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Pan Z, Liu Y, Li H, Qiu H, Zhang P, Li Z, Wang X, Tian Y, Feng Z, Zhu S, Wang X. The role and mechanism of aerobic glycolysis in nasopharyngeal carcinoma. PeerJ 2025; 13:e19213. [PMID: 40191756 PMCID: PMC11971989 DOI: 10.7717/peerj.19213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 03/05/2025] [Indexed: 04/09/2025] Open
Abstract
This review delves into the pivotal role and intricate mechanisms of aerobic glycolysis in nasopharyngeal carcinoma (NPC). NPC, a malignancy originating from the nasopharyngeal epithelium, displays distinct geographical and clinical features. The article emphasizes the significance of aerobic glycolysis, a pivotal metabolic alteration in cancer cells, in NPC progression. Key enzymes such as hexokinase 2, lactate dehydrogenase A, phosphofructokinase 1, and pyruvate kinase M2 are discussed for their regulatory functions in NPC glycolysis through signaling pathways like PI3K/Akt and mTOR. Further, the article explores how oncogenic signaling pathways and transcription factors like c-Myc and HIF-1α modulate aerobic glycolysis, thereby affecting NPC's proliferation, invasion, metastasis, angiogenesis, and immune evasion. By elucidating these mechanisms, the review aims to advance research and clinical practice in NPC, informing the development of targeted therapeutic strategies that enhance treatment precision and reduce side effects. Overall, this review offers a broad understanding of the multifaceted role of aerobic glycolysis in NPC and its potential impact on therapeutic outcomes.
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Affiliation(s)
- Zhiyong Pan
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Yuyi Liu
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Hui Li
- Department of Ophthalmology, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Huisi Qiu
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Pingmei Zhang
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Zhiying Li
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Xinyu Wang
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Yuxiao Tian
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Zhengfu Feng
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Song Zhu
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Xin Wang
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
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2
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Kondo A, Nakamura A. Overcoming cross-reactivity of antibodies against human lactate dehydrogenase. J Immunol Methods 2025; 538:113821. [PMID: 39900137 DOI: 10.1016/j.jim.2025.113821] [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: 08/08/2024] [Revised: 11/19/2024] [Accepted: 01/21/2025] [Indexed: 02/05/2025]
Abstract
Lactate dehydrogenase subunit A (LD-A) plays an important role in cancer regulation and therapy. We attempted to develop an enzyme-linked immune-solvent assay (ELISA) for LD-A in human serum. However, commercial antibodies against LD-A exhibited cross-reactivity with an unknown protein. The unknown protein was purified and characterized by protein sequencing and Western blotting. In addition, we attempted to prepare a specific antibody for the ELISA using partially synthesized peptides of LD-A as immunogens. The epitope position in LD-A was carefully selected based on bioinformatics analysis. Peptide sequencer elucidated a ten amino acid sequence of the purified protein at the N-terminal. A BLAST search revealed that this sequence perfectly matched that at the N-terminus of the IgG heavy chain (H-chain). Furthermore, we demonstrated that twelve commercially available antibodies targeting LD-A or LD-B (subunit B) primarily cross-reacted with IgG or its H-chain, with only one specific antibody for each subunit. As the specific antibody against LD-A is no longer commercially accessible, we successfully produced two kinds of specific antibodies using partially synthesized LD-A peptides as immunogens. In conclusion, we have successfully produced specific antibodies against LD-A. Moreover, our findings underscore the utility of bioinformatics tools for determining the optimal positions of immunizing peptides.
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Affiliation(s)
- Akira Kondo
- Department of Clinical Laboratory Science, Tenri University, Nara, Japan.
| | - Ayumu Nakamura
- Department of Clinical Laboratory Science, Tenri University, Nara, Japan
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3
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Nor WMFSBWM, Kwong SC, Fuzi AAM, Said NABM, Jamil AHA, Lee YY, Lee SC, Lim YAL, Chung I. Linking microRNA to metabolic reprogramming and gut microbiota in the pathogenesis of colorectal cancer (Review). Int J Mol Med 2025; 55:46. [PMID: 39820715 PMCID: PMC11759585 DOI: 10.3892/ijmm.2025.5487] [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: 06/11/2024] [Accepted: 12/03/2024] [Indexed: 01/19/2025] Open
Abstract
Colorectal cancer (CRC), an emerging public health concern, is one of the leading causes of cancer morbidity and mortality worldwide. An increasing body of evidence shows that dysfunction in metabolic reprogramming is a crucial characteristic of CRC progression. Specifically, metabolic reprogramming abnormalities in glucose, glutamine and lipid metabolism provide the tumour with energy and nutrients to support its rapid cell proliferation and survival. More recently, microRNAs (miRNAs) appear to be involved in the pathogenesis of CRC, including regulatory roles in energy metabolism. In addition, it has been revealed that dysbiosis in CRC might play a key role in impairing the host metabolic reprogramming processes, and while the exact interactions remain unclear, the link may lie with miRNAs. Hence, the aims of the current review include first, to delineate the metabolic reprogramming abnormalities in CRC; second, to explain how miRNAs mediate the aberrant regulations of CRC metabolic pathways; third, linking miRNAs with metabolic abnormalities and dysbiosis in CRC and finally, to discuss the roles of miRNAs as potential biomarkers.
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Affiliation(s)
| | - Soke Chee Kwong
- Centre for Population Health (CePH), Department of Social and Preventive Medicine, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Afiqah Alyaa Md Fuzi
- Office of Deputy Vice Chancellor (Research and Innovation), Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Nur Akmarina Binti Mohd Said
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Amira Hajirah Abd Jamil
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Yeong Yeh Lee
- School of Medical Sciences, Universiti Sains Malaysia, 16150 Kota Bharu, Malaysia
| | - Soo Ching Lee
- Department of Parasitology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Yvonne Ai-Lian Lim
- Department of Parasitology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Ivy Chung
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
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4
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Tini P, Cinelli E, Yavorska M, Donnini F, Marampon F, Pastina P, Rubino G, Chibbaro S, Cerase A, Mazzei MA, Di Giacomo AM, Minniti G. Serum lactate dehydrogenase as a prognostic marker for treatment response in IDH wild-type glioblastoma patients undergoing stupp protocol. J Neurooncol 2025; 171:413-421. [PMID: 39540980 DOI: 10.1007/s11060-024-04862-5] [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: 09/28/2024] [Accepted: 10/19/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND AND AIM Elevated lactate dehydrogenase (LDH), a marker of tumor aggressiveness and metabolic alterations, may predict treatment response and overall survival across various tumors. This study investigates the correlation between serum LDH levels and clinical outcomes in glioblastoma patients treated with radiotherapy (RT) and temozolomide (TMZ). MATERIALS AND METHODS This retrospective study analysed patients with IDH wild-type glioblastoma (IDH-wt GB) treated at the Radiotherapy Department of Azienda Ospedaliero-Universitaria Senese from 2018 to 2023. Clinical data, including hematologic parameters (e.g., LDH), imaging (MRI), and MGMT promoter methylation status, were collected. All patients received RT and TMZ following the Stupp protocol. Serum LDH levels were measured one week before RT, and Radiological Response (RR) was assessed using RANO criteria. Overall survival (OS), progression-free survival (PFS), and RR were primary endpoints. Statistical analyses included Kaplan-Meier, Cox regression, and decision tree analysis for LDH cut-off determination. RESULTS In a cohort of 147 IDH wild-type glioblastoma patients treated with the Stupp protocol, the median OS was 14 months and median PFS was 8 months. Elevated baseline LDH levels were associated with significantly poorer outcomes, showing a median OS of 9 months versus 20 months and a median PFS of 6 months versus 13 months for lower LDH levels (p < 0.001 and p = 0.0001, respectively). LDH levels also correlated with RR (p = 0,001), Multivariate analysis confirmed high LDH as an independent predictor of worse OS (HR = 2.31) and PFS (HR = 2.60), suggesting its utility as a prognostic biomarker. CONCLUSIONS Elevated LDH levels before starting the Stupp protocol are clinically significant as they predict poorer overall survival and progression-free survival in glioblastoma patients and worse RR. Incorporating LDH measurements into treatment planning can help identify patients at higher risk of poor outcomes, allowing for more tailored and potentially aggressive treatment strategies to improve management and therapeutic responses in glioblastoma.
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Affiliation(s)
- Paolo Tini
- Unit of Radiation Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.
| | - Elisa Cinelli
- Unit of Radiation Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Mariya Yavorska
- Unit of Radiation Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Flavio Donnini
- Unit of Radiation Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Francesco Marampon
- Radiation Oncology, Policlinico Umberto I, Department of Radiological, Oncological and Pathological Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Pierpaolo Pastina
- Unit of Radiation Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Giovanni Rubino
- Unit of Radiation Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
| | | | - Alfonso Cerase
- Unit of Neuroradiology, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Maria Antonietta Mazzei
- Unit of Diagnostic Imaging, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Anna Maria Di Giacomo
- Center for Immuno-Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Giuseppe Minniti
- Radiation Oncology, Policlinico Umberto I, Department of Radiological, Oncological and Pathological Sciences, "Sapienza" University of Rome, Rome, Italy
- IRCSS Neuromed, Pozzilli, Italy
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5
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Zhang H, Li S, Wang D, Liu S, Xiao T, Gu W, Yang H, Wang H, Yang M, Chen P. Metabolic reprogramming and immune evasion: the interplay in the tumor microenvironment. Biomark Res 2024; 12:96. [PMID: 39227970 PMCID: PMC11373140 DOI: 10.1186/s40364-024-00646-1] [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: 07/29/2024] [Accepted: 08/24/2024] [Indexed: 09/05/2024] Open
Abstract
Tumor cells possess complex immune evasion mechanisms to evade immune system attacks, primarily through metabolic reprogramming, which significantly alters the tumor microenvironment (TME) to modulate immune cell functions. When a tumor is sufficiently immunogenic, it can activate cytotoxic T-cells to target and destroy it. However, tumors adapt by manipulating their metabolic pathways, particularly glucose, amino acid, and lipid metabolism, to create an immunosuppressive TME that promotes immune escape. These metabolic alterations impact the function and differentiation of non-tumor cells within the TME, such as inhibiting effector T-cell activity while expanding regulatory T-cells and myeloid-derived suppressor cells. Additionally, these changes lead to an imbalance in cytokine and chemokine secretion, further enhancing the immunosuppressive landscape. Emerging research is increasingly focusing on the regulatory roles of non-tumor cells within the TME, evaluating how their reprogrammed glucose, amino acid, and lipid metabolism influence their functional changes and ultimately aid in tumor immune evasion. Despite our incomplete understanding of the intricate metabolic interactions between tumor and non-tumor cells, the connection between these elements presents significant challenges for cancer immunotherapy. This review highlights the impact of altered glucose, amino acid, and lipid metabolism in the TME on the metabolism and function of non-tumor cells, providing new insights that could facilitate the development of novel cancer immunotherapies.
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Affiliation(s)
- Haixia Zhang
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, China
- Department of Pediatrics, Third Xiangya Hospital, Central South University, Changsha, China
| | - Shizhen Li
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, China
| | - Dan Wang
- Department of Pediatrics, Third Xiangya Hospital, Central South University, Changsha, China
| | - Siyang Liu
- Department of Pediatrics, Third Xiangya Hospital, Central South University, Changsha, China
| | - Tengfei Xiao
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, China
| | - Wangning Gu
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, China
| | - Hongmin Yang
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, China
| | - Hui Wang
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, China.
| | - Minghua Yang
- Department of Pediatrics, Third Xiangya Hospital, Central South University, Changsha, China.
| | - Pan Chen
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, China.
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Nicolini A, Ferrari P. Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy. Front Immunol 2024; 15:1353787. [PMID: 39119332 PMCID: PMC11306065 DOI: 10.3389/fimmu.2024.1353787] [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: 12/11/2023] [Accepted: 03/04/2024] [Indexed: 08/10/2024] Open
Abstract
Metabolic reprogramming is a k`ey hallmark of tumors, developed in response to hypoxia and nutrient deficiency during tumor progression. In both cancer and immune cells, there is a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect, which then leads to lactate acidification, increased lipid synthesis, and glutaminolysis. This reprogramming facilitates tumor immune evasion and, within the tumor microenvironment (TME), cancer and immune cells collaborate to create a suppressive tumor immune microenvironment (TIME). The growing interest in the metabolic reprogramming of the TME, particularly its significance in colorectal cancer (CRC)-one of the most prevalent cancers-has prompted us to explore this topic. CRC exhibits abnormal glycolysis, glutaminolysis, and increased lipid synthesis. Acidosis in CRC cells hampers the activity of anti-tumor immune cells and inhibits the phagocytosis of tumor-associated macrophages (TAMs), while nutrient deficiency promotes the development of regulatory T cells (Tregs) and M2-like macrophages. In CRC cells, activation of G-protein coupled receptor 81 (GPR81) signaling leads to overexpression of programmed death-ligand 1 (PD-L1) and reduces the antigen presentation capability of dendritic cells. Moreover, the genetic and epigenetic cell phenotype, along with the microbiota, significantly influence CRC metabolic reprogramming. Activating RAS mutations and overexpression of epidermal growth factor receptor (EGFR) occur in approximately 50% and 80% of patients, respectively, stimulating glycolysis and increasing levels of hypoxia-inducible factor 1 alpha (HIF-1α) and MYC proteins. Certain bacteria produce short-chain fatty acids (SCFAs), which activate CD8+ cells and genes involved in antigen processing and presentation, while other mechanisms support pro-tumor activities. The use of immune checkpoint inhibitors (ICIs) in selected CRC patients has shown promise, and the combination of these with drugs that inhibit aerobic glycolysis is currently being intensively researched to enhance the efficacy of immunotherapy.
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Affiliation(s)
- Andrea Nicolini
- Department of Oncology, Transplantations and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Paola Ferrari
- Unit of Oncology, Department of Medical and Oncological Area, Azienda Ospedaliera-Universitaria Pisana, Pisa, Italy
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Moses RM, Stenhouse C, Halloran KM, Sah N, Newton MG, Hoskins EC, Washburn SE, Johnson GA, Wu G, Bazer FW. Metabolic pathways of glucose and fructose: II Spatiotemporal expression of genes involved in synthesis and transport of lactate in ovine conceptuses†. Biol Reprod 2024; 111:159-173. [PMID: 38531778 DOI: 10.1093/biolre/ioae047] [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: 12/06/2023] [Revised: 02/14/2024] [Accepted: 03/22/2024] [Indexed: 03/28/2024] Open
Abstract
Lactate, an abundant molecule in fetal fluids and blood of mammalian species, is often overlooked as a metabolic waste product generated during pregnancy. Most of the glucose and fructose consumed by ovine conceptuses is converted to lactate, but proteins involved in lactate metabolism and transport have not been investigated. This study characterized total lactate produced by ovine conceptuses throughout gestation, as well as expression of mRNAs and proteins involved in lactate metabolism. Lactate increased in abundance in the uterine lumen during the preimplantation period and was more abundant than pyruvate. The abundance of lactate in allantoic and amniotic fluids increased with advancing days of gestation and most abundant on Day 125 of pregnancy (P < 0.05). Lactate dehydrogenase subunits A (converts pyruvate to lactate) and B (converts lactate to pyruvate) were expressed by conceptuses throughout gestation. Lactate is transported via monocarboxylic acid transporters SLC16A1 and SLC16A3, both of which were expressed by the conceptus throughout gestation. Additionally, the interplacentomal chorioallantois from Day 126 expressed SLC16A1 and SLC16A3 and transported lactate across the tissue. Hydrocarboxylic acid receptor 1 (HCAR1), a receptor for lactate, was localized to the uterine luminal and superficial glandular epithelia of pregnant ewes throughout gestation and conceptus trophectoderm during the peri-implantation period of gestation. These results provide novel insights into the spatiotemporal profiles of enzymes, transporters, and receptor for lactate by ovine conceptuses throughout pregnancy.
