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Rolver MG, Camacho-Roda J, Dai Y, Flinck M, Ialchina R, Hindkær J, Dyhr RT, Bodilsen AN, Prasad NS, Baldan J, Yao J, Sandelin A, Arnes L, Pedersen SF. Tumor microenvironment acidosis favors pancreatic cancer stem cell properties and in vivo metastasis. iScience 2025; 28:111956. [PMID: 40083719 PMCID: PMC11904601 DOI: 10.1016/j.isci.2025.111956] [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: 09/06/2024] [Revised: 12/20/2024] [Accepted: 01/31/2025] [Indexed: 03/16/2025] Open
Abstract
The acidic tumor microenvironment (TME) favors cancer aggressiveness via incompletely understood pathways. Here, we asked whether adaptation to environmental acidosis (pH 6.5) selects for human pancreatic cancer stem cell (CSC) properties. RNA sequencing (RNA-seq) of acid-adapted (AA) Panc-1 cells revealed CSC pathway enrichment and upregulation of CSC markers. AA Panc-1 cells exhibited classical CSC characteristics including increased aldehyde dehydrogenase (ALDH) activity and β-catenin activity. Panc-1, PaTu8988s, and MiaPaCa-2 cells all exhibited increased pancreatosphere-forming efficiency after acid adaptation but differed in CSC marker expression and did not exhibit typical flow cytometric CSC populations. However, single-nucleus sequencing revealed the acid adaptation-induced emergence of Panc-1 cell subpopulations with clear CSC characteristics. In orthotopic mouse tumors, AA Panc-1 cells exhibited enhanced aggressiveness, liver and lung metastasis, compared to controls. Collectively, our work suggests that acid adaptation enriches for pancreatic CSC phenotypes with unusual traits via several trajectories, providing new insight into how acidic microenvironments favor cancer aggressiveness.
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Affiliation(s)
- Michala G. Rolver
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Juan Camacho-Roda
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Yifan Dai
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Mette Flinck
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Renata Ialchina
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Julie Hindkær
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Rigmor T. Dyhr
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - August N. Bodilsen
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Nanditha S. Prasad
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Jonathan Baldan
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Jiayi Yao
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Albin Sandelin
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Luis Arnes
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
| | - Stine F. Pedersen
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
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MK Nair P, Silwal K, Ramalakshmi R, Devibala M, Saranya M, Sivaranjani S, Ramasamy T, Palanisamy A, Mahalingam M. Beyond genetics: integrative oncology and the metabolic perspective on cancer treatment. Front Oncol 2024; 14:1455022. [PMID: 39376991 PMCID: PMC11456992 DOI: 10.3389/fonc.2024.1455022] [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: 06/26/2024] [Accepted: 08/29/2024] [Indexed: 10/09/2024] Open
Abstract
Cancer is traditionally approached as a genetic disease, with standard treatments including chemotherapy, radiation, targeted therapy, immunotherapy, and surgery significantly improving survival rates and patient outcomes. However, there is a growing recognition of the need for integrative oncology, which expands cancer management by considering cancer as a metabolic disease. Integrative medicine physicians employ holistic therapies focused on patients' needs, aiming to correct the metabolic imbalances associated with cancer and alleviate cancer-related symptoms. Viewing cancer as a metabolic disease involves addressing factors such as an acidic microenvironment, vitamin C deficiency, mitochondrial dysfunction, reduced intracellular oxygen levels, elevated oxidative stress, dysfunctional autophagy, and psychological stress. This paper presents an overview of the evidence and comprehensive strategies supporting integrative medicine approaches in addressing cancer metabolism in integrative oncology settings. Furthermore, the paper underscores the necessity of integrating different cancer theories-genetic and metabolic-for improved patient outcomes and experiences. By combining these perspectives, integrative oncology offers a more holistic, patient-centered approach to cancer treatment.
