus) infection can expand the population of regulatory B cells in mice, thereby inhibiting the anti-infective immunity. However, the underlying mechanism is still largely unknown. This study further investigated the holistic transcriptomic profiles of total splenic B cells following the chronic infection of the parasite. Methods The infection model of larval E. granulosus was established by intraperitoneal inoculation with 2000 protoscolexes. Magnetic-Activated Cell Separation (MACS) was used to isolate the total splenic B cells. RNA sequencing was performed to screen the differentially expressed genes (DEGs) after infection. The expression of selected DEGs was verified using qRT-PCR. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Co-expression network analysis were applied to predict these DEGs' underlying biological processes, pathways, and interactions respectively. Results A total of 413 DEGs were identified in larval E. granulosus infected B cells, including 303 up- and 110 down-regulated genes. Notably, most DEGs related to inflammation and chemotaxis were significantly upregulated after infection. In line with these changes, significant expression upregulation of DEGs associated with fatty acid oxidation, lipid synthesis, lipolysis, lipid transport, and cholesterol biosynthesis, were observed in infected B cells. Co-expression network analysis showed an intimate interaction between these DEGs associated with immune and metabolism. Conclusions The present study revealed that the larval E. granulosus infection induces metabolic reprogramming of B cells, which provides a novel clue to clarify the immunoregulatory mechanism of B cells in parasitic infection.
Collapse
Affiliation(s)
- Shiping Xu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- The First Clinical Medical College, Xuzhou Medical University, Xuzhou, China
- National Experimental Teaching Demonstration Center of Basic Medicine (Xuzhou Medical University), Xuzhou, China
| | - Yuxin Guo
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- The First Clinical Medical College, Xuzhou Medical University, Xuzhou, China
- National Experimental Teaching Demonstration Center of Basic Medicine (Xuzhou Medical University), Xuzhou, China
| | - Tiancheng Luo
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- The First Clinical Medical College, Xuzhou Medical University, Xuzhou, China
- National Experimental Teaching Demonstration Center of Basic Medicine (Xuzhou Medical University), Xuzhou, China
| | - Pengfei Jiang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- National Experimental Teaching Demonstration Center of Basic Medicine (Xuzhou Medical University), Xuzhou, China
| | - Ziyi Yan
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- The First Clinical Medical College, Xuzhou Medical University, Xuzhou, China
- National Experimental Teaching Demonstration Center of Basic Medicine (Xuzhou Medical University), Xuzhou, China
| | - Yan He
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- The First Clinical Medical College, Xuzhou Medical University, Xuzhou, China
- National Experimental Teaching Demonstration Center of Basic Medicine (Xuzhou Medical University), Xuzhou, China
| | - Linlin Fu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Hua Liu
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), Shanghai, China
- National Health Commission Key Laboratory of Parasite and Vector Biology, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
- National Center for International Research on Tropical Diseases, Shanghai, China
| | - Zixuan Gao
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | - Dingmin Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- The First Clinical Medical College, Xuzhou Medical University, Xuzhou, China
- National Experimental Teaching Demonstration Center of Basic Medicine (Xuzhou Medical University), Xuzhou, China
| | - Zhengxiu Sun
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- The First Clinical Medical College, Xuzhou Medical University, Xuzhou, China
- National Experimental Teaching Demonstration Center of Basic Medicine (Xuzhou Medical University), Xuzhou, China
| | - Xiaoying Yang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Wei Pan
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Fenfen Sun
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- National Experimental Teaching Demonstration Center of Basic Medicine (Xuzhou Medical University), Xuzhou, China
| |
Collapse
|
|
27
|