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Affiliation(s)
- Robyn M Moses
- Department of Animal Science, Texas A&M University, College Station, TX, USA
| | - Claire Stenhouse
- Department of Animal Science, Pennsylvania State University, University Park, PA, USA
| | - Katherine M Halloran
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor MI, USA
| | - Nirvay Sah
- Department of Pathology, University of California-San Diego, San Diego, CA, USA
| | - Makenzie G Newton
- Department of Animal Science, Texas A&M University, College Station, TX, USA
| | - Emily C Hoskins
- College of Biomedical and Diagnostic Sciences, University of Tennessee, Knoxville, TN, USA
| | - Shannon E Washburn
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA
| | - Gregory A Johnson
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA
| | - Guoyao Wu
- Department of Animal Science, Texas A&M University, College Station, TX, USA
| | - Fuller W Bazer
- Department of Animal Science, Texas A&M University, College Station, TX, USA
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8
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Sasajima N, Sumazaki M, Oshima Y, Ito M, Yajima S, Takizawa H, Wang H, Li SY, Zhang BS, Yoshida Y, Hiwasa T, Shimada H. Stage-Specific Alteration and Prognostic Relationship of Serum Fumarate Hydratase Autoantibodies in Gastric Cancer. Int J Mol Sci 2024; 25:5470. [PMID: 38791507 PMCID: PMC11121488 DOI: 10.3390/ijms25105470] [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: 04/10/2024] [Revised: 05/09/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024] Open
Abstract
The relationship between energy production and cancer is attracting attention. This study aimed to investigate the clinicopathological significance of fumarate hydratase (FH), a tricarboxylic acid cycle enzyme, in gastric cancer using autoantibodies as biomarkers. The study analyzed 116 patients who underwent gastric cancer surgery and 96 healthy controls. Preoperative serum FH autoantibody (s-FH-Ab) titers were analyzed using an immunosorbent assay with an amplified luminescent proximity homogeneous assay. Receiver operating characteristic analysis was used to determine the cutoff s-FH-Ab titer. Clinicopathological factors and prognosis were compared between the high and low s-FH-Ab groups. The s-FH-Ab levels were significantly higher in the gastric cancer group than in the control group (p = 0.01). Levels were elevated even in patients with stage I gastric cancer compared with healthy controls (p = 0.02). A low s-FH-Ab level was significantly associated with distant metastasis (p = 0.01), peritoneal dissemination (p < 0.05), and poor overall survival (p < 0.01). Multivariate analysis revealed that low s-FH-Ab levels were an independent risk factor for poor prognosis (p < 0.01). Therefore, s-FH-Ab levels may be a useful biomarker for early diagnosis and the prediction of prognosis in patients with gastric cancer.
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Affiliation(s)
- Natsuko Sasajima
- Department of Gastroenterological Surgery, Toho University School of Medicine, Tokyo 143-8541, Japan; (N.S.); (Y.O.); (S.Y.)
| | - Makoto Sumazaki
- Department of Clinical Oncology, Toho University Graduate School of Medicine, Tokyo 143-8541, Japan; (M.S.); (M.I.); (T.H.)
| | - Yoko Oshima
- Department of Gastroenterological Surgery, Toho University School of Medicine, Tokyo 143-8541, Japan; (N.S.); (Y.O.); (S.Y.)
| | - Masaaki Ito
- Department of Clinical Oncology, Toho University Graduate School of Medicine, Tokyo 143-8541, Japan; (M.S.); (M.I.); (T.H.)
| | - Satoshi Yajima
- Department of Gastroenterological Surgery, Toho University School of Medicine, Tokyo 143-8541, Japan; (N.S.); (Y.O.); (S.Y.)
| | - Hirotaka Takizawa
- Port Square Kashiwado Clinic, Kashiwado Memorial Foundation, Chiba 260-0025, Japan;
| | - Hao Wang
- Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; (H.W.); (S.-Y.L.); (B.-S.Z.); (Y.Y.)
| | - Shu-Yang Li
- Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; (H.W.); (S.-Y.L.); (B.-S.Z.); (Y.Y.)
| | - Bo-Shi Zhang
- Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; (H.W.); (S.-Y.L.); (B.-S.Z.); (Y.Y.)
| | - Yoichi Yoshida
- Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; (H.W.); (S.-Y.L.); (B.-S.Z.); (Y.Y.)
| | - Takaki Hiwasa
- Department of Clinical Oncology, Toho University Graduate School of Medicine, Tokyo 143-8541, Japan; (M.S.); (M.I.); (T.H.)
- Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; (H.W.); (S.-Y.L.); (B.-S.Z.); (Y.Y.)
| | - Hideaki Shimada
- Department of Gastroenterological Surgery, Toho University School of Medicine, Tokyo 143-8541, Japan; (N.S.); (Y.O.); (S.Y.)
- Department of Clinical Oncology, Toho University Graduate School of Medicine, Tokyo 143-8541, Japan; (M.S.); (M.I.); (T.H.)
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9
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Vlasiou M, Nicolaidou V, Papaneophytou C. Targeting Lactate Dehydrogenase-B as a Strategy to Fight Cancer: Identification of Potential Inhibitors by In Silico Analysis and In Vitro Screening. Pharmaceutics 2023; 15:2411. [PMID: 37896171 PMCID: PMC10609963 DOI: 10.3390/pharmaceutics15102411] [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: 08/29/2023] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 10/29/2023] Open
Abstract
Lactate dehydrogenase (LDH) is an enzyme that catalyzes the reversible conversion of lactate to pyruvate while reducing NAD+ to NADH (or oxidizing NADH to NAD+). Due to its central role in the Warburg effect, LDH-A isoform has been considered a promising target for treating several types of cancer. However, research on inhibitors targeting LDH-B isoform is still limited, despite the enzyme's implication in the development of specific cancer types such as breast and lung cancer. This study aimed to identify small-molecule compounds that specifically inhibit LDH-B. Our in silico analysis identified eight commercially available compounds that may affect LDH-B activity. The best five candidates, namely tucatinib, capmatinib, moxidectin, rifampicin, and acetyldigoxin, were evaluated further in vitro. Our results revealed that two compounds, viz., tucatinib and capmatinib, currently used for treating breast and lung cancer, respectively, could also act as inhibitors of LDH-B. Both compounds inhibited LDH-B activity through an uncompetitive mechanism, as observed in in vitro experiments. Molecular dynamics studies further support these findings. Together, our results suggest that two known drugs currently being used to treat specific cancer types may have a dual effect and target more than one enzyme that facilitates the development of these types of cancers. Furthermore, the results of this study could be used as a new starting point for identifying more potent and specific LDH-B inhibitors.
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Affiliation(s)
- Manos Vlasiou
- Department of Veterinary Medicine, University of Nicosia School of Veterinary Medicine, 2414 Nicosia, Cyprus
| | - Vicky Nicolaidou
- Department of Life Sciences, School of Life and Health Sciences, University of Nicosia, 2417 Nicosia, Cyprus
| | - Christos Papaneophytou
- Department of Life Sciences, School of Life and Health Sciences, University of Nicosia, 2417 Nicosia, Cyprus
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10
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Shu XP, Xiang YC, Liu F, Cheng Y, Zhang W, Peng D. Effect of serum lactate dehydrogenase-to-albumin ratio (LAR) on the short-term outcomes and long-term prognosis of colorectal cancer after radical surgery. BMC Cancer 2023; 23:915. [PMID: 37770882 PMCID: PMC10537469 DOI: 10.1186/s12885-023-11446-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 09/25/2023] [Indexed: 09/30/2023] Open
Abstract
BACKGROUND Whether serum lactate dehydrogenase-to-albumin ratio (LAR) influenced the outcomes of colorectal cancer (CRC) patients after radical surgery remained unclear. Therefore, this study sought to examine how LAR influences the short-term and long-term outcomes of CRC patients who have undergone radical surgery. METHODS This study retrospectively included CRC patients who underwent radical resection between January 2011 and January 2020. We compared short-term outcomes, as well as overall survival (OS) and disease-free survival (DFS), among various groups. Both univariate and multivariate logistic regression analyses were utilized to pinpoint independent risk factors associated with overall complications and major complications. Moreover, Cox regression analysis were conducted for OS and DFS. Odds ratio (OR) and Hazard ratio (HR) were adjusted. RESULTS This study encompassed a cohort of 3868 patients. 3440 patients were in the low LAR group and 428 patients constituted the high LAR group. In the high LAR group, patients experienced significantly longer operative times (p < 0.01), larger intraoperative blood loss (p < 0.01), and extended postoperative hospital stays (p < 0.01). Additionally, the incidence of both overall complications (p < 0.01) and major complications (p < 0.01) was higher in the high LAR group compared to the low LAR group. Furthermore, LAR was emerged as an independent prognostic factor for overall complications [OR/95% CI: (1.555/1.237 to 1.954), p < 0.01] and major complications [OR/95% CI: (2.178/1.279 to 3.707), p < 0.01]. As for long-term survival, the high LAR group had worse OS in stage II (p < 0.01) and stage III (p < 0.01). In both stage II (p < 0.01) and stage III (p < 0.01), the high LAR group exhibited poorer DFS. Additionally, according to Cox regression analysis, LAR was identified as an independent predictor for both OS [HR/95% CI: (1.930/1.554 to 2.398), p < 0.01] and DFS [HR/95% CI: (1.750/1.427 to 2.146), p < 0.01]. CONCLUSION LAR emerged as an independent predictor not only for overall complications and major complications but also for both OS and DFS, highlighting its significance and deserving the attention of surgeons.
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Affiliation(s)
- Xin-Peng Shu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Ying-Chun Xiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Fei Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yong Cheng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Wei Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Dong Peng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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Deen SS, Rooney C, Shinozaki A, McGing J, Grist JT, Tyler DJ, Serrão E, Gallagher FA. Hyperpolarized Carbon 13 MRI: Clinical Applications and Future Directions in Oncology. Radiol Imaging Cancer 2023; 5:e230005. [PMID: 37682052 PMCID: PMC10546364 DOI: 10.1148/rycan.230005] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 06/16/2023] [Accepted: 08/02/2023] [Indexed: 09/09/2023]
Abstract
Hyperpolarized carbon 13 MRI (13C MRI) is a novel imaging approach that can noninvasively probe tissue metabolism in both normal and pathologic tissues. The process of hyperpolarization increases the signal acquired by several orders of magnitude, allowing injected 13C-labeled molecules and their downstream metabolites to be imaged in vivo, thus providing real-time information on kinetics. To date, the most important reaction studied with hyperpolarized 13C MRI is exchange of the hyperpolarized 13C signal from injected [1-13C]pyruvate with the resident tissue lactate pool. Recent preclinical and human studies have shown the role of several biologic factors such as the lactate dehydrogenase enzyme, pyruvate transporter expression, and tissue hypoxia in generating the MRI signal from this reaction. Potential clinical applications of hyperpolarized 13C MRI in oncology include using metabolism to stratify tumors by grade, selecting therapeutic pathways based on tumor metabolic profiles, and detecting early treatment response through the imaging of shifts in metabolism that precede tumor structural changes. This review summarizes the foundations of hyperpolarized 13C MRI, presents key findings from human cancer studies, and explores the future clinical directions of the technique in oncology. Keywords: Hyperpolarized Carbon 13 MRI, Molecular Imaging, Cancer, Tissue Metabolism © RSNA, 2023.
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Affiliation(s)
- Surrin S Deen
- From the Department of Radiology, Cambridge University Hospitals, Biomedical Campus, Cambridge, CB2 0QQ, England (S.S.D., E.S., F.A.G.); Department of Physiology, Anatomy, and Genetics (C.R., A.S., J.T.G., D.J.T.) and the Oxford Centre for Clinical Magnetic Resonance Research (A.S., J.T.G., D.J.T.), University of Oxford, Oxford, England; Department of Radiology, Oxford University Hospitals, Oxford, England (J.M., J.T.G.); Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, England (J.T.G.); Department of Radiology, University of Cambridge, Cambridge, England (E.S., F.A.G.); Cancer Research UK Cambridge Centre, Cambridge, England (F.A.G.); and Joint Department of Medical Imaging, University Health Network, University of Toronto, Toronto, Canada (E.S.)
| | - Catriona Rooney
- From the Department of Radiology, Cambridge University Hospitals, Biomedical Campus, Cambridge, CB2 0QQ, England (S.S.D., E.S., F.A.G.); Department of Physiology, Anatomy, and Genetics (C.R., A.S., J.T.G., D.J.T.) and the Oxford Centre for Clinical Magnetic Resonance Research (A.S., J.T.G., D.J.T.), University of Oxford, Oxford, England; Department of Radiology, Oxford University Hospitals, Oxford, England (J.M., J.T.G.); Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, England (J.T.G.); Department of Radiology, University of Cambridge, Cambridge, England (E.S., F.A.G.); Cancer Research UK Cambridge Centre, Cambridge, England (F.A.G.); and Joint Department of Medical Imaging, University Health Network, University of Toronto, Toronto, Canada (E.S.)
| | - Ayaka Shinozaki
- From the Department of Radiology, Cambridge University Hospitals, Biomedical Campus, Cambridge, CB2 0QQ, England (S.S.D., E.S., F.A.G.); Department of Physiology, Anatomy, and Genetics (C.R., A.S., J.T.G., D.J.T.) and the Oxford Centre for Clinical Magnetic Resonance Research (A.S., J.T.G., D.J.T.), University of Oxford, Oxford, England; Department of Radiology, Oxford University Hospitals, Oxford, England (J.M., J.T.G.); Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, England (J.T.G.); Department of Radiology, University of Cambridge, Cambridge, England (E.S., F.A.G.); Cancer Research UK Cambridge Centre, Cambridge, England (F.A.G.); and Joint Department of Medical Imaging, University Health Network, University of Toronto, Toronto, Canada (E.S.)
| | - Jordan McGing
- From the Department of Radiology, Cambridge University Hospitals, Biomedical Campus, Cambridge, CB2 0QQ, England (S.S.D., E.S., F.A.G.); Department of Physiology, Anatomy, and Genetics (C.R., A.S., J.T.G., D.J.T.) and the Oxford Centre for Clinical Magnetic Resonance Research (A.S., J.T.G., D.J.T.), University of Oxford, Oxford, England; Department of Radiology, Oxford University Hospitals, Oxford, England (J.M., J.T.G.); Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, England (J.T.G.); Department of Radiology, University of Cambridge, Cambridge, England (E.S., F.A.G.); Cancer Research UK Cambridge Centre, Cambridge, England (F.A.G.); and Joint Department of Medical Imaging, University Health Network, University of Toronto, Toronto, Canada (E.S.)
| | - James T Grist
- From the Department of Radiology, Cambridge University Hospitals, Biomedical Campus, Cambridge, CB2 0QQ, England (S.S.D., E.S., F.A.G.); Department of Physiology, Anatomy, and Genetics (C.R., A.S., J.T.G., D.J.T.) and the Oxford Centre for Clinical Magnetic Resonance Research (A.S., J.T.G., D.J.T.), University of Oxford, Oxford, England; Department of Radiology, Oxford University Hospitals, Oxford, England (J.M., J.T.G.); Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, England (J.T.G.); Department of Radiology, University of Cambridge, Cambridge, England (E.S., F.A.G.); Cancer Research UK Cambridge Centre, Cambridge, England (F.A.G.); and Joint Department of Medical Imaging, University Health Network, University of Toronto, Toronto, Canada (E.S.)
| | - Damian J Tyler
- From the Department of Radiology, Cambridge University Hospitals, Biomedical Campus, Cambridge, CB2 0QQ, England (S.S.D., E.S., F.A.G.); Department of Physiology, Anatomy, and Genetics (C.R., A.S., J.T.G., D.J.T.) and the Oxford Centre for Clinical Magnetic Resonance Research (A.S., J.T.G., D.J.T.), University of Oxford, Oxford, England; Department of Radiology, Oxford University Hospitals, Oxford, England (J.M., J.T.G.); Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, England (J.T.G.); Department of Radiology, University of Cambridge, Cambridge, England (E.S., F.A.G.); Cancer Research UK Cambridge Centre, Cambridge, England (F.A.G.); and Joint Department of Medical Imaging, University Health Network, University of Toronto, Toronto, Canada (E.S.)
| | - Eva Serrão
- From the Department of Radiology, Cambridge University Hospitals, Biomedical Campus, Cambridge, CB2 0QQ, England (S.S.D., E.S., F.A.G.); Department of Physiology, Anatomy, and Genetics (C.R., A.S., J.T.G., D.J.T.) and the Oxford Centre for Clinical Magnetic Resonance Research (A.S., J.T.G., D.J.T.), University of Oxford, Oxford, England; Department of Radiology, Oxford University Hospitals, Oxford, England (J.M., J.T.G.); Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, England (J.T.G.); Department of Radiology, University of Cambridge, Cambridge, England (E.S., F.A.G.); Cancer Research UK Cambridge Centre, Cambridge, England (F.A.G.); and Joint Department of Medical Imaging, University Health Network, University of Toronto, Toronto, Canada (E.S.)
| | - Ferdia A Gallagher
- From the Department of Radiology, Cambridge University Hospitals, Biomedical Campus, Cambridge, CB2 0QQ, England (S.S.D., E.S., F.A.G.); Department of Physiology, Anatomy, and Genetics (C.R., A.S., J.T.G., D.J.T.) and the Oxford Centre for Clinical Magnetic Resonance Research (A.S., J.T.G., D.J.T.), University of Oxford, Oxford, England; Department of Radiology, Oxford University Hospitals, Oxford, England (J.M., J.T.G.); Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, England (J.T.G.); Department of Radiology, University of Cambridge, Cambridge, England (E.S., F.A.G.); Cancer Research UK Cambridge Centre, Cambridge, England (F.A.G.); and Joint Department of Medical Imaging, University Health Network, University of Toronto, Toronto, Canada (E.S.)