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Affiliation(s)
- Pradeep MK Nair
- Department of Integrative Oncology, Mirakle Integrated Health Centre, Pollachi, India
| | - Karishma Silwal
- Department of Naturopathy, Sant Hirdaram Medical College of Naturopathy and Yogic Sciences, Bhopal, India
| | | | - Muniappan Devibala
- Department of Integrative Oncology, Mirakle Integrated Health Centre, Pollachi, India
| | | | - Sekar Sivaranjani
- Department of Integrative Oncology, Mirakle Integrated Health Centre, Pollachi, India
| | - Thangavelu Ramasamy
- Department of Integrative Oncology, Mirakle Integrated Health Centre, Pollachi, India
| | - Ayyappan Palanisamy
- Department of Integrative Oncology, Mirakle Integrated Health Centre, Pollachi, India
| | - Manickam Mahalingam
- Department of Integrative Oncology, Mirakle Integrated Health Centre, Pollachi, India
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3
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Bua S, Nocentini A, Bonardi A, Palma G, Ciampi G, Giliberti A, Iannelli F, Bruzzese F, Supuran CT, de Nigris F. Harnessing Nitric Oxide-Donating Benzofuroxans for Targeted Inhibition of Carbonic Anhydrase IX in Cancer. J Med Chem 2024; 67:15892-15907. [PMID: 39207927 DOI: 10.1021/acs.jmedchem.4c01563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
We describe here the design and antitumor evaluation of benzofuroxan-based nitric oxide (NO)-donor hybrid derivatives targeting human carbonic anhydrases (hCAs) IX and XII. The most effective compounds, 27 and 28, demonstrated potent dual action, exhibiting low nanomolar inhibition constants against hCA IX and significant NO release. Notably, compound 27 showed significant antiproliferative effects against various cancer cell lines, particularly renal carcinoma A-498 cells. In these cells, it significantly reduced the expression of CA IX and iron-regulatory proteins, inducing apoptosis via mitochondrial caspase activity and ferroptosis pathways, as evidenced by increases in ROS, nitrite, and down-regulated expression of ferritin-encoding genes. In three-dimensional tumor models, compound 27 effectively reduced spheroid size and viability. In vivo toxicity studies in mice indicated that the compounds were well-tolerated, with no significant alterations in kidney function. These findings underscore the potential of benzofuroxan-based CA inhibitors for further preclinical evaluations as therapeutic agents targeting renal cell carcinoma.
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Affiliation(s)
- Silvia Bua
- NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, 50019 Sesto Fiorentino, Firenze Italy
| | - Alessio Nocentini
- NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, 50019 Sesto Fiorentino, Firenze Italy
| | - Alessandro Bonardi
- NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, 50019 Sesto Fiorentino, Firenze Italy
| | - Giuseppe Palma
- Experimental Animal Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli 80131, Italy
| | - Giulia Ciampi
- Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli″, Napoli 80138, Italy
| | - Angela Giliberti
- Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli″, Napoli 80138, Italy
| | - Federica Iannelli
- Experimental Pharmacology Unit, Istituto Nazionale Tumori - IRCCS -Fondazione G. Pascale, Napoli 80131, Italy
| | - Francesca Bruzzese
- Experimental Animal Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli 80131, Italy
| | - Claudiu T Supuran
- NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, 50019 Sesto Fiorentino, Firenze Italy
| | - Filomena de Nigris
- Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli″, Napoli 80138, Italy
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4
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Dong W, Lu J, Li Y, Zeng J, Du X, Yu A, Zhao X, Chi F, Xi Z, Cao S. SIRT1: a novel regulator in colorectal cancer. Biomed Pharmacother 2024; 178:117176. [PMID: 39059350 DOI: 10.1016/j.biopha.2024.117176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 07/08/2024] [Accepted: 07/22/2024] [Indexed: 07/28/2024] Open
Abstract
The class-III histone deacetylase SIRT1 is the most extensively investigated sirtuin deacetylase. It is resistant to the broad deacetylase inhibitor trichostatin A and depends on oxidized nicotinamide adenine nucleotide (NAD+). SIRT1 plays a crucial role in the tumorigenesis of numerous types of cancers, including colorectal cancer (CRC). Accumulating evidence indicates that SIRT1 is a therapeutic target for CRC; however, the function and underlying mechanism of SIRT1 in CRC still need to be elucidated. Herein, we provide a detailed and updated review to illustrate that SIRT1 regulates many processes that go awry in CRC cells, such as apoptosis, autophagy, proliferation, migration, invasion, metastasis, oxidative stress, resistance to chemo-radio therapy, immune evasion, and metabolic reprogramming. Moreover, we closely link our review to the clinical practice of CRC treatment, summarizing the mechanisms and prospects of SIRT1 inhibitors in CRC therapy. SIRT1 inhibitors as monotherapy in CRC or in combination with chemotherapy, radiotherapy, and immune therapies are comprehensively discussed. From epigenetic regulation to its potential therapeutic effect, we hope to offer novel insights and a comprehensive understanding of SIRT1's role in CRC.