Karagiota A, Chachami G, Paraskeva E. Lipid Metabolism in Cancer: The Role of Acylglycerolphosphate Acyltransferases (AGPATs). Cancers (Basel) 2022; 14:cancers14010228. [PMID: 35008394 PMCID: PMC8750616 DOI: 10.3390/cancers14010228] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 12/28/2021] [Accepted: 12/31/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Rapidly proliferating cancer cells reprogram lipid metabolism to keep the balance between fatty acid uptake, synthesis, consumption, and storage as triacylglycerides (TAG). Acylglycerolphosphate acyltransferases (AGPATs)/lysophosphatidic acid acyltransferases (LPAATs) are a family of enzymes that catalyze the synthesis of phosphatidic acid (PA), an intermediate in TAG synthesis, a signaling molecule, and a precursor of phospholipids. Importantly, the expression of AGPATs has been linked to diverse physiological and pathological phenotypes, including cancer. In this review, we present an overview of lipid metabolism reprogramming in cancer cells and give insight into the expression of AGPAT isoforms as well as their association with cancers, parameters of tumor biology, patient classification, and prognosis. Abstract Altered lipid metabolism is an emerging hallmark of aggressive tumors, as rapidly proliferating cancer cells reprogram fatty acid (FA) uptake, synthesis, storage, and usage to meet their increased energy demands. Central to these adaptive changes, is the conversion of excess FA to neutral triacylglycerides (TAG) and their storage in lipid droplets (LDs). Acylglycerolphosphate acyltransferases (AGPATs), also known as lysophosphatidic acid acyltransferases (LPAATs), are a family of five enzymes that catalyze the conversion of lysophosphatidic acid (LPA) to phosphatidic acid (PA), the second step of the TAG biosynthesis pathway. PA, apart from its role as an intermediate in TAG synthesis, is also a precursor of glycerophospholipids and a cell signaling molecule. Although the different AGPAT isoforms catalyze the same reaction, they appear to have unique non-overlapping roles possibly determined by their distinct tissue expression and substrate specificity. This is best exemplified by the role of AGPAT2 in the development of type 1 congenital generalized lipodystrophy (CGL) and is also manifested by recent studies highlighting the involvement of AGPATs in the physiology and pathology of various tissues and organs. Importantly, AGPAT isoform expression has been shown to enhance proliferation and chemoresistance of cancer cells and correlates with increased risk of tumor development or aggressive phenotypes of several types of tumors.
Collapse
Affiliation(s)
- Angeliki Karagiota
- Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, BIOPOLIS, 41500 Larissa, Greece; (A.K.); (G.C.)
- Laboratory of Physiology, Faculty of Medicine, University of Thessaly, BIOPOLIS, 41500 Larissa, Greece
| | - Georgia Chachami
- Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, BIOPOLIS, 41500 Larissa, Greece; (A.K.); (G.C.)
| | - Efrosyni Paraskeva
- Laboratory of Physiology, Faculty of Medicine, University of Thessaly, BIOPOLIS, 41500 Larissa, Greece
- Correspondence:
| |
Collapse
|
|
28
|
Yang J, Wei H, Zhou Y, Szeto CH, Li C, Lin Y, Coker OO, Lau HCH, Chan AWH, Sung JJY, Yu J. High-Fat Diet Promotes Colorectal Tumorigenesis Through Modulating Gut Microbiota and Metabolites. Gastroenterology 2022; 162:135-149.e2. [PMID: 34461052 DOI: 10.1053/j.gastro.2021.08.041] [Citation(s) in RCA: 272] [Impact Index Per Article: 90.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 08/05/2021] [Accepted: 08/21/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Dietary fat intake is associated with increased risk of colorectal cancer (CRC). We examined the role of high-fat diet (HFD) in driving CRC through modulating gut microbiota and metabolites. METHODS HFD or control diet was fed to mice littermates in CRC mouse models of an azoxymethane (AOM) model and Apcmin/+ model, with or without antibiotics cocktail treatment. Germ-free mice for fecal microbiota transplantation were used for validation. Gut microbiota and metabolites were detected using metagenomic sequencing and high-performance liquid chromatography-mass spectrometry, respectively. Gut barrier function was determined using lipopolysaccharides level and transmission electron microscopy. RESULTS HFD promoted colorectal tumorigenesis in both AOM-treated mice and Apcmin/+ mice compared with control diet-fed mice. Gut microbiota depletion using antibiotics attenuated colon tumor formation in HFD-fed mice. A significant shift of gut microbiota composition with increased pathogenic bacteria Alistipessp.Marseille-P5997 and Alistipessp.5CPEGH6, and depleted probiotic Parabacteroides distasonis, along with impaired gut barrier function was exhibited in HFD-fed mice. Moreover, HFD-modulated gut microbiota promotes colorectal tumorigenesis in AOM-treated germ-free mice, indicating gut microbiota was essential in HFD-associated colorectal tumorigenesis. Gut metabolites alteration, including elevated lysophosphatidic acid, which was confirmed to promote CRC cell proliferation and impair cell junction, was also observed in HFD-fed mice. Moreover, transfer of stools from HFD-fed mice to germ-free mice without interference increased colonic cell proliferation, impaired gut barrier function, and induced oncogenic genes expression. CONCLUSIONS HFD drives colorectal tumorigenesis through inducing gut microbial dysbiosis, metabolomic dysregulation with elevated lysophosphatidic acid, and gut barrier dysfunction in mice.