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Song M, Zhang T, Yang D, Xiao H, Wang H, Ye Q, Zhai Z. Chromosomal aberrations and prognostic analysis of secondary acute myeloid leukemia-a retrospective study. PeerJ 2023; 11:e15333. [PMID: 37214104 PMCID: PMC10194067 DOI: 10.7717/peerj.15333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 04/11/2023] [Indexed: 05/24/2023] Open
Abstract
Background Secondary acute myeloid leukemia (S-AML) patients generally have a poor prognosis, but the chromosomal aberrations of S-AML have been rarely reported. We aimed to explore the chromosomal aberrations and clinical significance in patients with S-AML. Patients and methods The clinical characteristics and karyotypes of 26 patients with S-AML were retrospectively analyzed. The overall survival (OS) was measured from the time of the patients' transition to AML (i.e., at S-AML diagnosis). Results The study included 26 S-AML patients (13 males and 13 females), with a median age of 63 years (range, 20-77 years). They transformed from various hematologic malignancies or solid tumors; most of them were secondary to myelodysplastic syndrome (MDS). About 62% of the S-AML patients showed chromosomal aberrations. The serum lactate dehydrogenase (LDH) level in S-AML patients with abnormal karyotype was higher than those with normal karyotype. Apart from the differences in treatment regimens, S-AML patients with chromosomal aberrations had shorter OS (P < 0.05). Conclusion S-AML patients with abnormal karyotype have higher LDH levels and shorter OS than normal karyotype patients, and the OS of hypodiploidy was much shorter than hyperdiploid.
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Affiliation(s)
- Mingzhu Song
- Transfusion, The Affiliated Hospital of Anhui Medical University (Lu’an People’s Hospital), lu’an, Anhui Province, China
- Anhui Medical University, Anhui Medical University, Hefei, Anhui Province, China
| | - Tun Zhang
- Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, Hefei, Anhui Province, China
| | - Dongdong Yang
- Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, Hefei, Anhui Province, China
| | - Hao Xiao
- Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, Hefei, Anhui Province, China
| | - Huiping Wang
- Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, Hefei, Anhui Province, China
| | - Qianling Ye
- Oncology, East Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai, Shanghai, China
| | - Zhimin Zhai
- Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, Hefei, Anhui Province, China
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13
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Wang Z, Shao Y, Zhang H, Lu Y, Chen Y, Shen H, Huang C, Wu J, Fu Z. Machine learning-based glycolysis-associated molecular classification reveals differences in prognosis, TME, and immunotherapy for colorectal cancer patients. Front Immunol 2023; 14:1181985. [PMID: 37228620 PMCID: PMC10203873 DOI: 10.3389/fimmu.2023.1181985] [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: 03/08/2023] [Accepted: 04/25/2023] [Indexed: 05/27/2023] Open
Abstract
Background Aerobic glycolysis is a process that metabolizes glucose under aerobic conditions, finally producing pyruvate, lactic acid, and ATP for tumor cells. Nevertheless, the overall significance of glycolysis-related genes in colorectal cancer and how they affect the immune microenvironment have not been investigated. Methods By combining the transcriptome and single-cell analysis, we summarize the various expression patterns of glycolysis-related genes in colorectal cancer. Three glycolysis-associated clusters (GAC) were identified with distinct clinical, genomic, and tumor microenvironment (TME). By mapping GAC to single-cell RNA sequencing analysis (scRNA-seq), we next discovered that the immune infiltration profile of GACs was similar to that of bulk RNA sequencing analysis (bulk RNA-seq). In order to determine the kind of GAC for each sample, we developed the GAC predictor using markers of single cells and GACs that were most pertinent to clinical prognostic indications. Additionally, potential drugs for each GAC were discovered using different algorithms. Results GAC1 was comparable to the immune-desert type, with a low mutation probability and a relatively general prognosis; GAC2 was more likely to be immune-inflamed/excluded, with more immunosuppressive cells and stromal components, which also carried the risk of the poorest prognosis; Similar to the immune-activated type, GAC3 had a high mutation rate, more active immune cells, and excellent therapeutic potential. Conclusion In conclusion, we combined transcriptome and single-cell data to identify new molecular subtypes using glycolysis-related genes in colorectal cancer based on machine-learning methods, which provided therapeutic direction for colorectal patients.
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Affiliation(s)
- Zhenling Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yu Shao
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hongqiang Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yunfei Lu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yang Chen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hengyang Shen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Changzhi Huang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jingyu Wu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zan Fu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
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Yang Y, Zhang Z, Li W, Li L, Zhou Y, Du W. ME2 Promotes Hepatocellular Carcinoma Cell Migration through Pyruvate. Metabolites 2023; 13:metabo13040540. [PMID: 37110198 PMCID: PMC10145348 DOI: 10.3390/metabo13040540] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/03/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Cancer metastasis is still a major challenge in clinical cancer treatment. The migration and invasion of cancer cells into surrounding tissues and blood vessels is the primary step in cancer metastasis. However, the underlying mechanism of regulating cell migration and invasion are not fully understood. Here, we show the role of malic enzyme 2 (ME2) in promoting human liver cancer cell lines SK-Hep1 and Huh7 cells migration and invasion. Depletion of ME2 reduces cell migration and invasion, whereas overexpression of ME2 increases cell migration and invasion. Mechanistically, ME2 promotes the production of pyruvate, which directly binds to β-catenin and increases β-catenin protein levels. Notably, pyruvate treatment restores cell migration and invasion of ME2-depleted cells. Our findings provide a mechanistic understanding of the link between ME2 and cell migration and invasion.
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Affiliation(s)
- Yanting Yang
- State Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Department of Cell Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Zhenxi Zhang
- State Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Department of Cell Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Wei Li
- State Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Department of Cell Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Li Li
- State Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Department of Cell Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
| | - Ying Zhou
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030606, China
| | - Wenjing Du
- State Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Department of Cell Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030606, China
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Liu Y, Jiang C, Liu Q, Huang R, Wang M, Guo X. CircRNAs: emerging factors for regulating glucose metabolism in colorectal cancer. Clin Transl Oncol 2023:10.1007/s12094-023-03131-7. [PMID: 36944731 DOI: 10.1007/s12094-023-03131-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 02/19/2023] [Indexed: 03/23/2023]
Abstract
Colorectal cancer is a malignant disease with a high incidence and low survival rate, and the effectiveness of traditional treatments, such as surgery and radiotherapy, is very limited. CircRNAs, a kind of stable endogenous circular RNA, generally function by sponging miRNAs and binding or translating proteins. CircRNAs have been identified to play an important role in regulating the proliferation and metabolism of CRC. In recent years, many reports have indicated that by regulating the expression of glycolysis-related proteins, such as GLUT1 and HK2, or directly translating proteins, circRNAs can promote the Warburg effect in cancer cells, thereby driving CRC metabolism. Moreover, the Warburg effect increases lactate production in cancer cells and promotes acidification of the TME, which further drives cancer progression. In this review, we summarized the remarkable role of circRNAs in regulating glucose metabolism in CRC in recent years, which might be useful for finding new targets for the clinical treatment of CRC.
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Affiliation(s)
- Yulin Liu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, The People's Republic of China
| | - Chenjun Jiang
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, The People's Republic of China
| | - Qianqian Liu
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, The People's Republic of China
| | - Runchun Huang
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, The People's Republic of China
| | - Mancai Wang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, The People's Republic of China
- General Surgery Department, The Second Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Xiaohu Guo
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, The People's Republic of China.
- General Surgery Department, The Second Hospital of Lanzhou University, Lanzhou, 730000, China.
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16
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Tumor Microenvironment and Immune Response in Lip Cancer. Cancers (Basel) 2023; 15:cancers15051478. [PMID: 36900270 PMCID: PMC10001350 DOI: 10.3390/cancers15051478] [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: 01/28/2023] [Revised: 02/18/2023] [Accepted: 02/24/2023] [Indexed: 03/03/2023] Open
Abstract
Tumor-infiltrating lymphocytes (TILs) play a significant role in cancer progression and prognosis of patients. The tumor microenvironment (TME) may affect the anti-tumor immune response. We examined the TIL and tertiary lymphoid structure (TLS) density in the invading front and inner tumor stroma, and the lymphocyte subpopulation (CD8, CD4, FOXP3) density in 60 squamous cell carcinomas of the lip. Analysis was performed in parallel with markers of hypoxia (hypoxia-inducible factor (HIF1α), lactate dehydrogenase (LDHA)) and angiogenesis. Low TIL density in the invading tumor front was related with larger tumor size (p = 0.05), deep invasion (p = 0.01), high smooth-muscle actin (SMA) expression (p = 0.01), and high HIF1α and LDH5 expression (p = 0.04). FOXP3+ TILs infiltration and FOXP3+/CD8+ ratios were higher in inner tumor areas, linked with LDH5 expression, and higher MIB1 proliferation index (p = 0.03) and SMA expression (p = 0.001). Dense CD4+ lymphocytic infiltration in the invading front is related to high tumor-budding (TB) (p = 0.04) and angiogenesis (p = 0.04 and p = 0.006, respectively). Low CD8+ TIL density, high CD20+ B-cell density, high FOXP3+/CD8+ ratio and high CD68+ macrophage presence characterized tumors with local invasion (p = 0.02, 0.01, 0.02 and 0.006, respectively). High angiogenic activity was linked with high CD4+, FOXP3+, and low CD8+ TIL density (p = 0.05, 0.01 and 0.01, respectively), as well as high CD68+ macrophage presence (p = 0.003). LDH5 expression was linked with high CD4+ and FOXP3+ TIL density (p = 0.05 and 0.01, respectively). Further research is needed to explore the prognostic and therapeutic value of TME/TIL interactions.
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Understanding the Contribution of Lactate Metabolism in Cancer Progress: A Perspective from Isomers. Cancers (Basel) 2022; 15:cancers15010087. [PMID: 36612084 PMCID: PMC9817756 DOI: 10.3390/cancers15010087] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/13/2022] [Accepted: 12/21/2022] [Indexed: 12/28/2022] Open
Abstract
Lactate mediates multiple cell-intrinsic effects in cancer metabolism in terms of development, maintenance, and metastasis and is often correlated with poor prognosis. Its functions are undertaken as an energy source for neighboring carcinoma cells and serve as a lactormone for oncogenic signaling pathways. Indeed, two isomers of lactate are produced in the Warburg effect: L-lactate and D-lactate. L-lactate is the main end-production of glycolytic fermentation which catalyzes glucose, and tiny D-lactate is fabricated through the glyoxalase system. Their production inevitably affects cancer development and therapy. Here, we systematically review the mechanisms of lactate isomers production, and highlight emerging evidence of the carcinogenic biological effects of lactate and its isomers in cancer. Accordingly, therapy that targets lactate and its metabolism is a promising approach for anticancer treatment.
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Gum Arabic nanoformulation rescues neuronal lesions in bromobenzene-challenged rats by its antioxidant, anti-apoptotic and cytoprotective potentials. Sci Rep 2022; 12:21213. [PMID: 36481816 PMCID: PMC9731957 DOI: 10.1038/s41598-022-24556-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 11/16/2022] [Indexed: 12/13/2022] Open
Abstract
Bromobenzene (BB) is a hazardous environmental contaminant because of its multiple routes of exposure and the toxicity of its bio-derivates. It could elicit neuronal alterations by stimulating redox imbalance and apoptotic pathways. Gum Arabic (GA) protected the hippocampus of a type 2 diabetic rat model from cognitive decline. Whether gum Arabic nanoemulsion (GANE) can increase the neuroprotectant potency of GA in fighting BB-associated neurological lesions is the question to be answered. To accomplish this objective, 25 adult male Wistar rats were randomly and equally assigned into five groups. Control received olive oil (vehicle of BB). BB group received BB at a dose of 460 mg/kg BW. Blank nanoemulsion (BNE) group supplemented with BNE at 2 mL of 10% w/v aqueous suspension/kg BW. GANE group received GANE at a dose of 2 mL of 10% w/v aqueous suspension/kg BW. BB + GANE group exposed to BB in concomitant with GANE at the same previous doses. All interventions were carried out daily by oral gavage for ten consecutive days. BB caused a marked increase in malondialdehyde and succinate dehydrogenase together with a marked decrease in reduced glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase, and lactate dehydrogenase in the brain. BB was accompanied by pathological deteriorations, amyloidosis, and reduced immuno-expression of integrase interactor 1 in the hippocampal region. Administration of GANE was beneficial in reversing the aforementioned abnormalities. These results pave the road for further discovery of nano-formulated natural products to counter the threats of BB.
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Guyon J, Fernandez‐Moncada I, Larrieu CM, Bouchez CL, Pagano Zottola AC, Galvis J, Chouleur T, Burban A, Joseph K, Ravi VM, Espedal H, Røsland GV, Daher B, Barre A, Dartigues B, Karkar S, Rudewicz J, Romero‐Garmendia I, Klink B, Grützmann K, Derieppe M, Molinié T, Obad N, Léon C, Seano G, Miletic H, Heiland DH, Marsicano G, Nikolski M, Bjerkvig R, Bikfalvi A, Daubon T. Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis. EMBO Mol Med 2022; 14:e15343. [PMID: 36278433 PMCID: PMC9728051 DOI: 10.15252/emmm.202115343] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 09/26/2022] [Accepted: 09/27/2022] [Indexed: 12/14/2022] Open
Abstract
Lactate is a central metabolite in brain physiology but also contributes to tumor development. Glioblastoma (GB) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its altered metabolism. We show herein that lactate fuels GB anaplerosis by replenishing the tricarboxylic acid (TCA) cycle in absence of glucose. Lactate dehydrogenases (LDHA and LDHB), which we found spatially expressed in GB tissues, catalyze the interconversion of pyruvate and lactate. However, ablation of both LDH isoforms, but not only one, led to a reduction in tumor growth and an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OXPHOS) in the LDHA/B KO group which sensitized tumors to cranial irradiation, thus improving mouse survival. When mice were treated with the antiepileptic drug stiripentol, which targets LDH activity, tumor growth decreased. Our findings unveil the complex metabolic network in which both LDHA and LDHB are integrated and show that the combined inhibition of LDHA and LDHB strongly sensitizes GB to therapy.