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Affiliation(s)
- Weiwei Dong
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Jinjing Lu
- Department of Health Management, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - You Li
- Nursing Department, Liaoning Jinqiu Hospital, Shenyang, Liaoning Province 110016, China
| | - Juan Zeng
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Xiaoyun Du
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Ao Yu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Xuechan Zhao
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Feng Chi
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China.
| | - Zhuo Xi
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China.
| | - Shuo Cao
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China.
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Cai Q, He Y, Zhou Y, Zheng J, Deng J. Nanomaterial-Based Strategies for Preventing Tumor Metastasis by Interrupting the Metastatic Biological Processes. Adv Healthc Mater 2024; 13:e2303543. [PMID: 38411537 DOI: 10.1002/adhm.202303543] [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: 10/17/2023] [Revised: 02/01/2024] [Indexed: 02/28/2024]
Abstract
Tumor metastasis is the primary cause of cancer-related deaths. The prevention of tumor metastasis has garnered notable interest and interrupting metastatic biological processes is considered a potential strategy for preventing tumor metastasis. The tumor microenvironment (TME), circulating tumor cells (CTCs), and premetastatic niche (PMN) play crucial roles in metastatic biological processes. These processes can be interrupted using nanomaterials due to their excellent physicochemical properties. However, most studies have focused on only one aspect of tumor metastasis. Here, the hypothesis that nanomaterials can be used to target metastatic biological processes and explore strategies to prevent tumor metastasis is highlighted. First, the metastatic biological processes and strategies involving nanomaterials acting on the TME, CTCs, and PMN to prevent tumor metastasis are briefly summarized. Further, the current challenges and prospects of nanomaterials in preventing tumor metastasis by interrupting metastatic biological processes are discussed. Nanomaterial-and multifunctional nanomaterial-based strategies for preventing tumor metastasis are advantageous for the long-term fight against tumor metastasis and their continued exploration will facilitate rapid progress in the prevention, diagnosis, and treatment of tumor metastasis. Novel perspectives are outlined for developing more effective strategies to prevent tumor metastasis, thereby improving the outcomes of patients with cancer.
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Affiliation(s)
- Qingjin Cai
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Yijia He
- School of Basic Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Yang Zhou
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Ji Zheng
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, 400037, China
| | - Jun Deng
- Institute of Burn Research, Southwest Hospital, State Key Lab of Trauma, Burn and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Third Military Medical University (Army Medical University), Chongqing, 400038, China
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Wang L, Zhang L, Dunmall LC, Wang YY, Fan Z, Cheng Z, Wang Y. The dilemmas and possible solutions for CAR-T cell therapy application in solid tumors. Cancer Lett 2024; 591:216871. [PMID: 38604310 DOI: 10.1016/j.canlet.2024.216871] [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: 10/27/2023] [Revised: 03/26/2024] [Accepted: 04/06/2024] [Indexed: 04/13/2024]
Abstract
Chimeric antigen receptor T (CAR-T) cell therapy, as an adoptive immunotherapy, is playing an increasingly important role in the treatment of malignant tumors. CAR-T cells are referred to as "living drugs" as they not only target tumor cells directly, but also induce long-term immune memory that has the potential to provide long-lasting protection. CD19.CAR-T cells have achieved complete response rates of over 90 % for acute lymphoblastic leukemia and over 60 % for non-Hodgkin's lymphoma. However, the response rate of CAR-T cells in the treatment of solid tumors remains extremely low and the side effects potentially severe. In this review, we discuss the limitations that the solid tumor microenvironment poses for CAR-T application and the solutions that are being developed to address these limitations, in the hope that in the near future, CAR-T cell therapy for solid tumors can attain the same success rates as are now being seen clinically for hematological malignancies.