Collapse
Affiliation(s)
- Jia Yang
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Hong Wei
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China; Department of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yunfei Zhou
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Chun-Ho Szeto
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Chuangen Li
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Yufeng Lin
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Olabisi O Coker
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Harry Cheuk Hay Lau
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Anthony W H Chan
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China
| | - Joseph J Y Sung
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
| |
Collapse
|
|
29
|
Lu L, Liu YJ, Cheng PQ, Hu D, Xu HC, Ji G. Macrophages play a role in inflammatory transformation of colorectal cancer. World J Gastrointest Oncol 2021; 13:2013-2028. [PMID: 35070038 PMCID: PMC8713318 DOI: 10.4251/wjgo.v13.i12.2013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/21/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide, and it is also a typical inflammatory cancer. The function of macrophages is very important in the tissue immune microenvironment during inflammatory and carcinogenic transformation. Here, we evaluated the function and mechanism of macrophages in intestinal physiology and in different pathological stages. Furthermore, the role of macrophages in the immune microenvironment of CRC and the influence of the intestinal population and hypoxic environment on macrophage function are summarized. In addition, in the era of tumor immunotherapy, CRC currently has a limited response rate to immune checkpoint inhibitors, and we summarize potential therapeutic strategies for targeting tumor-associated macrophages.
Collapse
Affiliation(s)
- Lu Lu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yu-Jing Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Pei-Qiu Cheng
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Dan Hu
- Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai 200120, China
| | - Han-Chen Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai 200120, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| |
Collapse
|
|
30
|
Construction and validation of a metabolic gene-associated prognostic model for cervical carcinoma and the role on tumor microenvironment and immunity. Aging (Albany NY) 2021; 13:25072-25088. [PMID: 34852326 PMCID: PMC8714137 DOI: 10.18632/aging.203723] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 10/25/2021] [Indexed: 12/14/2022]
Abstract
Metabolic reprogramming is a common feature of tumor cells and is associated with tumorigenesis and progression. In this study, a metabolic gene-associated prognostic model (MGPM) was constructed using multiple bioinformatics analysis methods in cervical carcinoma (CC) tissues from The Cancer Genome Atlas (TCGA) database, which comprised fifteen differentially expressed metabolic genes (DEMGs). Patients were divided into a high-risk group with shorter overall survival (OS) and a low-risk group with better survival. Receiver operating characteristic (ROC) curve analysis showed that the MGPM precisely predicted the 1-, 3- and 5-year survival of CC patients. As expected, MGPM exhibited a favorable prognostic significance in the training and testing datasets of TCGA. And the clinicopathological parameters including stage, tumor (T) and metastasis (M) classifications had significant differences in low- and high-risk groups, which further demonstrated the MGPM had a favorite prognostic prediction ability. Additionally, patients with low-ESTMATEScore had a shorter OS and when those combined with high-risk scores presented a worse prognosis. Through “CIBERSORT” package and Wilcoxon rank-sum test, patients in the high-risk group with a poor prognosis showed lower levels of infiltration of T cell CD8 (P < 0.001), T cells memory activated (P = 0.010) and mast cells resting (P < 0.001), and higher levels of mast cells activated (P < 0.001), and we also found these patients had a worse response for immunosuppressive therapy. These findings demonstrate that MGPM accurately predicts survival outcomes in CC patients, which will be helpful for further optimizing immunotherapies for cancer by reprogramming its cell metabolism.
Collapse
|
|
31
|
Qiu L, Yang X, Wu J, Huang C, Miao Y, Fu Z. HIST2H2BF Potentiates the Propagation of Cancer Stem Cells via Notch Signaling to Promote Malignancy and Liver Metastasis in Colorectal Carcinoma. Front Oncol 2021; 11:677646. [PMID: 34476209 PMCID: PMC8406628 DOI: 10.3389/fonc.2021.677646] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 06/18/2021] [Indexed: 11/17/2022] Open
Abstract
Background Growing evidence demonstrates that the initiation and progression of colorectal carcinoma (CRC) is related to the presence of cancer stem cells (CSCs). However, the mechanism through which the stem cell features of CRC cells are maintained is poorly understood. In this study, we identified the oncogenic histone cluster 2 H2B family member F (HIST2H2BF) and aimed to investigate the function of upregulated HIST2H2BF expression in maintaining the stem cell features of CRC cells, which accelerate the progression of CRC. Methods HIST2H2BF expression was quantified using real-time polymerase chain reaction, immunohistochemistry, and western blotting. The correlation between CpG island methylation status and HIST2H2BF re-expression was assessed through bisulfite sequencing polymerase chain reaction, methylation-specific polymerase chain reaction, and 5-Aza-dC treatment. Functional assays were performed on CRC cells and mice to investigate the HIST2H2BF-induced stem cell-like and cancer properties of CRC. Using the Notch pathway inhibitor FLI-06, the regulatory effect of HIST2H2BF on downstream Notch signaling was confirmed. Results HIST2H2BF was highly expressed in CRC tissues and cell lines. The reactivation of HIST2H2BF in CRC stems at least in part from the hypomethylated CpG islands. CRC patients with high HIST2H2BF expression have poor survival outcomes. Functional studies have shown that HIST2H2BF promotes CSC phenotype, malignancy, and liver metastasis through the activation of Notch signaling in CRC. Blockage of the Notch pathway reduced the stem cell-like and cancer properties. Conclusion Our study suggests that HIST2H2BF upregulation enhances the CSC phenotype, malignancy, and liver metastasis through the activation of Notch signaling in CRC. These results identified a new perspective on the mechanism by which the stem cell features of CRC cells are maintained and highlighted the potential novel therapeutic targets for CRC.