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Affiliation(s)
- Joris Guyon
- University Bordeaux, INSERM U1312, BRICPessacFrance
| | | | | | | | | | - Johanna Galvis
- University Bordeaux, CNRS, IBGC, UMR 5095BordeauxFrance,Bordeaux Bioinformatic Center CBiBUniversity of BordeauxBordeauxFrance
| | | | - Audrey Burban
- University Bordeaux, CNRS, IBGC, UMR 5095BordeauxFrance
| | - Kevin Joseph
- Microenvironment and Immunology Research Laboratory, Medical CenterUniversity of FreiburgFreiburgGermany,Department of Neurosurgery, Medical CenterUniversity of FreiburgFreiburgGermany,Faculty of Medicine, University of FreiburgFreiburgGermany,Translational NeuroOncology Research Group, Medical CenterUniversity of FreiburgFreiburgGermany,Center of Advanced Surgical Tissue Analysis (CAST)University of FreiburgFreiburgGermany
| | - Vidhya M Ravi
- Microenvironment and Immunology Research Laboratory, Medical CenterUniversity of FreiburgFreiburgGermany,Department of Neurosurgery, Medical CenterUniversity of FreiburgFreiburgGermany,Faculty of Medicine, University of FreiburgFreiburgGermany,Translational NeuroOncology Research Group, Medical CenterUniversity of FreiburgFreiburgGermany,Center of Advanced Surgical Tissue Analysis (CAST)University of FreiburgFreiburgGermany,Freiburg Institute for Advanced Studies (FRIAS)University of FreiburgFreiburgGermany
| | - Heidi Espedal
- NorLux Neuro‐Oncology, Department of BiomedicineUniversity of BergenBergenNorway
| | | | | | - Aurélien Barre
- Bordeaux Bioinformatic Center CBiBUniversity of BordeauxBordeauxFrance
| | | | - Slim Karkar
- Bordeaux Bioinformatic Center CBiBUniversity of BordeauxBordeauxFrance
| | - Justine Rudewicz
- Bordeaux Bioinformatic Center CBiBUniversity of BordeauxBordeauxFrance
| | | | - Barbara Klink
- Department of OncologyLuxembourg Institute of HealthLuxembourgLuxembourg,German Cancer Consortium (DKTK)DresdenGermany,Core Unit for Molecular Tumor Diagnostics (CMTD)National Center for Tumor Diseases (NCT)DresdenGermany
| | - Konrad Grützmann
- Core Unit for Molecular Tumor Diagnostics (CMTD)National Center for Tumor Diseases (NCT)DresdenGermany
| | | | | | - Nina Obad
- NorLux Neuro‐Oncology, Department of BiomedicineUniversity of BergenBergenNorway
| | - Céline Léon
- University Bordeaux, INSERM U1312, BRICPessacFrance
| | - Giorgio Seano
- Institut Curie, INSERM U1021, CNRS UMR3347, Tumor Microenvironment LabUniversity Paris‐SaclayOrsayFrance
| | - Hrvoje Miletic
- NorLux Neuro‐Oncology, Department of BiomedicineUniversity of BergenBergenNorway,Department of PathologyHaukeland University HospitalBergenNorway
| | - Dieter Henrik Heiland
- Microenvironment and Immunology Research Laboratory, Medical CenterUniversity of FreiburgFreiburgGermany,Department of Neurosurgery, Medical CenterUniversity of FreiburgFreiburgGermany,Faculty of Medicine, University of FreiburgFreiburgGermany,Translational NeuroOncology Research Group, Medical CenterUniversity of FreiburgFreiburgGermany,German Cancer Consortium (DKTK), partner site FreiburgFreiburgGermany
| | | | - Macha Nikolski
- University Bordeaux, CNRS, IBGC, UMR 5095BordeauxFrance,Bordeaux Bioinformatic Center CBiBUniversity of BordeauxBordeauxFrance
| | - Rolf Bjerkvig
- NorLux Neuro‐Oncology, Department of BiomedicineUniversity of BergenBergenNorway
| | | | - Thomas Daubon
- University Bordeaux, INSERM U1312, BRICPessacFrance,University Bordeaux, CNRS, IBGC, UMR 5095BordeauxFrance
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20
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Zhu D, Jiang Y, Cao H, Yang J, Shu Y, Feng H, Yang X, Sun X, Shao M. Lactate: A regulator of immune microenvironment and a clinical prognosis indicator in colorectal cancer. Front Immunol 2022; 13:876195. [PMID: 36091047 PMCID: PMC9458902 DOI: 10.3389/fimmu.2022.876195] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 08/09/2022] [Indexed: 11/13/2022] Open
Abstract
Lactate can play an immunosuppressive role in the tumor microenvironment and promote tumor development by recruiting and inducing the activity of immunosuppressive cells and molecules. High lactate concentrations are important for tumor cell metastasis, angiogenesis, and treatment resistance. With the in-depth studies on tumor metabolism, lactate, one of the key factors involved in glycolysis, has been increasing emerged its characteristic clinical value in colorectal cancer (CRC). In this study, lactate genes were screened based on lactate metabolism pathways. Subsequently, the lactate subtypes were determined by clustering and analysis of the subtypes at all levels, including immune checkpoints, immune infiltration, and clinical characteristics, which revealed the biological significance of lactate metabolism in CRC. Subtype-based differential gene analysis resulted in a lactate score, which stratifies the prognosis of CRC. We discovered that 27 lactate genes and 61 lactate-phenotype genes are associated with immune cell infiltration and have a significant prognostic efficacy. The CRC patients were clustered into four subtypes and five clusters, based on lactate genes and lactate-phenotype genes, respectively. There are significant differences in survival time and activities of hallmark pathways, namely immune-related signatures and chemokines, among these subtypes and clusters. Particularly, cluster 2 and subtype 1 have significantly higher lactate scores than that of the others. In conclusion, lactate score is an independent prognostic factor for cancer that can be used as a clinical guide for predicting CRC progression and as an evaluation factor for the effect of immunotherapy in CRC.
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Affiliation(s)
- Daoqi Zhu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Yiping Jiang
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai, China
| | - Huihui Cao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Traditional Chinese Pharmacological, Third Level Research Laboratory of State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Jiabin Yang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Yuqi Shu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Haowei Feng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Xiaoyu Yang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Xiaomin Sun
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- *Correspondence: Meng Shao, ; Xiaomin Sun,
| | - Meng Shao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- *Correspondence: Meng Shao, ; Xiaomin Sun,
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21
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Lindholm H, Ejeskär K, Szekeres F. Digitoxin Affects Metabolism, ROS Production and Proliferation in Pancreatic Cancer Cells Differently Depending on the Cell Phenotype. Int J Mol Sci 2022; 23:8237. [PMID: 35897809 PMCID: PMC9331846 DOI: 10.3390/ijms23158237] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/19/2022] [Accepted: 07/23/2022] [Indexed: 02/07/2023] Open
Abstract
Digitoxin has repeatedly shown to have negative effects on cancer cell viability; however, the actual mechanism is still unknown. In this study, we investigated the effects of digitoxin (1-100 nM) in four pancreatic cancer cell lines, BxPC-3, CFPAC-1, Panc-1, and AsPC-1. The cell lines differ in their KRAS/BRAF mutational status and primary tumor or metastasis origin. We could detect differences in the basal rates of cell proliferation, glycolysis, and ROS production, giving the cell lines different phenotypes. Digitoxin treatment induced apoptosis in all four cell lines, but to different degrees. Cells derived from primary tumors (Panc-1 and BxPC-3) were highly proliferating with a high proportion of cells in the S/G2 phase, and were more sensitive to digitoxin treatment than the cell lines derived from metastases (CFPAC-1 and AsPC-1), with a high proportion of cells in G0/G1. In addition, the effects of digitoxin on the rate of glycolysis, ROS production, and proliferation were dependent on the basal metabolism and origin of the cells. The KRAS downstream signaling pathways were not altered by digitoxin treatment, thus the effects exerted by digitoxin were probably disconnected from these signaling pathways. We conclude that digitoxin is a promising treatment in highly proliferating pancreatic tumors.
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Affiliation(s)
| | | | - Ferenc Szekeres
- Biomedicine, School of Health Sciences, University of Skövde, 54145 Skövde, Sweden; (H.L.); (K.E.)
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22
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Luecke S, Fottner C, Lahner H, Jann H, Zolnowski D, Quietzsch D, Grabowski P, Cremer B, Maasberg S, Pape UF, Mueller HH, Gress TM, Rinke A, the members of the German NET Registry. Treatment Approaches and Outcome of Patients with Neuroendocrine Neoplasia Grade 3 in German Real-World Clinical Practice. Cancers (Basel) 2022; 14:2718. [PMID: 35681701 PMCID: PMC9179270 DOI: 10.3390/cancers14112718] [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: 04/19/2022] [Revised: 05/20/2022] [Accepted: 05/25/2022] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND Neuroendocrine neoplasia grade 3 (NEN G3) represents a rare and heterogeneous cancer type with a poor prognosis. The aim of our study was to analyze real-world data from the German NET Registry with a focus on therapeutic and prognostic aspects. METHODS NEN G3 patients were identified within the German NET Registry. Demographic data and data on treatments and outcomes were retrieved. Univariate analyses were performed using the Kaplan-Meier-method. Multivariate analysis was performed using a Cox proportional hazard model. RESULTS Of 445 included patients, 318 (71.5%) were diagnosed at stage IV. Well-differentiated morphology (NET G3) was described in 31.7%, 60% of cases were classified as neuroendocrine carcinoma (NEC), and the median Ki67 value was 50%. First-line treatment comprised chemotherapy in 43.8%, with differences in the choice of regimen with regard to NET or NEC, and surgery in 41.6% of patients. Median overall survival for the entire cohort was 31 months. Stage, performance status and Ki67 were significant prognostic factors in multivariate analysis. CONCLUSIONS The survival data of our national registry compare favorably to population-based data, probably mainly because of a relatively low median Ki67 of 50%. Nevertheless, the best first- and second-line approaches for specific subgroups remain unclear, and an international effort to fill these gaps is needed.
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Affiliation(s)
- Simone Luecke
- UKGM Marburg, Department of Gastroenterology, Philipps University Marburg, 35037 Marburg, Germany; (S.L.); (T.M.G.)
| | - Christian Fottner
- Department of Internal Medicine I, Endocrinology, University Hospital Mainz, 55131 Mainz, Germany;
| | - Harald Lahner
- Department of Endocrinology and Metabolism, University Hospital of Essen, 45147 Essen, Germany;
| | - Henning Jann
- Department of Gastroenterology and Hepatology, Campus Virchow Klinikum, University Medicine Charité, 10117 Berlin, Germany;
| | | | - Detlef Quietzsch
- Praxis Dr. med. habil. Diener, 09376 Oelsnitz/Erzgebirge, Germany;
| | - Patricia Grabowski
- Klinikum Havelhöhe, Campus Virchow Klinikum, Institute of Medical Immunology, MVZ Oncology, University Medicine Charité, 10117 Berlin, Germany;
| | - Birgit Cremer
- Department of Oncology, University Hospital of Cologne, 50923 Cologne, Germany;
| | - Sebastian Maasberg
- Department of Internal Medicine and Gastroenterology, Asklepios Klinik St. Georg, 20099 Hamburg, Germany; (S.M.); (U.-F.P.)
| | - Ulrich-Frank Pape
- Department of Internal Medicine and Gastroenterology, Asklepios Klinik St. Georg, 20099 Hamburg, Germany; (S.M.); (U.-F.P.)
| | - Hans-Helge Mueller
- Institute of Medical Biometry and Epidemiology, Philipps University Marburg, 35037 Marburg, Germany;
| | - Thomas Matthias Gress
- UKGM Marburg, Department of Gastroenterology, Philipps University Marburg, 35037 Marburg, Germany; (S.L.); (T.M.G.)
| | - Anja Rinke
- UKGM Marburg, Department of Gastroenterology, Philipps University Marburg, 35037 Marburg, Germany; (S.L.); (T.M.G.)
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23
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Wang R, Li J, Zhang C, Guan X, Qin B, Jin R, Qin L, Xu S, Zhang X, Liu R, Ye Q, Cheng L. Lactate Dehydrogenase B Is Required for Pancreatic Cancer Cell Immortalization Through Activation of Telomerase Activity. Front Oncol 2022; 12:821620. [PMID: 35669414 PMCID: PMC9163669 DOI: 10.3389/fonc.2022.821620] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 04/22/2022] [Indexed: 11/13/2022] Open
Abstract
Telomerase activity is elevated in most cancer cells and is required for telomere length maintenance and immortalization of cancer cells. Glucose metabolic reprogramming is a hallmark of cancer and accompanied with increased expression of key metabolic enzymes. Whether these enzymes influence telomerase activity and cell immortalization remains unclear. In the current study, we screened metabolic enzymes using telomerase activity assay and identified lactate dehydrogenase B (LDHB) as a regulator of telomerase activity. Sodium lactate and sodium pyruvate did not influence telomerase activity, indicating LDHB regulates telomerase activity independent of its metabolism regulating function. Further studies revealed that LDHB directly interacted with TERT and regulated the interaction between TERT and TERC. Additionally, long-term knockdown of LDHB inhibited cancer cell growth and induced cell senescence in vitro and in vivo. Higher LDHB expression was detected in pancreatic cancer tissues compared with that in adjacent normal tissues and expression of LDHB correlated negatively with prognosis. Thus, we identified LDHB as the first glucose metabolic enzyme contributing to telomerase activity and pancreatic cancer cell immortalization.