Collapse
Affiliation(s)
- Lei Qiu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of General Surgery, The Second People's Hospital of Lianyungang, Lianyungang Tumor Hospital, Lianyungang Hospital Affiliated to Bengbu Medical University, Lianyungang, China
| | - Xiuwei Yang
- Department of General Surgery, The Second People's Hospital of Lianyungang, Lianyungang Tumor Hospital, Lianyungang Hospital Affiliated to Bengbu Medical University, Lianyungang, China
| | - Jingyu Wu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Changzhi Huang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yongchang Miao
- Department of General Surgery, The Second People's Hospital of Lianyungang, Lianyungang Tumor Hospital, Lianyungang Hospital Affiliated to Bengbu Medical University, Lianyungang, China
| | - Zan Fu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
32
|
Lysophosphatidic Acid Signaling in Cancer Cells: What Makes LPA So Special? Cells 2021; 10:cells10082059. [PMID: 34440828 PMCID: PMC8394178 DOI: 10.3390/cells10082059] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/06/2021] [Accepted: 08/07/2021] [Indexed: 12/13/2022] Open
Abstract
Lysophosphatidic acid (LPA) refers to a family of simple phospholipids that act as ligands for G protein-coupled receptors. While LPA exerts effects throughout the body in normal physiological circumstances, its pathological role in cancer is of great interest from a therapeutic viewpoint. The numerous LPA receptors (LPARs) are coupled to a variety of G proteins, and more than one LPAR is typically expressed on any given cell. While the individual receptors signal through conventional GPCR pathways, LPA is particularly efficacious in stimulating cancer cell proliferation and migration. This review addresses the mechanistic aspects underlying these pro-tumorigenic effects. We provide examples of LPA signaling responses in various types of cancers, with an emphasis on those where roles have been identified for specific LPARs. While providing an overview of LPAR signaling, these examples also reveal gaps in our knowledge regarding the mechanisms of LPA action at the receptor level. The current understanding of the LPAR structure and the roles of LPAR interactions with other receptors are discussed. Overall, LPARs provide insight into the potential molecular mechanisms that underlie the ability of individual GPCRs (or combinations of GPCRs) to elicit a unique spectrum of responses from their agonist ligands. Further knowledge of these mechanisms will inform drug discovery, since GPCRs are promising therapeutic targets for cancer.
Collapse
|
|
33
|
Wang Y, Miao Z, Qin X, Li B, Han Y. NOD2 deficiency confers a pro-tumorigenic macrophage phenotype to promote lung adenocarcinoma progression. J Cell Mol Med 2021; 25:7545-7558. [PMID: 34268854 PMCID: PMC8335701 DOI: 10.1111/jcmm.16790] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 06/23/2021] [Accepted: 07/02/2021] [Indexed: 12/14/2022] Open
Abstract
Nucleotide‐binding and oligomerization domain‐containing protein 2 (NOD2) was a member of the NOD‐like receptor family and played an important role in the innate immune response. Dysregulated NOD2 had been reported to contribute to tumorigenesis and progression. Here, we investigated that decreased NOD2 expressions could affect the phenotypic polarization of tumour‐associated macrophages and thus lead to the poor prognosis of lung adenocarcinoma patients. We clustered the patients by the single‐sample gene set enrichment analysis of tumour microenvironment and 13 prognostic differentially expressed immune‐related genes (PDEIRGs) were obtained based on prognostic analyses. After multiple assessments on the 13 PDEIRGs, NOD2 was considered to be the central immune gene and had a strong effect on suppressing tumour progression. Decreased NOD2 expression could be induced by cancer cells and lead to the phenotypic polarization of macrophages from protective M1 phenotype to pro‐tumorigenic M2 subtype which might be attributed to the down‐regulating of NF‐κB signalling pathway. This study draw attention to the role of inhibited innate immune function mediated by depletion of NOD2 in the TME. Our work also points to a potential strategy of NOD2‐mediated TAM‐targeted immunotherapy.
Collapse
Affiliation(s)
- Yibei Wang
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, China.,Department of Developmental Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
| | - Ziwei Miao
- Department of Developmental Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
| | - Xiaoxue Qin
- Department of Developmental Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
| | - Bo Li
- Department of Developmental Cell Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
| | - Yun Han
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| |
Collapse
|
|
34
|
Yang SB, Lee MH, Kim BR, Choi YM, Kim BJ. A Hepatitis B Virus-Derived Peptide Exerts an Anticancer Effect via TNF/iNOS-producing Dendritic Cells in Tumor-Bearing Mouse Model. Cancers (Basel) 2021; 13:407. [PMID: 33499256 PMCID: PMC7865762 DOI: 10.3390/cancers13030407] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/12/2021] [Accepted: 01/18/2021] [Indexed: 02/07/2023] Open
Abstract
Recently, we reported a 6-mer hepatitis B virus (HBV)-derived peptide, Poly6, that exerts antiviral effects against human immunodeficiency virus type 1 (HIV-1). Here, we explored the immunotherapeutic potential of Poly6 via its administration into dendritic cells (DCs) in a mouse model. Our data revealed that Poly6 treatment led to enhanced production of tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS)-producing DCs (Tip-DCs) in a type 1 interferon (IFN-I)-dependent manner via the induction of mitochondrial stress. Poly6 treatment in mice implanted with MC38 cells, a murine colon adenocarcinoma line, led to attenuated tumor formation, primarily due to direct cell death induced by Tip-DC mediated nitric oxide (NO) production and indirect killing by Tip-DC mediated cluster of differentiation 8 (CD8) cytotoxic T lymphocyte (CTL) activation via CD40 activation. Moreover, Poly6 treatment demonstrated an enhanced anticancer effect with one of the checkpoint inhibitors, the anti PD-L1 antibody. In conclusion, our data reveal that Poly6 treatment elicits an antitumor immune response in mice, possibly through NO-mediated oncolytic activity via Tip-DC activation and Tip-DC mediated CTL activation. This suggests that Poly6 represents a potential adjuvant for cancer immunotherapy by enhancing the anticancer effects of immune checkpoint inhibitors.
Collapse
Affiliation(s)
- Soo-Bin Yang
- Department of Biomedical Sciences, Microbiology and Immunology and Liver Research Institute, College of Medicine, Seoul National University, Seoul 03080, Korea; (S.-B.Y.); (M.-H.L.); (Y.-M.C.)
| | - Mi-Hyun Lee
- Department of Biomedical Sciences, Microbiology and Immunology and Liver Research Institute, College of Medicine, Seoul National University, Seoul 03080, Korea; (S.-B.Y.); (M.-H.L.); (Y.-M.C.)
| | - Bo-Ram Kim
- R&D Institute, Cellivery Therapeutics, Inc., K-BIZ DMC Tower, F9, 189 Sungam-Ro, Mapo-Gu, Seoul 03929, Korea;
| | - Yu-Min Choi
- Department of Biomedical Sciences, Microbiology and Immunology and Liver Research Institute, College of Medicine, Seoul National University, Seoul 03080, Korea; (S.-B.Y.); (M.-H.L.); (Y.-M.C.)
| | - Bum-Joon Kim
- Department of Biomedical Sciences, Microbiology and Immunology and Liver Research Institute, College of Medicine, Seoul National University, Seoul 03080, Korea; (S.-B.Y.); (M.-H.L.); (Y.-M.C.)
| |
Collapse
|
|
35
|
Nagarajan SR, Butler LM, Hoy AJ. The diversity and breadth of cancer cell fatty acid metabolism. Cancer Metab 2021; 9:2. [PMID: 33413672 PMCID: PMC7791669 DOI: 10.1186/s40170-020-00237-2] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 12/16/2020] [Indexed: 12/13/2022] Open
Abstract
Tumor cellular metabolism exhibits distinguishing features that collectively enhance biomass synthesis while maintaining redox balance and cellular homeostasis. These attributes reflect the complex interactions between cell-intrinsic factors such as genomic-transcriptomic regulation and cell-extrinsic influences, including growth factor and nutrient availability. Alongside glucose and amino acid metabolism, fatty acid metabolism supports tumorigenesis and disease progression through a range of processes including membrane biosynthesis, energy storage and production, and generation of signaling intermediates. Here, we highlight the complexity of cellular fatty acid metabolism in cancer, the various inputs and outputs of the intracellular free fatty acid pool, and the numerous ways that these pathways influence disease behavior.