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Affiliation(s)
- Ruiguan Wang
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Department of Hepatobiliary Surgery, the Eight Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Jiangbo Li
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Changjian Zhang
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
- Senior Department of Otolaryngology-Head & Neck Surgery, the Sixth Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Xin Guan
- Strategic Support Force Medical Center, Beijing, China
| | - Boyu Qin
- Department of Medical Oncology, the First Medical Centre, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Rui Jin
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Lingmei Qin
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Shanrong Xu
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
- School of Life Science, Anqing Normal University, Anqing, China
| | - Xiaona Zhang
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
- College of Life Sciences, Capital Normal University, Beijing, China
| | - Rong Liu
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Department of Hepatobiliary Surgery, the Eight Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- *Correspondence: Long Cheng, ; Qinong Ye, ; Rong Liu,
| | - Qinong Ye
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
- *Correspondence: Long Cheng, ; Qinong Ye, ; Rong Liu,
| | - Long Cheng
- Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
- *Correspondence: Long Cheng, ; Qinong Ye, ; Rong Liu,
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24
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Shindo M, Maeda M, Myat K, Mane MM, Cohen IJ, Vemuri K, Albeg AS, Serganova I, Blasberg R. LDH-A—Modulation and the Variability of LDH Isoenzyme Profiles in Murine Gliomas: A Link with Metabolic and Growth Responses. Cancers (Basel) 2022; 14:cancers14092303. [PMID: 35565432 PMCID: PMC9100845 DOI: 10.3390/cancers14092303] [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: 12/04/2021] [Revised: 04/11/2022] [Accepted: 04/28/2022] [Indexed: 02/04/2023] Open
Abstract
Three murine glioma cell lines (GL261, CT2A, and ALTS1C1) were modified to downregulate the expression of the murine LDH-A gene using shRNA, and compared to shRNA scrambled control (NC) cell lines. Differences in the expression of LDH-A and LDH-B mRNA, protein and enzymatic activity, as well as their LDH isoenzyme profiles, were observed in the six cell lines, and confirmed successful LDH-A KD. LDH-A KD (knock-down) resulted in metabolic changes in cells with a reduction in glycolysis (GlycoPER) and an increase in basal respiratory rate (mitoOCR). GL261 cells had a more limited ATP production capacity compared to CT2A and ALTS1C1 cells. An analysis of mRNA expression data indicated that: (i) GL261 LDH-A KD cells may have an improved ability to metabolize lactate into the TCA cycle; and (ii) that GL261 LDH-A KD cells can upregulate lipid metabolism/fatty acid oxidation pathways, whereas the other glioma cell lines do not have this capacity. These two observations suggest that GL261 LDH-A KD cells can develop/activate alternative metabolic pathways for enhanced survival in a nutrient-limited environment, and that specific nutrient limitations have a variable impact on tumor cell metabolism and proliferation. The phenotypic effects of LDH-A KD were compared to those in control (NC) cells and tumors. LDH-A KD prolonged the doubling time of GL261 cells in culture and prevented the formation of subcutaneous flank tumors in immune-competent C57BL/6 mice, whereas GL261 NC tumors had a prolonged growth delay in C57BL/6 mice. In nude mice, both LDH-A KD and NC GL261 tumors grew rapidly (more rapidly than GL261 NC tumors in C57BL/6 mice), demonstrating the impact of an intact immune system on GL261 tumor growth. No differences between NC and KD cell proliferation (in vitro) or tumor growth in C57BL/6 mice (doubling time) were observed for CT2A and ALTS1C1 cells and tumors, despite the small changes to their LDH isoenzyme profiles. These results suggest that GL261 glioma cells (but not CT2A and ALTS1C1 cells) are pre-programmed to have the capacity for activating different metabolic pathways with higher TCA cycle activity, and that this capacity is enhanced by LDH-A depletion. We observed that the combined impact of LDH-A depletion and the immune system had a significant impact on the growth of subcutaneous-located GL261 tumors.
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Affiliation(s)
- Masahiro Shindo
- Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 52, New York, NY 10065, USA; (M.S.); (M.M.); (K.M.); (M.M.M.); (K.V.); (A.S.A.); (I.S.)
- Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
- Department of Neurosurgery, Nozaki Tokushukai Hospital, Osaka 5740074, Japan
| | - Masatomo Maeda
- Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 52, New York, NY 10065, USA; (M.S.); (M.M.); (K.M.); (M.M.M.); (K.V.); (A.S.A.); (I.S.)
- Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
- Department of Neurosurgery, Nozaki Tokushukai Hospital, Osaka 5740074, Japan
| | - Ko Myat
- Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 52, New York, NY 10065, USA; (M.S.); (M.M.); (K.M.); (M.M.M.); (K.V.); (A.S.A.); (I.S.)
- Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Mayuresh M. Mane
- Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 52, New York, NY 10065, USA; (M.S.); (M.M.); (K.M.); (M.M.M.); (K.V.); (A.S.A.); (I.S.)
- Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Ivan J. Cohen
- Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
- Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kiranmayi Vemuri
- Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 52, New York, NY 10065, USA; (M.S.); (M.M.); (K.M.); (M.M.M.); (K.V.); (A.S.A.); (I.S.)
- Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
- Department of Genetics, Rutgers University, New Brunswick, NJ 08901, USA
| | - Avi S. Albeg
- Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 52, New York, NY 10065, USA; (M.S.); (M.M.); (K.M.); (M.M.M.); (K.V.); (A.S.A.); (I.S.)
- Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - Inna Serganova
- Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 52, New York, NY 10065, USA; (M.S.); (M.M.); (K.M.); (M.M.M.); (K.V.); (A.S.A.); (I.S.)
- Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Ronald Blasberg
- Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 52, New York, NY 10065, USA; (M.S.); (M.M.); (K.M.); (M.M.M.); (K.V.); (A.S.A.); (I.S.)
- Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Correspondence: ; Tel.: +1-212-639-2211
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25
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Riedel A, Helal M, Pedro L, Swietlik JJ, Shorthouse D, Schmitz W, Haas L, Young T, da Costa ASH, Davidson S, Bhandare P, Wolf E, Hall BA, Frezza C, Oskarsson T, Shields JD. Tumor-Derived Lactic Acid Modulates Activation and Metabolic Status of Draining Lymph Node Stroma. Cancer Immunol Res 2022; 10:482-497. [PMID: 35362044 DOI: 10.1158/2326-6066.cir-21-0778] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/13/2021] [Accepted: 02/16/2022] [Indexed: 01/21/2023]
Abstract
Communication between tumors and the stroma of tumor-draining lymph nodes (TDLN) exists before metastasis arises, altering the structure and function of the TDLN niche. Transcriptional profiling of fibroblastic reticular cells (FRC), the dominant stromal population of lymph nodes, has revealed that FRCs in TDLNs are reprogrammed. However, the tumor-derived factors driving the changes in FRCs remain to be identified. Taking an unbiased approach, we have shown herein that lactic acid (LA), a metabolite released by cancer cells, was not only secreted by B16.F10 and 4T1 tumors in high amounts, but also that it was enriched in TDLNs. LA supported an upregulation of Podoplanin (Pdpn) and Thy1 and downregulation of IL7 in FRCs of TDLNs, making them akin to activated fibroblasts found at the primary tumor site. Furthermore, we found that tumor-derived LA altered mitochondrial function of FRCs in TDLNs. Thus, our results demonstrate a mechanism by which a tumor-derived metabolite connected with a low pH environment modulates the function of fibroblasts in TDLNs. How lymph node function is perturbed to support cancer metastases remains unclear. The authors show that tumor-derived LA drains to lymph nodes where it modulates the function of lymph node stromal cells, prior to metastatic colonization.
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Affiliation(s)
- Angela Riedel
- Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.,MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom.,The Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.,Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Moutaz Helal
- Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany
| | - Luisa Pedro
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom
| | - Jonathan J Swietlik
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom
| | - David Shorthouse
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom
| | - Werner Schmitz
- Institute for Biochemistry and Molecular Biology, Theodor Boveri Institute, University of Würzburg, Würzburg, Germany
| | - Lisa Haas
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom
| | - Timothy Young
- Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Ana S H da Costa
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom
| | - Sarah Davidson
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom
| | - Pranjali Bhandare
- Cancer Systems Biology Group, Theodor Boveri Institute, University of Würzburg, Würzburg, Germany
| | - Elmar Wolf
- Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.,Cancer Systems Biology Group, Theodor Boveri Institute, University of Würzburg, Würzburg, Germany
| | - Benjamin A Hall
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom
| | - Christian Frezza
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom
| | - Thordur Oskarsson
- The Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.,Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jacqueline D Shields
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom
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Kooshki L, Mahdavi P, Fakhri S, Akkol EK, Khan H. Targeting lactate metabolism and glycolytic pathways in the tumor microenvironment by natural products: A promising strategy in combating cancer. Biofactors 2022; 48:359-383. [PMID: 34724274 DOI: 10.1002/biof.1799] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 10/06/2021] [Indexed: 12/12/2022]
Abstract
Anticancer drugs are not purely effective because of their toxicity, side effects, high cost, inaccessibility, and associated resistance. On the other hand, cancer is a complex public health problem that could intelligently adopt different signaling pathways and alter the body's metabolism to escape from the immune system. One of the cancer strategies to metastasize is modifying pH in the tumor microenvironment, ranging between 6.5 and 6.9. As a powerful determiner, lactate is responsible for this acidosis. It is involved in immune stimulation, including innate and adaptive immunity, apoptotic-related factors (Bax/Bcl-2, caspase), and glycolysis pathways (e.g., GLUT-1, PKM2, PFK, HK2, MCT-1, and LDH). Lactate metabolism, in turn, is interconnected with several dysregulated signaling mediators, including PI3K/Akt/mTOR, AMPK, NF-κB, Nrf2, JAK/STAT, and HIF-1α. Because of lactate's emerging and critical role, targeting lactate production and its transporters is important for preventing and managing tumorigenesis. Hence, exploring and developing novel promising anticancer agents to minimize human cancers is urgent. Based on numerous studies, natural secondary metabolites as multi-target alternative compounds with health-promoting properties possess more high effectiveness and low side effects than conventional agents. Besides, the mechanism of multi-targeted natural sources is related to lactate production and cancer-associated cross-talked factors. This review focuses on targeting the lactate metabolism/transporters, and lactate-associated mediators, including glycolytic pathways. Besides, interconnected mediators to lactate metabolism are also targeted by natural products. Accordingly, plant-derived secondary metabolites are introduced as alternative therapies in combating cancer through modulating lactate metabolism and glycolytic pathways.
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Affiliation(s)
- Leila Kooshki
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
- USERN Office, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Parisa Mahdavi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Esra Küpeli Akkol
- Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara, Turkey
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
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Baryła M, Semeniuk-Wojtaś A, Róg L, Kraj L, Małyszko M, Stec R. Oncometabolites-A Link between Cancer Cells and Tumor Microenvironment. BIOLOGY 2022; 11:biology11020270. [PMID: 35205136 PMCID: PMC8869548 DOI: 10.3390/biology11020270] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/31/2022] [Accepted: 02/02/2022] [Indexed: 12/12/2022]
Abstract
The tumor microenvironment is the space between healthy tissues and cancer cells, created by the extracellular matrix, blood vessels, infiltrating cells such as immune cells, and cancer-associated fibroblasts. These components constantly interact and influence each other, enabling cancer cells to survive and develop in the host organism. Accumulated intermediate metabolites favoring dysregulation and compensatory responses in the cell, called oncometabolites, provide a method of communication between cells and might also play a role in cancer growth. Here, we describe the changes in metabolic pathways that lead to accumulation of intermediate metabolites: lactate, glutamate, fumarate, and succinate in the tumor and their impact on the tumor microenvironment. These oncometabolites are not only waste products, but also link all types of cells involved in tumor survival and progression. Oncometabolites play a particularly important role in neoangiogenesis and in the infiltration of immune cells in cancer. Oncometabolites are also associated with a disrupted DNA damage response and make the tumor microenvironment more favorable for cell migration. The knowledge summarized in this article will allow for a better understanding of associations between therapeutic targets and oncometabolites, as well as the direct effects of these particles on the formation of the tumor microenvironment. In the future, targeting oncometabolites could improve treatment standards or represent a novel method for fighting cancer.
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Affiliation(s)
- Maksymilian Baryła
- Department of Oncology, Medical University of Warsaw, 02-097 Warsaw, Poland; (M.B.); (L.R.); (L.K.); (M.M.); (R.S.)
| | - Aleksandra Semeniuk-Wojtaś
- Department of Oncology, Medical University of Warsaw, 02-097 Warsaw, Poland; (M.B.); (L.R.); (L.K.); (M.M.); (R.S.)
- Correspondence:
| | - Letycja Róg
- Department of Oncology, Medical University of Warsaw, 02-097 Warsaw, Poland; (M.B.); (L.R.); (L.K.); (M.M.); (R.S.)
| | - Leszek Kraj
- Department of Oncology, Medical University of Warsaw, 02-097 Warsaw, Poland; (M.B.); (L.R.); (L.K.); (M.M.); (R.S.)
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Jastrzębiec, Poland
| | - Maciej Małyszko
- Department of Oncology, Medical University of Warsaw, 02-097 Warsaw, Poland; (M.B.); (L.R.); (L.K.); (M.M.); (R.S.)
| | - Rafał Stec
- Department of Oncology, Medical University of Warsaw, 02-097 Warsaw, Poland; (M.B.); (L.R.); (L.K.); (M.M.); (R.S.)
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Hippocalcin-like 1 is a key regulator of LDHA activation that promotes the growth of non-small cell lung carcinoma. Cell Oncol (Dordr) 2022; 45:179-191. [PMID: 35102488 DOI: 10.1007/s13402-022-00661-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/17/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Hippocalcin-like 1 (HPCAL1), a neuronal calcium sensor protein family member, has been reported to regulate cancer growth. As yet, however, the biological functions of HPCAL1 and its molecular mechanisms have not been investigated in non-small cell lung carcinoma (NSCLC). METHODS HPCAL1 expression in NSCLC samples was detected using immunohistochemistry, Western blotting and RT-PCR. The anticancer effects of HPCAL1 knockdown were determined by MTT, soft agar, cell cycle, oxygen consumption and reactive oxygen species assays. The effect of HPCAL1 knockdown on in vivo tumor growth was assessed using NSCLC cancer patient-derived xenograft models. Potentially interacting protein partners of HPCAL1 were identified using IP-MS/MS, immunoprecipitation and Western blotting assays. Metabolic alterations resulting from HPCAL1 knockdown were investigated using non-targeted metabolomics and RNA sequencing analyses. RESULTS We found that HPCAL1 is highly expressed in NSCLC tissues and is positively correlated with low survival rates and AJCC clinical staging in lung cancer patients. Knockdown of HPCAL1 strongly increased oxygen consumption rates and the production of reactive oxygen species. HPCAL1 knockdown also inhibited NSCLC cell growth and patient-derived NSCLC tumor growth in vivo. Mechanistically, we found that HPCAL1 can directly bind to LDHA and enhance SRC-mediated phosphorylation of LDHA at tyrosine 10. The metabolomics and RNA sequencing analyses indicated that HPCAL1 knockdown reduces amino acid levels and induces fatty acid synthesis through regulating the expression of metabolism-related genes. Additionally, rescued cells expressing wild-type or mutant LDHA in HPCAL1 knockdown cells suggest that LDHA may serve as the main substrate of HPCAL1. CONCLUSIONS Our data indicate that the effect of HPCAL1 knockdown on reducing SRC-mediated LDHA activity attenuates NSCLC growth. Our findings reveal novel biological functions and a mechanism underlying the role of HPCAL1 in NSCLC growth in vitro and in vivo.
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[OVERALL SURVIVAL EVALUATION OF PROSTATE CANCER PATIENTS TREATED WITH ANDROGEN DEPRIVATION THERAPY BY ESTIMATING FLUCTUANT PATTERNS OF METABOLIC FACTOR SERUM LEVELS]. Nihon Hinyokika Gakkai Zasshi 2022; 113:1-11. [PMID: 36682805 DOI: 10.5980/jpnjurol.113.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
(Background) The effects of fluctuant patterns of serum alkaline phosphatase (ALP) and lactic acid dehydrogenase (LDH) levels on overall survival of patients with prostate cancer (PC) treated with androgen deprivation therapy (ADT) remain unclear. (Methods) We enrolled 236 patients with PC and divided into 3 cohorts by fluctuant patterns of serum levels of ALP and LDH between at baseline and at 1 year later, or at diagnosis of castration-resistant prostate cancer (CRPC): intermediate, within interquartile range (IQR) [I]; lower than IQR [L]; higher than IQR [H]. (Results) In the 1 year later ALP cohort, all parameters except age were significantly different. In the L cohort, 75% of patients had bone metastasis and > 50% developed CRPC or died. In the 1 year later LDH cohort, Eastern Cooperative Oncology Group-performance status (ECOG-PS) and clinical metastasis classification were significantly different among the cohorts. In the CRPC/ALP cohorts, baseline prostate-specific antigen values and clinical metastasis classification were significantly different among the cohorts, and all cases had metastasis in the L cohort. In the CRPC/LDH cohort, the L cohort had higher ECOG-PS and shorter time to CRPC. In the 1 year later ALP cohort, the hazard ratio (HR) for death of the L and H cohort to the I cohort was 3.77 and 2.27, respectively and both were significant. In the CRPC/LDH cohort, the HR for death of L cohort to I cohort was 1.99. (Conclusions) Larger fluctuations in serum ALP and LDH levels were a sign of poorer prognosis, especially for patients in the L cohort.