Collapse
Affiliation(s)
- Shilpa R Nagarajan
- Discipline of Physiology, School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.,Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | - Lisa M Butler
- Adelaide Medical School and Freemasons Foundation Centre for Men's Health, University of Adelaide, Adelaide, SA, Australia.,South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Andrew J Hoy
- Discipline of Physiology, School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
| |
Collapse
|
|
36
|
Xiang Y, Miao H. Lipid Metabolism in Tumor-Associated Macrophages. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1316:87-101. [PMID: 33740245 DOI: 10.1007/978-981-33-6785-2_6] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Macrophages are essential components of the immune system in tumors. It can be recruited and educated to two mainly polarized subpopulations (M1-like and M2-like) of tumor-associated macrophages (TAMs) to display anti-tumor or protumor function during the tumor occurrence and progression. Reprogramming of metabolism, especially lipid metabolism, is a typical characteristic of TAMs polarization, which was confirmed recently as a vital target for tumor therapy. However, the relationship between TAMs and lipid metabolism is still obscure in the past decade. In this review, we will first introduce the historical aspects of TAMs, and then discuss the correlation of main lipids (triglycerides, cholesterol, and phospholipids) to TAMs activation and summarize the mechanisms by which lipid metabolism mediated tumor escape the immunological surveillance as well as currently available drugs targeting these mechanisms. We hope that this chapter will give a better understanding of lipid metabolism in TAMs for those who are interested in this field, and lay a foundation to develop novel strategies for tumor therapy by targeting lipid metabolism.
Collapse
Affiliation(s)
- Yuancai Xiang
- Department of Biochemistry and Molecular Biology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China
| | - Hongming Miao
- Department of Biochemistry and Molecular Biology, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
| |
Collapse
|
|
37
|
Ma K, Zhang L. Overview: Lipid Metabolism in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1316:41-47. [PMID: 33740242 DOI: 10.1007/978-981-33-6785-2_3] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The tumor microenvironment represents the dynamic network consisting of tumor cells, stromal cells, and multiple lineages of immune subsets. It is well recognized that metabolic crosstalk within the tumor microenvironment (TME) greatly shapes both the composition and functionality of the infiltrated immune cells and therefore critically regulate the antitumor immunity. In general, most solid tumors are considered as lipid-enriched environment, which is beneficial for tumor cell growth and immune escape. Here we briefly summarize the effects of accumulated lipids on tumor cells and immune cells. We also discuss the possibility of targeting lipid metabolism within the TME and potential strategies for optimizing cancer treatment.
Collapse
Affiliation(s)
- Kaili Ma
- Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China.,Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lianjun Zhang
- Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China. .,Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| |
Collapse
|
|
38
|
赵 昆, 时 荣, 缪 洪. [A Review of the Lipid Metabolism Reprogramming in Tumor Associated Macrophages]. SICHUAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF SICHUAN UNIVERSITY. MEDICAL SCIENCE EDITION 2021; 52:45-49. [PMID: 33474888 PMCID: PMC10408937 DOI: 10.12182/20210160202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Indexed: 11/23/2022]
Abstract
Tumor associated macrophages (TAMs) are one of the most common types of stromal cells in solid tumors. They are closely related to the immunosuppressive status of tumor microenvironment and potentiate the malignant progress of tumors. Studies have shown that metabolism in tumor associated macrophages has been reprogrammed and involved in the regulation of their own polarization and corresponding functions and phenotypes. Metabolic reprogramming refers to the alteration of key enzymes activity, substrate and its associated metabolites' concentration in a certain metabolic pathway, which accounts for the disorder of original metabolic states. In this paper, we mainly concentrated on the lipid metabolic reprogramming of TAMs, including triglycerides, fatty acids and their derivatives, cholesterol, phospholipids, and their regulations on tumor progression. However, the metabolism of tumor and tumor microenvironment cells is highly heterogeneous. It is worthy of further exploration on the similarities and differences of lipid metabolism reprogramming between stromal cells and tumor cells, and the mechanism of how reprogramming modulates cell activity. It will be a new strategy for immunotherapy of tumor with metabolic intervention to accurately target the lipid metabolism reprogramming of TAMs, so as to promote the polarization of TAMs to M1 like macrophages, when synthetically considering the diverse types of tumors and different stages of development.
Collapse
Affiliation(s)
- 昆 赵
- 中国人民解放军陆军军医大学（第三军医大学）基础医学院 生物化学与分子生物学教研室 （重庆 400038）Department of Biochemistry and Molecular Biology, School of Basic Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - 荣臣 时
- 中国人民解放军陆军军医大学（第三军医大学）基础医学院 生物化学与分子生物学教研室 （重庆 400038）Department of Biochemistry and Molecular Biology, School of Basic Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - 洪明 缪
- 中国人民解放军陆军军医大学（第三军医大学）基础医学院 生物化学与分子生物学教研室 （重庆 400038）Department of Biochemistry and Molecular Biology, School of Basic Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China
| |
Collapse
|
|
39
|
Dietary fats suppress the peritoneal seeding of colorectal cancer cells through the TLR4/Cxcl10 axis in adipose tissue macrophages. Signal Transduct Target Ther 2020; 5:239. [PMID: 33060562 PMCID: PMC7566605 DOI: 10.1038/s41392-020-00327-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/31/2020] [Accepted: 09/14/2020] [Indexed: 12/27/2022] Open
Abstract
Peritoneal carcinomatosis (PC) of colorectal cancer (CRC) is a terminal phase of malignancy with no effective strategies for the prevention of this condition. Here we established PC models in mice by intraperitoneal engraftment of CRC cells and revealed an unexpected role for a high-fat diet (HFD) in preventing metastatic seeding in the visceral fat. Mechanistically, the HFD stimulated the activation of adipose tissue macrophages (ATMs) toward an M1-like phenotype and enhanced ATM tumor phagocytosis in a TLR4-dependent manner. Furthermore, the TLR4–Cxcl10 axis in ATMs promoted T cell recruitment, and M1-like macrophages stimulated T cell activation in tumor-seeded fats. The inhibitory effect of the HFD on tumor seeding was abolished with the ablation of macrophages, inactivation of T cells, or blockade of the TLR4–Cxcl10 axis in macrophages. Finally, we showed that a HFD and conventional chemotherapeutic agents (oxaliplatin or 5-fluorouracil) synergistically improved the survival of tumor-seeded mice. Collectively, our findings demonstrate that peritoneal seeding of CRC can be suppressed by short-term treatment with a HFD in the early phase, providing a novel concept for the management of these patients in the clinic.
Collapse
|
|
40
|
Zhou K, Cheng T, Zhan J, Peng X, Zhang Y, Wen J, Chen X, Ying M. Targeting tumor-associated macrophages in the tumor microenvironment. Oncol Lett 2020; 20:234. [PMID: 32968456 PMCID: PMC7500051 DOI: 10.3892/ol.2020.12097] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 06/23/2020] [Indexed: 12/13/2022] Open
Abstract
Tumor-associated macrophages (TAMs) are the most abundant population type of tumor-infiltrating immune cells found in the tumor microenvironment (TME), and are evolutionarily associated with microvessel density in tumor tissues. TAMs can be broadly divided into M1-like and M2-like TAMs, which demonstrate antitumor and pro-tumor activity in the TME, respectively. Studies have indicated that: i) The predominate presence of M2-like TAMs in the TME can result in tumor immunosuppression and chemoresistance; ii) the ratio of M1-like to M2-like TAMs in the TME is positively correlated with better long-term prognosis of patients with cancer; iii) epigenetic silencing, preventing the secretion of M1-like TAM-associated molecules, is an important immune evasion mechanism during tumor progression; and iv) the transformation from M2-like to M1-like TAMs following exposure to specific conditions can result in tumor regression. The present study discusses the molecular events underlying the recruitment of macrophages and their polarization into M1-like or M2-like TAMs, and their differential roles in angiogenesis, angiostasis, invasion, metastasis and immune activity in the TME. This insight may inform the improved design of TAM-targeted cancer immunotherapy. Some of these therapeutic strategies show promising effects; however, challenges remain.