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Khajah MA, Khushaish S, Luqmani YA. Lactate Dehydrogenase A or B Knockdown Reduces Lactate Production and Inhibits Breast Cancer Cell Motility in vitro. Front Pharmacol 2021; 12:747001. [PMID: 34744727 PMCID: PMC8564068 DOI: 10.3389/fphar.2021.747001] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 10/06/2021] [Indexed: 12/20/2022] Open
Abstract
Background: Lactate dehydrogenase (LDH) plays an important role in cancer pathogenesis and enhanced expression/activity of this enzyme has been correlated with poor prognosis. In this study we determined the expression profile of LDH-A and B in normal as well as in endocrine-resistant and -responsive breast cancer cells and the effect of their knockdown on LDH activity, lactate production, proliferation and cell motility. Methods: Knockdown experiments were performed using siRNA and shRNA. The expression profile of LDH and signaling molecules was determined using PCR and western blotting. Intracellular LDH activity and extracellular lactate levels were measured by a biochemical assay. Cell motility was determined using wound healing, while proliferation was determined using MTT assay. Results: LDH-A was expressed in all of the tested cell lines, while LDH-B was specifically expressed only in normal and endocrine-resistant breast cancer cells. This was correlated with significantly enhanced LDH activity and lactate production in endocrine resistant breast cancer cells when compared to normal or endocrine responsive cancer cells. LDH-A or -B knockdown significantly reduced LDH activity and lactate production, which led to reduced cell motility. Exogenous lactate supplementation enhanced cell motility co-incident with enhanced phosphorylation of ERK1/2 and reduced E-cadherin expression. Also, LDH-A or -B knockdown reduced ERK 1/2 phosphorylation. Conclusion: Enhanced cell motility in endocrine resistant breast cancer cells is at least in part mediated by enhanced extracellular lactate levels, and LDH inhibition might be a promising therapeutic target to inhibit cancer cell motility.
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He M, Chi X, Shi X, Sun Y, Yang X, Wang L, Wang B, Li H. Value of pretreatment serum lactate dehydrogenase as a prognostic and predictive factor for small-cell lung cancer patients treated with first-line platinum-containing chemotherapy. Thorac Cancer 2021; 12:3101-3109. [PMID: 34725930 PMCID: PMC8636211 DOI: 10.1111/1759-7714.13581] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 06/29/2020] [Accepted: 06/30/2020] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND The current study aimed to evaluate the serum pretreatment lactate dehydrogenase (LDH) and overall survival (OS) in small cell lung cancer (SCLC) patients who received first-line platinum-containing chemotherapy. METHODS A total of 234 SCLC patients, who received first-line platinum-based chemotherapy between 2013 and 2018, were retrospectively analyzed. The data of hematological characteristics, age, gender, ECOG score, staging, metastatic site, smoking history, chemotherapy cycle, thoracic radiotherapy and hyponatremia were collected. Overall survival was calculated using the Kaplan-Meier method. The statistically significant factors in the univariate analysis were selected for the multivariate COX model analysis. RESULTS Age, ECOG score, stage, thoracic radiotherapy, hyponatremia, liver metastasis, brain metastasis, bone metastasis, LDH, NSE and neutrophil-to-lymphocyte ratio (NLR) were closely correlated to OS in the univariate analysis. Furthermore, the multivariate analysis revealed that age (<65 years), ECOG score (<2 points), limited-stage (LD), thoracic radiotherapy and LDH <215.70 U/L were the independent prognostic factors for survival. The median OS time was worse for patients with LDH ≥215.70 U/L. In the subgroup analysis, LDH ≥215.70 U/L was significant for survival in both limited and extensive disease. Patients who achieved CR + PR in the first-line treatment had lower initial LDH levels. It was found that the pretreatment LDH increased the incidence of patients with liver metastasis. CONCLUSIONS Positive independent prognostic factors for SCLC patients were age < 65 years old, ECOG score < 2 points, LD-SCLC, and pretreatment LDH <215.70 U/L. These factors may be useful for stratifying patients with SCLC for treatment approaches. KEY POINTS SIGNIFICANT FINDINGS OF THE STUDY: Age < 65 years old, ECOG score < 2 points, LD-SCLC, and pretreatment LDH <215.70 U/L are the positive independent prognostic factors for SCLC patients. WHAT THIS STUDY ADDS The current study provided more references for SCLC diagnosis and treatment and determined more factors for stratifying patients with SCLC for treatment approaches.
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Affiliation(s)
- Man He
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaorui Chi
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xinyan Shi
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yang Sun
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xue Yang
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Leirong Wang
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Bingrui Wang
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hongmei Li
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Ethoxyquin Inhibits the Progression of Murine Ehrlich Ascites Carcinoma through the Inhibition of Autophagy and LDH. Biomedicines 2021; 9:biomedicines9111526. [PMID: 34829755 PMCID: PMC8615101 DOI: 10.3390/biomedicines9111526] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/13/2021] [Accepted: 10/22/2021] [Indexed: 12/20/2022] Open
Abstract
Cancer cells exhibit an increased glycolysis rate for ATP generation (the Warburg effect) to sustain an increased proliferation rate. In tumor cells, the oxidation of pyruvate in the Krebs cycle is substituted by lactate production, catalyzed by LDH. In this study, we use ethoxyquin (EQ) as a novel inhibitor to target LDH in murine Ehrlich ascites carcinoma (EAC) and as a combination therapy to improve the therapeutic efficacy of the conventional chemotherapy drug, cisplatin (CIS). We investigated the anti-tumor effect of EQ on EAC-bearing mice and checked whether EQ can sustain the anti-tumor potential of CIS and whether it influences LDH activity. Treatment with EQ had evident anti-tumor effects on EAC as revealed by the remarkable decrease in the expression of the anti-apoptotic gene Bcl-2 and by a significant increase in the expression of apoptotic genes (BAX and caspase-3). EQ also caused a significant decrease in the autophagic activity of EAC cells, as shown by a reduction in the fluorescence intensity of the autophagosome marker. Additionally, EQ restored the altered hematological and biochemical parameters and improved the disrupted hepatic tissues of EAC-bearing mice. Co-administration of EQ and CIS showed the highest anti-tumor effect against EAC. Collectively, our findings propose EQ as a novel inhibitor of LDH in cancer cells and as a combinatory drug to increase the efficacy of cisplatin. Further studies are required to validate this therapeutic strategy in different cancer models and preclinical trials.
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Bai L, Lin ZY, Lu YX, Chen Q, Zhou H, Meng Q, Lin CP, Huang WL, Wan YL, Pan ZZ, Wang DS. The prognostic value of preoperative serum lactate dehydrogenase levels in patients underwent curative-intent hepatectomy for colorectal liver metastases: A two-center cohort study. Cancer Med 2021; 10:8005-8019. [PMID: 34636145 PMCID: PMC8607270 DOI: 10.1002/cam4.4315] [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: 04/22/2021] [Revised: 08/18/2021] [Accepted: 09/08/2021] [Indexed: 12/13/2022] Open
Abstract
Background The prognostic value of lactate dehydrogenase (LDH) in colorectal cancer patients has remained inconsistent between nonmetastatic and metastatic settings. So far, very few studies have included LDH in the prognostic analysis of curative‐intent surgery for colorectal liver metastases (CRLM). Patients and Methods Five hundred and eighty consecutive metastatic colorectal cancer patients who underwent curative‐intent CRLM resection from Sun Yat‐sen University Cancer Center (434 patients) and Sun Yat‐sen University Sixth Affiliated Hospital (146 patients) in 2000–2019 were retrospectively collected. Overall survival (OS) was the primary end point. Cox regression model was performed to identify the prognostic values of preoperative serum LDH levels and other clinicopathology variables. A modification of the established Fong CRS scoring system comprising LDH was developed within this Chinese population. Results At the median follow‐up time of 60.5 months, median OS was 59.5 months in the pooled cohort. In the multivariate analysis, preoperative LDH >upper limit of normal (250 U/L) was the strongest independent prognostic factor for OS (HR 1.73, 95% confidence interval [CI], 1.22–2.44; p < 0.001). Patients with elevated LDH levels showed impaired OS than patients with normal LDH levels (27.6 months vs. 68.8 months). Five‐year survival rates were 53.7% and 22.5% in the LDH‐normal group and LDH‐high group, respectively. Similar results were also confirmed in each cohort. In the subgroup analysis, LDH could distinguish the survival regardless of most established prognostic factors (number and size of CRLM, surgical margin, extrahepatic metastases, CEA, and CA19‐9 levels, etc.). Integrating LDH into the Fong score contributed to an improvement in the predictive value. Conclusion Our study implicates serum LDH as a reliable and independent laboratory biomarker to predict the clinical outcome of curative‐intent surgery for CRLM. Composite of LDH and Fong score is a potential stratification tool for CRLM resection. Prospective, international studies are needed to validate these results across diverse populations.
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Affiliation(s)
- Long Bai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China.,Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China.,Department of VIP region, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Ze-Yu Lin
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yun-Xin Lu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China.,Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China.,Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Qin Chen
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Han Zhou
- Department of Medical Administration, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qi Meng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China.,Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China.,Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Chun-Ping Lin
- Department of Oncology, Jieyang Affiliated Hospital, Sun Yat-sen University, Jieyang, China
| | - Wan-Lan Huang
- Department of Oncology, Jieyang Affiliated Hospital, Sun Yat-sen University, Jieyang, China
| | - Yun-Le Wan
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhi-Zhong Pan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China.,Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China.,Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - De-Shen Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China.,Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China.,Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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Long Term Survival With Regorafenib: REALITY (Real Life in Italy) Trial - A GISCAD Study. Clin Colorectal Cancer 2021; 20:e253-e262. [PMID: 34429245 DOI: 10.1016/j.clcc.2021.07.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 07/06/2021] [Accepted: 07/13/2021] [Indexed: 11/20/2022]
Abstract
BACKGROUND Regorafenib is a key agent in metastatic colorectal cancer (mCRC), but no validated factors predicting longer survival are available. PATIENTS AND METHODS REALITY was a retrospective multicenter trial in regorafenib-treated mCRC patients with overall survival (OS) ≥ 6 months. We aimed to assess the association between clinical parameters and outcome to define a panel identifying long term survivors among regorafenib candidates. Primary and secondary endpoints were OS and progression free survival (PFS), respectively. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; independent role of significant variables at univariate analysis: logistic regression). RESULTS Hundred regorafenib-treated mCRC patients with OS ≥ 6 months were enrolled. Median OS was 11.5 m (95%CI:9.60-12.96); median PFS was 4.2 months (95% CI:3.43-43.03). The absence of liver progression and of dose and/or schedule changes during the first 4 cycles (mainly for good tolerability) were independently correlated at multivariate analysis with OS (Exp(b)1.8869, P= .0277and Exp(b)2.2000, P = .0313) and PFS (Exp(b)2.1583, P = .0065 and Exp(b)2.3036, P= .0169). Patients with neither of these variables had a significantly improved OS (n = 14, 20.8 months; 95% CI:12.967-55.267) versus others (n = 86, 10 months; 95% CI:8.367-12.167; HR = 0.4902, P = .0045) and PFS (11.3 months, 95%CI:4.267-35.8 vs. 3.9 months, 95% CI:3.167-43.033; HR = 0.4648, P = .0086). CONCLUSION These 2 factors might allow clinicians to better identify patients more likely to benefit from regorafenib. Toxicity management remains crucial.
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Wu H, Wang Y, Ying M, Jin C, Li J, Hu X. Lactate dehydrogenases amplify reactive oxygen species in cancer cells in response to oxidative stimuli. Signal Transduct Target Ther 2021; 6:242. [PMID: 34176927 PMCID: PMC8236487 DOI: 10.1038/s41392-021-00595-3] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 03/11/2021] [Accepted: 03/30/2021] [Indexed: 12/21/2022] Open
Abstract
Previous studies demonstrated that superoxide could initiate and amplify LDH-catalyzed hydrogen peroxide production in aqueous phase, but its physiological relevance is unknown. Here we showed that LDHA and LDHB both exhibited hydrogen peroxide-producing activity, which was significantly enhanced by the superoxide generated from the isolated mitochondria from HeLa cells and patients' cholangiocarcinoma specimen. After LDHA or LDHB were knocked out, hydrogen peroxide produced by Hela or 4T1 cancer cells were significantly reduced. Re-expression of LDHA in LDHA-knockout HeLa cells partially restored hydrogen peroxide production. In HeLa and 4T1 cells, LDHA or LDHB knockout or LDH inhibitor FX11 significantly decreased ROS induction by modulators of the mitochondrial electron transfer chain (antimycin, oligomycin, rotenone), hypoxia, and pharmacological ROS inducers piperlogumine (PL) and phenethyl isothiocyanate (PEITC). Moreover, the tumors formed by LDHA or LDHB knockout HeLa or 4T1 cells exhibited a significantly less oxidative state than those formed by control cells. Collectively, we provide a mechanistic understanding of a link between LDH and cellular hydrogen peroxide production or oxidative stress in cancer cells in vitro and in vivo.
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Grants
- This work has been supported in part by the China National 973 project (2013CB911303), China Natural Sciences Foundation projects (81470126), a key project (2018C03009) funded by Zhejiang Provincial Department of Sciences and Technologies, and the Fundamental Research Funds for the Central Universities (2017XZZX001-012019FZJD009), National Ministry of Education, China, to XH, and Zhejiang Provincial Natural Science Foundation of China (LY17H160036), the Fundamental Research Funds for the Central Universities (2017FZA7010) and China Natural Sciences Foundation project (81301707), to HW.
- Zhejiang Provincial Natural Science Foundation of China (LY17H160036), the Fundamental Research Funds for the Central Universities and China Natural Sciences Foundation project 2017FZA7010, to HW.
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Affiliation(s)
- Hao Wu
- Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuqi Wang
- Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Minfeng Ying
- Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chengmeng Jin
- Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiangtao Li
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xun Hu
- Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22126434. [PMID: 34208601 PMCID: PMC8234711 DOI: 10.3390/ijms22126434] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/04/2021] [Accepted: 06/14/2021] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common aggressive carcinoma types worldwide, characterized by unfavorable curative effect and poor prognosis. Epidemiological data re-vealed that CRC risk is increased in patients with metabolic syndrome (MetS) and its serum components (e.g., hyperglycemia). High glycemic index diets, which chronically raise post-prandial blood glucose, may at least in part increase colon cancer risk via the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. However, the underlying mechanisms linking IGF-1 and MetS are still poorly understood. Hyperactivated glucose uptake and aerobic glycolysis (the Warburg effect) are considered as a one of six hallmarks of cancer, including CRC. However, the role of insulin/IGF-1 signaling during the acquisition of the Warburg metabolic phenotypes by CRC cells is still poorly understood. It most likely results from the interaction of multiple processes, directly or indirectly regulated by IGF-1, such as activation of PI3K/Akt/mTORC, and Raf/MAPK signaling pathways, activation of glucose transporters (e.g., GLUT1), activation of key glycolytic enzymes (e.g., LDHA, LDH5, HK II, and PFKFB3), aberrant expression of the oncogenes (e.g., MYC, and KRAS) and/or overexpression of signaling proteins (e.g., HIF-1, TGF-β1, PI3K, ERK, Akt, and mTOR). This review describes the role of IGF-1 in glucose metabolism in physiology and colorectal carcinogenesis, including the role of the insulin/IGF system in the Warburg effect. Furthermore, current therapeutic strategies aimed at repairing impaired glucose metabolism in CRC are indicated.