Collapse
Affiliation(s)
- Kaiwen Zhou
- Department of Molecular Biology and Biochemistry, Basic Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.,The First Clinical Medical College, School of Medicine, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Tan Cheng
- Queen Mary School of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jinyue Zhan
- School of Public Health, School of Medicine, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xuan Peng
- The Fourth Clinical Medical College, School of Medicine, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yue Zhang
- The Fourth Clinical Medical College, School of Medicine, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jianpei Wen
- The Fourth Clinical Medical College, School of Medicine, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xiaoman Chen
- Department of Molecular Biology and Biochemistry, Basic Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Muying Ying
- Department of Molecular Biology and Biochemistry, Basic Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| |
Collapse
|
|
41
|
Horvath L, Thienpont B, Zhao L, Wolf D, Pircher A. Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook. Mol Cancer 2020; 19:141. [PMID: 32917214 PMCID: PMC7488475 DOI: 10.1186/s12943-020-01260-z] [Citation(s) in RCA: 179] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 09/04/2020] [Indexed: 12/16/2022] Open
Abstract
Immunotherapy (IO) has revolutionized the therapy landscape of non-small cell lung cancer (NSCLC), significantly prolonging the overall survival (OS) of advanced stage patients. Over the recent years IO therapy has been broadly integrated into the first-line setting of non-oncogene driven NSCLC, either in combination with chemotherapy, or in selected patients with PD-L1high expression as monotherapy. Still, a significant proportion of patients suffer from disease progression. A better understanding of resistance mechanisms depicts a central goal to avoid or overcome IO resistance and to improve patient outcome.We here review major cellular and molecular pathways within the tumor microenvironment (TME) that may impact the evolution of IO resistance. We summarize upcoming treatment options after IO resistance including novel IO targets (e.g. RIG-I, STING) as well as interesting combinational approaches such as IO combined with anti-angiogenic agents or metabolic targets (e.g. IDO-1, adenosine signaling, arginase). By discussing the fundamental mode of action of IO within the TME, we aim to understand and manage IO resistance and to seed new ideas for effective therapeutic IO concepts.
Collapse
MESH Headings
- Arginase/genetics
- B7-H1 Antigen/antagonists & inhibitors
- B7-H1 Antigen/genetics
- B7-H1 Antigen/immunology
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/immunology
- Carcinoma, Non-Small-Cell Lung/therapy
- DEAD Box Protein 58/antagonists & inhibitors
- DEAD Box Protein 58/genetics
- DEAD Box Protein 58/immunology
- Drug Resistance, Neoplasm/genetics
- Drug Resistance, Neoplasm/immunology
- Humans
- Immunotherapy/adverse effects
- Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics
- Membrane Proteins/antagonists & inhibitors
- Membrane Proteins/genetics
- Membrane Proteins/immunology
- Receptors, Immunologic/antagonists & inhibitors
- Receptors, Immunologic/genetics
- Receptors, Immunologic/immunology
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/immunology
Collapse
Affiliation(s)
- Lena Horvath
- Internal Medicine V, Department of Hematology and Oncology, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - Bernard Thienpont
- Laboratory for Functional Epigenetics, Department of Human Genetics, KU Leuven, Herestraat 49, 3000, Leuven, Belgium
| | - Liyun Zhao
- Laboratory for Functional Epigenetics, Department of Human Genetics, KU Leuven, Herestraat 49, 3000, Leuven, Belgium
| | - Dominik Wolf
- Internal Medicine V, Department of Hematology and Oncology, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
- Medical Clinic III, Department of Oncology, Hematology, Immunoncology and Rheumatology, University Hospital Bonn (UKB), Sigmund-Freud-Street 25, 53127, Bonn, Germany
| | - Andreas Pircher
- Internal Medicine V, Department of Hematology and Oncology, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.
| |
Collapse
|
|
42
|
Regulation of Tumor Immunity by Lysophosphatidic Acid. Cancers (Basel) 2020; 12:cancers12051202. [PMID: 32397679 PMCID: PMC7281403 DOI: 10.3390/cancers12051202] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/08/2020] [Accepted: 05/09/2020] [Indexed: 12/16/2022] Open
Abstract
The tumor microenvironment (TME) may be best conceptualized as an ecosystem comprised of cancer cells interacting with a multitude of stromal components such as the extracellular matrix (ECM), blood and lymphatic networks, fibroblasts, adipocytes, and cells of the immune system. At the center of this crosstalk between cancer cells and their TME is the bioactive lipid lysophosphatidic acid (LPA). High levels of LPA and the enzyme generating it, termed autotaxin (ATX), are present in many cancers. It is also well documented that LPA drives tumor progression by promoting angiogenesis, proliferation, survival, invasion and metastasis. One of the hallmarks of cancer is the ability to modulate and escape immune detection and eradication. Despite the profound role of LPA in regulating immune functions and inflammation, its role in the context of tumor immunity has not received much attention until recently where emerging studies highlight that this signaling axis may be a means that cancer cells adopt to evade immune detection and eradication. The present review aims to look at the immunomodulatory actions of LPA in baseline immunity to provide a broad understanding of the subject with a special emphasis on LPA and cancer immunity, highlighting the latest progress in this area of research.
Collapse
|