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Nenkov M, Ma Y, Gaßler N, Chen Y. Metabolic Reprogramming of Colorectal Cancer Cells and the Microenvironment: Implication for Therapy. Int J Mol Sci 2021; 22:6262. [PMID: 34200820 PMCID: PMC8230539 DOI: 10.3390/ijms22126262] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/07/2021] [Accepted: 06/08/2021] [Indexed: 12/20/2022] Open
Abstract
Colorectal carcinoma (CRC) is one of the most frequently diagnosed carcinomas and one of the leading causes of cancer-related death worldwide. Metabolic reprogramming, a hallmark of cancer, is closely related to the initiation and progression of carcinomas, including CRC. Accumulating evidence shows that activation of oncogenic pathways and loss of tumor suppressor genes regulate the metabolic reprogramming that is mainly involved in glycolysis, glutaminolysis, one-carbon metabolism and lipid metabolism. The abnormal metabolic program provides tumor cells with abundant energy, nutrients and redox requirements to support their malignant growth and metastasis, which is accompanied by impaired metabolic flexibility in the tumor microenvironment (TME) and dysbiosis of the gut microbiota. The metabolic crosstalk between the tumor cells, the components of the TME and the intestinal microbiota further facilitates CRC cell proliferation, invasion and metastasis and leads to therapy resistance. Hence, to target the dysregulated tumor metabolism, the TME and the gut microbiota, novel preventive and therapeutic applications are required. In this review, the dysregulation of metabolic programs, molecular pathways, the TME and the intestinal microbiota in CRC is addressed. Possible therapeutic strategies, including metabolic inhibition and immune therapy in CRC, as well as modulation of the aberrant intestinal microbiota, are discussed.
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Affiliation(s)
| | | | | | - Yuan Chen
- Section Pathology of the Institute of Forensic Medicine, University Hospital Jena, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany; (M.N.); (Y.M.); (N.G.)
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Ji L, Shen W, Zhang F, Qian J, Jiang J, Weng L, Tan J, Li L, Chen Y, Cheng H, Sun D. Worenine reverses the Warburg effect and inhibits colon cancer cell growth by negatively regulating HIF-1α. Cell Mol Biol Lett 2021; 26:19. [PMID: 34006215 PMCID: PMC8130299 DOI: 10.1186/s11658-021-00263-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 05/10/2021] [Indexed: 12/11/2022] Open
Abstract
Background Some natural compounds inhibit cancer cell growth in various cancer cell lines with fewer side effects than traditional chemotherapy. Here, we explore the pharmacological effects and mechanisms of worenine (isolated from Coptis chinensis) against colorectal cancer. Methods The effects of worenine on colorectal cancer cell proliferation, colony formation and cell cycle distribution were measured. Glycolysis was investigated by examining glucose uptake and consumption, lactate production, and the activities and expressions of glycolysis enzymes (PFK-L, HK2 and PKM2). HIF-1α was knocked down and stimulated in vitro to investigate the underlying mechanisms. Results Worenine somewhat altered the glucose metabolism and glycolysis (Warburg effect) of cancer cells. Its anti-cancer effects and capability to reverse the Warburg effect were similar to those of HIF-1α siRNA and weakened by deferoxamine (an HIF-1α agonist). Conclusion It is suggested that worenine targets HIF-1α to inhibit colorectal cancer cell growth, proliferation, cell cycle progression and the Warburg effect. Supplementary Information The online version contains supplementary material available at 10.1186/s11658-021-00263-y.
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Affiliation(s)
- Lijiang Ji
- Changshu TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, 215500, China.,Collaborative Innovation Center of Jiangsu Province of Cancer Prevention and Treatment of Chinese Medicine, Nanjing, 210023, China
| | - Weixing Shen
- Collaborative Innovation Center of Jiangsu Province of Cancer Prevention and Treatment of Chinese Medicine, Nanjing, 210023, China.,The First School of Clinical Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Feng Zhang
- Collaborative Innovation Center of Jiangsu Province of Cancer Prevention and Treatment of Chinese Medicine, Nanjing, 210023, China
| | - Jie Qian
- Collaborative Innovation Center of Jiangsu Province of Cancer Prevention and Treatment of Chinese Medicine, Nanjing, 210023, China
| | - Jie Jiang
- Changshu TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, 215500, China.,Collaborative Innovation Center of Jiangsu Province of Cancer Prevention and Treatment of Chinese Medicine, Nanjing, 210023, China
| | - Liping Weng
- Changshu TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, 215500, China
| | - Jiani Tan
- Collaborative Innovation Center of Jiangsu Province of Cancer Prevention and Treatment of Chinese Medicine, Nanjing, 210023, China.,The First School of Clinical Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Liu Li
- Collaborative Innovation Center of Jiangsu Province of Cancer Prevention and Treatment of Chinese Medicine, Nanjing, 210023, China.,The First School of Clinical Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Yugen Chen
- Collaborative Innovation Center of Jiangsu Province of Cancer Prevention and Treatment of Chinese Medicine, Nanjing, 210023, China.,The First School of Clinical Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Haibo Cheng
- Collaborative Innovation Center of Jiangsu Province of Cancer Prevention and Treatment of Chinese Medicine, Nanjing, 210023, China. .,The First School of Clinical Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
| | - Dongdong Sun
- Collaborative Innovation Center of Jiangsu Province of Cancer Prevention and Treatment of Chinese Medicine, Nanjing, 210023, China. .,School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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Kiran D, Basaraba RJ. Lactate Metabolism and Signaling in Tuberculosis and Cancer: A Comparative Review. Front Cell Infect Microbiol 2021; 11:624607. [PMID: 33718271 PMCID: PMC7952876 DOI: 10.3389/fcimb.2021.624607] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 01/13/2021] [Indexed: 12/16/2022] Open
Abstract
Infection with Mycobacterium tuberculosis (Mtb) leading to tuberculosis (TB) disease continues to be a major global health challenge. Critical barriers, including but not limited to the development of multi-drug resistance, lack of diagnostic assays that detect patients with latent TB, an effective vaccine that prevents Mtb infection, and infectious and non-infectious comorbidities that complicate active TB, continue to hinder progress toward a TB cure. To complement the ongoing development of new antimicrobial drugs, investigators in the field are exploring the value of host-directed therapies (HDTs). This therapeutic strategy targets the host, rather than Mtb, and is intended to augment host responses to infection such that the host is better equipped to prevent or clear infection and resolve chronic inflammation. Metabolic pathways of immune cells have been identified as promising HDT targets as more metabolites and metabolic pathways have shown to play a role in TB pathogenesis and disease progression. Specifically, this review highlights the potential role of lactate as both an immunomodulatory metabolite and a potentially important signaling molecule during the host response to Mtb infection. While long thought to be an inert end product of primarily glucose metabolism, the cancer research field has discovered the importance of lactate in carcinogenesis and resistance to chemotherapeutic drug treatment. Herein, we discuss similarities between the TB granuloma and tumor microenvironments in the context of lactate metabolism and identify key metabolic and signaling pathways that have been shown to play a role in tumor progression but have yet to be explored within the context of TB. Ultimately, lactate metabolism and signaling could be viable HDT targets for TB; however, critical additional research is needed to better understand the role of lactate at the host-pathogen interface during Mtb infection before adopting this HDT strategy.
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Affiliation(s)
| | - Randall J. Basaraba
- Metabolism of Infectious Diseases Laboratory, Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States
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Mattos SECD, Diel LF, Bittencourt LS, Schnorr CE, Gonçalves FA, Bernardi L, Lamers ML. Glycolytic pathway candidate markers in the prognosis of oral squamous cell carcinoma: a systematic review with meta-analysis. ACTA ACUST UNITED AC 2021; 54:e10504. [PMID: 33503201 PMCID: PMC7836401 DOI: 10.1590/1414-431x202010504] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 09/09/2020] [Indexed: 11/22/2022]
Abstract
Molecular changes that affect mitochondrial glycolysis have been associated with the maintenance of tumor cells. Some metabolic factors have already been described as predictors of disease severity and outcomes. This systematic review was conducted to answer the question: Is the glycolytic pathway correlated with the prognosis of oral squamous cell carcinoma (OSCC)? A search strategy was developed to retrieve studies in English from PubMed, Scopus, and ISI Web of Science using keywords related to squamous cell carcinoma, survival, and glycolytic pathway, with no restriction of publication date. The search retrieved 1273 publications. After the titles and abstracts were analyzed, 27 studies met inclusion criteria. Studies were divided into groups according to two subtopics, glycolytic pathways and diagnosis, which describe the glycolytic profile of OSCC tumors. Several components of tumor energy metabolism found in this review are important predictors of survival of patients with OSCC.
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Affiliation(s)
- S E C de Mattos
- Programa de Pós-graduação em Ciências Biológicas, Fisiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - L F Diel
- Faculdade de Odontologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - L S Bittencourt
- Faculdade de Odontologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.,Instituto Federal da Educação, Ciência e Tecnologia do Rio Grande do Sul - Porto Alegre Campus, Porto Alegre, RS, Brasil.,Secretaria de Educação do Estado do Rio Grande do Sul, Escola Técnica em Saúde, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil
| | - C E Schnorr
- Departamento de Ciências Naturales y Exactas, Universidad De La Costa, Barranquilla, Atlántico, Colombia
| | - F A Gonçalves
- Faculdade de Odontologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - L Bernardi
- Faculdade de Odontologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.,Departamento de Ciências Morfológicas, Instituto Básico de Ciências da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - M L Lamers
- Faculdade de Odontologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.,Departamento de Ciências Morfológicas, Instituto Básico de Ciências da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
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Bose S, Zhang C, Le A. Glucose Metabolism in Cancer: The Warburg Effect and Beyond. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1311:3-15. [PMID: 34014531 PMCID: PMC9639450 DOI: 10.1007/978-3-030-65768-0_1] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Otto Warburg observed a peculiar phenomenon in 1924, unknowingly laying the foundation for the field of cancer metabolism. While his contemporaries hypothesized that tumor cells derived the energy required for uncontrolled replication from proteolysis and lipolysis, Warburg instead found them to rapidly consume glucose, converting it to lactate even in the presence of oxygen. The significance of this finding, later termed the Warburg effect, went unnoticed by the broader scientific community at that time. The field of cancer metabolism lay dormant for almost a century awaiting advances in molecular biology and genetics, which would later open the doors to new cancer therapies [2, 3].
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Affiliation(s)
- Sminu Bose
- Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - Cissy Zhang
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Biology, Johns Hopkins University Krieger School of Arts and Sciences, Baltimore, MD, USA
| | - Anne Le
- Department of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD, USA.
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Nanou A, Mol L, Coumans FAW, Koopman M, Punt CJA, Terstappen LWMM. Endothelium-Derived Extracellular Vesicles Associate with Poor Prognosis in Metastatic Colorectal Cancer. Cells 2020; 9:E2688. [PMID: 33333805 PMCID: PMC7765205 DOI: 10.3390/cells9122688] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 12/01/2020] [Accepted: 12/11/2020] [Indexed: 12/14/2022] Open
Abstract
Elevated, tumor-derived extracellular vesicle (tdEV) and circulating tumor cell (CTC) loads in metastatic cancer are associated with poor clinical outcome. Herein, we investigate whether endothelium-derived extracellular vesicles (edEVs) can be detected in the blood of metastatic colorectal cancer (mCRC) patients, and whether those vesicles associate with prognosis. The open-source ACCEPT (Automated CTC Classification, Enumeration, and Phenotyping) software was used to enumerate edEVs, tdEVs, and other objects from digitally stored CellSearch images acquired after CTC and circulating endothelial cell (CEC) enrichment from the blood of 395 mCRC patients before the initiation of a new therapy. Patients had participated in the prospective phase III CAIRO2 study. The presence of edEVs was found 5- to 10-fold higher than CECs. The hazard ratio (HR) (95% CI) of progression-free survival (PFS) for increased CTCs (≥3 in 7.5 mL), tdEVs (≥40 in 7.5 mL), and edEVs (≥287 in 4.0 mL.) was 1.4 (1.1-1.9), 2.0 (1.5-2.6), and 1.7 (1.2-2.5), respectively. The HR of Overall Survival (OS) for increased CTCs, tdEVs and edEVs was 2.2 (1.7-3.0), 2.7 (2.0-3.5), and 2.1 (1.5-2.8), respectively. There was no cut-off value for CECs, leading to a dichotomization of patients with a significant HR. Only tdEVs remained a significant predictor of OS in the final multivariable model.
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Affiliation(s)
- Afroditi Nanou
- Department of Medical Cell BioPhysics, University of Twente, 7522ND Enschede, The Netherlands;
| | - Linda Mol
- Netherlands Comprehensive Cancer Organization, 6533AA Nijmegen, The Netherlands;
| | - Frank A. W. Coumans
- Department of Medical Cell BioPhysics, University of Twente, 7522ND Enschede, The Netherlands;
| | - Miriam Koopman
- Department of Medical Oncology, University Medical Center Utrecht, 3584CS Utrecht, The Netherlands;
| | - Cornelis J. A. Punt
- Julius Center for Health Sciences and Primary Care, Department of Epidemiology, University Medical Center Utrecht, 3584CG Utrecht, The Netherlands;
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Kurilova I, Bendet A, Petre EN, Boas FE, Kaye E, Gonen M, Covey A, Brody LA, Brown KT, Kemeny NE, Yarmohammadi H, Ziv E, D'Angelica MI, Kingham TP, Cercek A, Solomon SB, Beets-Tan RGH, Sofocleous CT. Factors Associated With Local Tumor Control and Complications After Thermal Ablation of Colorectal Cancer Liver Metastases: A 15-year Retrospective Cohort Study. Clin Colorectal Cancer 2020; 20:e82-e95. [PMID: 33246789 DOI: 10.1016/j.clcc.2020.09.005] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 09/03/2020] [Accepted: 09/14/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The purpose of this study was to identify risk factors associated with local tumor progression-free survival (LTPFS) and complications after colorectal liver metastases (CLM) thermal ablation (TA). PATIENTS AND METHODS This retrospective analysis included 286 patients with 415 CLM undergoing TA (radiofrequency and microwave ablation) in 378 procedures from January 2003 to July 2017. Prior hepatic artery infusion (HAI), bevacizumab, pre-existing biliary dilatation, ablation modality, minimal ablation margin (MM), prior hepatectomy, CLM number, and size were analyzed as factors influencing complications and LTPFS. Statistical analysis included the Kaplan-Meier method, Cox proportional hazards model, competing risk analysis, univariate/multivariate logistic/exact logistic regressions, and the Fisher exact test. Complications were reported according to modified Society of Interventional Radiology guidelines. RESULTS The median follow-up was 31 months. There was no LTP for MM > 10 mm. Smaller tumor size, increased MM, and prior hepatectomy correlated with longer LTPFS. The major complications occurred following 28 (7%) of 378 procedures. There were no biliary complications in HAI-naive patients, versus 11% in HAI patients (P < .001), of which 7% were major. Biliary complications predictors in HAI patients included biliary dilatation, bevacizumab, and MM > 10 mm. In HAI patients, ablation with 6 to 10 mm and > 10 mm MM resulted in major biliary complication rates of 4% and 21% (P = .0011), with corresponding LTP rates of 24% and 0% (P = .0033). In HAI-naive patients, the LTP rates for 6 to 10 mm and > 10 mm MM were 27% and 0%, respectively. CONCLUSIONS No LTP was seen for MM > 10 mm. Biliary complications occurred only in HAI patients, especially in those with biliary dilatation, bevacizumab, and MM > 10 mm. In HAI patients, MM of 6 to 10 mm resulted in 76% local tumor control and 4% major biliary complications incidence.
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Affiliation(s)
- Ieva Kurilova
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Radiology, Netherlands Cancer Institute, Amsterdam, The Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Achiude Bendet
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Elena N Petre
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Franz E Boas
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Elena Kaye
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Mithat Gonen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Anne Covey
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Lynn A Brody
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Karen T Brown
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Nancy E Kemeny
- Department of Gastrointestinal Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Hooman Yarmohammadi
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Etay Ziv
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Michael I D'Angelica
- Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - T Peter Kingham
- Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Andrea Cercek
- Department of Gastrointestinal Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Steven B Solomon
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Regina G H Beets-Tan
- Department of Radiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Constantinos T Sofocleous
- Department of Radiology, Interventional Radiology Service, Memorial Sloan Kettering Cancer Center, New York, NY.
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Oncometabolites lactate and succinate drive pro-angiogenic macrophage response in tumors. Biochim Biophys Acta Rev Cancer 2020; 1874:188427. [PMID: 32961257 DOI: 10.1016/j.bbcan.2020.188427] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/21/2020] [Accepted: 09/02/2020] [Indexed: 02/07/2023]
Abstract
Macrophages are innate phagocytic leukocytes that are highly present in solid tumors, where they are referred to as tumor-associated macrophages (TAMs). In solid tumors, the microenvironment is often immunosuppressive and hypoxic regions are prevalent. These hypoxic conditions impose tumor cells to reprogram their metabolism, shifting from oxidative phosphorylation to anaerobic glycolysis. This so-called glycolytic switch enables hypoxic tumor cells to survive, proliferate, and eventually to outcompete untransformed cells. The hypoxia-induced change in tumor cell metabolism leads to the production of oncometabolites, among which are the glycolytic end-metabolite lactate and the tricarboxylic acid cycle intermediate succinate. TAMs can react to these oncometabolites, resulting in an altered maturation and the adoption of pro-angiogenic features. These angiogenesis-promoting TAMs have been reported to cooperate with tumor cells in the formation of new vessels, and even have been considered an important cause of resistance against anti-angiogenic therapies. For a long time, the mechanisms by which lactate and succinate activated pro-angiogenic TAMs were not understood. Researchers now start to unravel and understand some of the underlying mechanisms. Here, the importance of microenvironmental cues in inducing different macrophage activation states is discussed, as well as the role of hypoxia in the recruitment and activation of pro-angiogenic macrophages. In addition, the latest findings on the oncometabolites lactate and succinate in the activation of angiogenesis supporting macrophages are reviewed. Finally, various oncometabolite-targeting therapeutic strategies are proposed that could improve the response to anti-angiogenic therapies. SIGNIFICANCE STATEMENT: Tumor-associated macrophages (TAMs) are known promotors of tumor neovascularization, and significantly contribute to the emergence of resistance to anti-angiogenic therapies. Recent evidence suggests that the angiogenesis promoting phenotype of TAMs can be activated by hypoxic tumor cell-derived oncometabolites, including lactate and succinate. Here, the latest findings into the lactate- and succinate-mediated mechanistic activation of pro-angiogenic TAMs are reviewed, and therapeutic strategies that interfere with this mechanism and may delay or even prevent acquired resistance to anti-angiogenic agents are discussed.
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Lisanti C, Basile D, Parnofiello A, Bertoli E, Andreotti VJ, Garattini SK, Bartoletti M, Cattaneo M, Di Nardo P, Bonotto M, Casagrande M, Da Ros L, Cinausero M, Foltran L, Pella N, Buonadonna A, Aprile G, Fasola G, Puglisi F. The SENECA study: Prognostic role of serum biomarkers in older patients with metastatic colorectal cancer. J Geriatr Oncol 2020; 11:1268-1273. [PMID: 32576519 DOI: 10.1016/j.jgo.2020.06.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/27/2020] [Accepted: 06/03/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Aging induces meaningful changes in the immune system and inflammation response with increase in monocyte-lymphocyte ratio (MLR) and serum lactate dehydrogenase (LDH) levels. Aim of this study was to explore the prognostic role of MLR and LDH levels in older patients (pts) with metastatic colorectal cancer (mCRC). METHODS We conducted a retrospective analysis of a consecutive cohort of 168 older (>70 years) patients with mCRC. The prognostic impact of MLR and LDH levels on overall survival (OS) was investigated through uni-and multivariate Cox regression analyses. Moreover, we categorized patients into three groups according to MLR and LDH levels (group 1: MLR-low and LDH-low; group 2: MLR-high or LDH-high; group 3: MLR-high and LDH-high). RESULTS By univariate analysis, high LDH level (HR 1.74, 95% CI 1.05-2.90) and high MLR level (HR 2.19, 95% CI 1.48-3.44) were significantly associated with a worse OS. Conversely, primary tumor resection and left-sidedness were significantly associated with a longer OS. By multivariate analysis, high LDH level (HR 2.00, 95% CI 1.13-3.55) and high MLR level (HR 2.99, 95% CI 1.68-5.33) were independent prognostic factors of worse prognosis. Compared to group 1, a shorter survival was reported for patients included in group 2 (HR 1.97, 95% CI 1.21-3.23 in univariate; HR 2.54, 95% CI 1.43-4.51 in multivariate) or in group 3 (HR 2.42, 95% CI 24-4.74, p = .010 in univariate; HR 5.59, 95% CI 2.15-14.54 in multivariate) CONCLUSIONS: High baseline levels of LDH, MLR or both are independent unfavorable prognostic factors in older patients treated with first-line chemotherapy for mCRC.
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Affiliation(s)
- Camilla Lisanti
- Department of Medicine (DAME), University of Udine, Udine, IT, Italy; Department of Medical Oncology, Unit of medical oncology and cancer prevention, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, IT, Italy
| | - Debora Basile
- Department of Medicine (DAME), University of Udine, Udine, IT, Italy; Department of Medical Oncology, Unit of medical oncology and cancer prevention, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, IT, Italy.
| | - Annamaria Parnofiello
- Department of Medicine (DAME), University of Udine, Udine, IT, Italy; Department of Medical Oncology, Unit of medical oncology and cancer prevention, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, IT, Italy
| | - Elisa Bertoli
- Department of Medicine (DAME), University of Udine, Udine, IT, Italy; Department of Oncology, ASUIUD Santa Maria della Misericordia, Udine, IT, Italy
| | - Victoria Josephine Andreotti
- Department of Medicine (DAME), University of Udine, Udine, IT, Italy; Department of Oncology, ASUIUD Santa Maria della Misericordia, Udine, IT, Italy
| | - Silvio Ken Garattini
- Department of Medicine (DAME), University of Udine, Udine, IT, Italy; Department of Oncology, ASUIUD Santa Maria della Misericordia, Udine, IT, Italy
| | - Michele Bartoletti
- Department of Medicine (DAME), University of Udine, Udine, IT, Italy; Department of Medical Oncology, Unit of medical oncology and cancer prevention, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, IT, Italy
| | - Monica Cattaneo
- Department of Medicine (DAME), University of Udine, Udine, IT, Italy; Department of Oncology, ASUIUD Santa Maria della Misericordia, Udine, IT, Italy
| | - Paola Di Nardo
- Department of Medical Oncology, Unit of medical oncology and cancer prevention, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, IT, Italy
| | - Marta Bonotto
- Department of Oncology, ASUIUD Santa Maria della Misericordia, Udine, IT, Italy
| | | | - Lucia Da Ros
- Department of Medical Oncology, Unit of medical oncology and cancer prevention, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, IT, Italy
| | - Marika Cinausero
- Department of Oncology, ASUIUD Santa Maria della Misericordia, Udine, IT, Italy
| | - Luisa Foltran
- Department of Medical Oncology, Unit of medical oncology and cancer prevention, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, IT, Italy
| | - Nicoletta Pella
- Department of Oncology, ASUIUD Santa Maria della Misericordia, Udine, IT, Italy
| | - Angela Buonadonna
- Department of Medical Oncology, Unit of medical oncology and cancer prevention, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, IT, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8 Berica, Vicenza, Italy
| | - Gianpiero Fasola
- Department of Oncology, ASUIUD Santa Maria della Misericordia, Udine, IT, Italy
| | - Fabio Puglisi
- Department of Medicine (DAME), University of Udine, Udine, IT, Italy; Department of Medical Oncology, Unit of medical oncology and cancer prevention, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, IT, Italy
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Zhu WW, Lu M, Wang XY, Zhou X, Gao C, Qin LX. The fuel and engine: The roles of reprogrammed metabolism in metastasis of primary liver cancer. Genes Dis 2020; 7:299-307. [PMID: 32884984 PMCID: PMC7452537 DOI: 10.1016/j.gendis.2020.01.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/30/2019] [Accepted: 01/28/2020] [Indexed: 02/06/2023] Open
Abstract
Metastasis and metabolism reprogramming are two major hallmarks of cancer. In the initiation and progression of cancer, tumor cells are known to undergo fundamental metabolic changes to sustain their development and progression. In recent years, much more attentions have been drawn to their important roles in facilitating cancer metastasis through regulating the biological properties. In this review, we summarized the recent progresses in the studies of metabolism reprogramming of cancer metastasis, particularly of primary liver cancer, and highlight their potential applications.
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Affiliation(s)
- Wen-Wei Zhu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Ming Lu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Xiang-Yu Wang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Xu Zhou
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Chao Gao
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
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Silva-Almeida C, Ewart MA, Wilde C. 3D gastrointestinal models and organoids to study metabolism in human colon cancer. Semin Cell Dev Biol 2020; 98:98-104. [DOI: 10.1016/j.semcdb.2019.05.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/17/2019] [Accepted: 05/17/2019] [Indexed: 12/22/2022]
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Khan AA, Allemailem KS, Alhumaydhi FA, Gowder SJT, Rahmani AH. The Biochemical and Clinical Perspectives of Lactate Dehydrogenase: An Enzyme of Active Metabolism. Endocr Metab Immune Disord Drug Targets 2020; 20:855-868. [PMID: 31886754 DOI: 10.2174/1871530320666191230141110] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 11/05/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Lactate dehydrogenase (LDH) is a group of oxidoreductase isoenzymes catalyzing the reversible reaction between pyruvate and lactate. The five isoforms of this enzyme, formed from two subunits, vary in isoelectric points and these isoforms have different substrate affinity, inhibition constants and electrophoretic mobility. These diverse biochemical properties play a key role in its cellular, tissue and organ specificity. Though LDH is predominantly present in the cytoplasm, it has a multi-organellar location as well. OBJECTIVE The primary objective of this review article is to provide an update in parallel, the previous and recent biochemical views and its clinical significance in different diseases. METHODS With the help of certain inhibitors, its active site three-dimensional view, reactions mechanisms and metabolic pathways have been sorted out to a greater extent. Overexpression of LDH in different cancers plays a principal role in anaerobic cellular metabolism, hence several inhibitors have been designed to employ as novel anticancer agents. DISCUSSION LDH performs a very important role in overall body metabolism and some signals can induce isoenzyme switching under certain circumstances, ensuring that the tissues consistently maintain adequate ATP supply. This enzyme also experiences some posttranslational modifications, to have diversified metabolic roles. Different toxicological and pathological complications damage various organs, which ultimately result in leakage of this enzyme in serum. Hence, unusual LDH isoform level in serum serves as a significant biomarker of different diseases. CONCLUSION LDH is an important diagnostic biomarker for some common diseases like cancer, thyroid disorders, tuberculosis, etc. In general, LDH plays a key role in the clinical diagnosis of various common and rare diseases, as this enzyme has a prominent role in active metabolism.
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Affiliation(s)
- Amjad A Khan
- Department of Basic Health Sciences, College of Applied Medical Science, Qassim University, Qassim, Saudi Arabia
| | - Khaled S Allemailem
- Department of Basic Health Sciences, College of Applied Medical Science, Qassim University, Qassim, Saudi Arabia
- Department of Medical Laboratories, College of Applied Medical Science, Qassim University, Qassim, Saudi Arabia
| | - Fahad A Alhumaydhi
- Department of Medical Laboratories, College of Applied Medical Science, Qassim University, Qassim, Saudi Arabia
| | - Sivakumar J T Gowder
- Department for Management of Science and Technology Development, Ton Duc Thang University, Ho Chi Minh City,
Vietnam
- Faculty of Applied Sciences, Ton Duc Thang University, Vietnam
| | - Arshad H Rahmani
- Department of Medical Laboratories, College of Applied Medical Science, Qassim University, Qassim, Saudi Arabia
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49
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Guddeti RK, Bali P, Karyala P, Pakala SB. MTA1 coregulator regulates LDHA expression and function in breast cancer. Biochem Biophys Res Commun 2019; 520:54-59. [PMID: 31570164 DOI: 10.1016/j.bbrc.2019.09.078] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Accepted: 09/19/2019] [Indexed: 12/20/2022]
Abstract
Metastasis Associated Protein1 (MTA1) is a chromatin modifier and its expression is significantly associated with prognosis of many cancers. However, its role in glucose metabolism remains unexplored. Here, we report that MTA1 has a significant role in glucose metabolism where MTA1 regulates the LDHA expression and activity and subsequently its function in breast cancer motility. The results showed that MTA1 expression is positively correlated with the LDHA expression levels in breast cancer patients. Further, it was found that MTA1 is necessary for the optimal expression of LDHA. The underlying molecular mechanism involves the interaction of MTA1 with c-Myc and recruitment of MTA1-c-Myc complex on to the LDHA promoter to regulate its transcription. Consequently, the LDHA knock down using LDHA specific siRNA in MCF7 cells stably expressing MTA1 reduced the migration of MCF7 cells. Altogether these findings revealed the regulatory role for MTA1 in LDHA expression and its resulting biological function.
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Affiliation(s)
- Rohith Kumar Guddeti
- Biology Division, Indian Institute of Science Education and Research (IISER) Tirupati, Karakambadi Road, Mangalam, Tirupati, 517507, Andhra Pradesh, India
| | - Prerna Bali
- Biology Division, Indian Institute of Science Education and Research (IISER) Tirupati, Karakambadi Road, Mangalam, Tirupati, 517507, Andhra Pradesh, India
| | - Prashanthi Karyala
- Department of Biochemistry, Indian Academy Degree College Autonomous, Hennur Main Road, Bengaluru, 560043, Karnataka, India
| | - Suresh B Pakala
- Biology Division, Indian Institute of Science Education and Research (IISER) Tirupati, Karakambadi Road, Mangalam, Tirupati, 517507, Andhra Pradesh, India.
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Vengoji R, Ponnusamy MP, Rachagani S, Mahapatra S, Batra SK, Shonka N, Macha MA. Novel therapies hijack the blood-brain barrier to eradicate glioblastoma cancer stem cells. Carcinogenesis 2019; 40:2-14. [PMID: 30475990 DOI: 10.1093/carcin/bgy171] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 10/12/2018] [Accepted: 11/21/2018] [Indexed: 12/11/2022] Open
Abstract
Glioblastoma (GBM) is amongst the most aggressive brain tumors with a dismal prognosis. Despite significant advances in the current multimodality therapy including surgery, postoperative radiotherapy (RT) and temozolomide (TMZ)-based concomitant and adjuvant chemotherapy (CT), tumor recurrence is nearly universal with poor patient outcomes. These limitations are in part due to poor drug penetration through the blood-brain barrier (BBB) and resistance to CT and RT by a small population of cancer cells recognized as tumor-initiating cells or cancer stem cells (CSCs). Though CT and RT kill the bulk of the tumor cells, they fail to affect CSCs, resulting in their enrichment and their development into more refractory tumors. Therefore, identifying the mechanisms of resistance and developing therapies that specifically target CSCs can improve response, prevent the development of refractory tumors and increase overall survival of GBM patients. Small molecule inhibitors that can breach the BBB and selectively target CSCs are emerging. In this review, we have summarized the recent advancements in understanding the GBM CSC-specific signaling pathways, the CSC-tumor microenvironment niche that contributes to CT and RT resistance and the use of novel combination therapies of small molecule inhibitors that may be used in conjunction with TMZ-based chemoradiation for effective management of GBM.
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Affiliation(s)
- Raghupathy Vengoji
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sidharth Mahapatra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.,Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Nicole Shonka
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.,Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Muzafar A Macha
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Department of Otolaryngology/Head and Neck Surgery, University of Nebraska Medical Center, Omaha, NE, USA
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