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Affiliation(s)
- Lihong Wang
- Department of Oncology, Air Force Medical Center, PLA, Beijing, China; National Centre for International Research in Cell and Gene Therapy, Sino British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Lufang Zhang
- National Centre for International Research in Cell and Gene Therapy, Sino British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Louisa Chard Dunmall
- Centre for Cancer Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Yang Yang Wang
- Department of General Pediatrics, Newham General Hospital, E13 8SL, London, United Kingdom
| | - Zaiwen Fan
- Department of Oncology, Air Force Medical Center, PLA, Beijing, China
| | - Zhenguo Cheng
- National Centre for International Research in Cell and Gene Therapy, Sino British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yaohe Wang
- National Centre for International Research in Cell and Gene Therapy, Sino British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China; Centre for Cancer Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
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7
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Tafech A, Stéphanou A. On the Importance of Acidity in Cancer Cells and Therapy. BIOLOGY 2024; 13:225. [PMID: 38666837 PMCID: PMC11048434 DOI: 10.3390/biology13040225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/25/2024] [Accepted: 03/27/2024] [Indexed: 04/28/2024]
Abstract
Cancer cells are associated with high glycolytic activity, which results in acidification of the tumor microenvironment. The occurrence of this stressful condition fosters tumor aggressiveness, with the outcome of invasiveness and metastasis that are linked to a poor clinical prognosis. Acidosis can be both the cause or consequence of alterations in the functions and expressions of transporters involved in intracellular acidity regulation. This review aims to explore the origin of acidity in cancer cells and the various mechanisms existing in tumors to resist, survive, or thrive in the acidic environment. It highlights the difficulties in measuring the intracellular pH evolution that impedes our understanding of the many regulatory and feedback mechanisms. It finally presents the consequences of acidity on tumor development as well as the friend or foe role of acidity in therapy.
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Affiliation(s)
| | - Angélique Stéphanou
- Université Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, 38000 Grenoble, France
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8
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Shie WY, Cheng SJ, Chen KC, Tang CC, Peng HH, Ko HH, Hou HH, Elizabeth Chou HY. Fibroblast growth factor 5 expression predicts the progression of oral squamous cell carcinoma. J Formos Med Assoc 2024; 123:390-399. [PMID: 37704482 DOI: 10.1016/j.jfma.2023.08.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/05/2023] [Accepted: 08/15/2023] [Indexed: 09/15/2023] Open
Abstract
BACKGROUND/PURPOSE Fibroblast growth factor (FGF) 5 is a member of the FGF family that functions as a regulator of tissue growth and regeneration. Aberrant FGF5 expression has been previously associated with the progression of a number of different malignancies. However, its potential role in oral cancer remains unclear. In this study, we explored the relationship between the expression of FGF5 protein in oral squamous cell carcinomas (OSCCs) and the clinicopathological parameters of OSCCs and whether the expression of FGF5 protein in OSCCs could be a prognostic factor for OSCC patients. METHODS The FGF5 protein expression was examined in 64 OSCC and 34 normal oral mucosal specimens by immunohistochemical staining. Stress induced upregulation and intracellular redistribution of FGF5 were verified using xenograft animal model and OSCC cell lines. RESULTS The mean FGF5 protein labelling index was significantly higher in OSCC than in normal oral mucosal samples, with high FGF5 protein labelling index (>58%) being correlated with advanced stage and poor survival of OSCC patients. Apart from the peri-cytoplasmic staining pattern characteristic of paracrine growth factors, FGF5 protein was localized as distinct punctate structures in the cytoplasm of advanced stage or stressed-induced cells. This redistribution and upregulation of FGF5 protein could be sustained after termination of the stress induction in cell line and xenograft animal models. CONCLUSION FGF5 can be induced by cellular stress and risk factors of OSCC, where high expression levels of FGF5 is potentially a useful parameter for predicting OSCC progression and patient survival.
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Affiliation(s)
- Wan-Yi Shie
- Graduate Institute of Oral Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shih-Jung Cheng
- Graduate Institute of Oral Biology, College of Medicine, National Taiwan University, Taipei, Taiwan; School of Dentistry, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan
| | - Kuan-Chi Chen
- Graduate Institute of Oral Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ching-Chun Tang
- Graduate Institute of Oral Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hsin-Hui Peng
- School of Dentistry, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital Hsin-Chu Branch, College of Medicine, Hsin-Chu, Taiwan
| | - Hui-Hsin Ko
- School of Dentistry, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital Hsin-Chu Branch, College of Medicine, Hsin-Chu, Taiwan
| | - Hsin-Han Hou
- Graduate Institute of Oral Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Han-Yi Elizabeth Chou
- Graduate Institute of Oral Biology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Dentistry, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan; Center for Biotechnology, National Taiwan University, Taipei, Taiwan.
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Abstract
Cancers undergo sequential changes to proton (H+) concentration and sensing that are consequences of the disease and facilitate its further progression. The impact of protonation state on protein activity can arise from alterations to amino acids or their titration. Indeed, many cancer-initiating mutations influence pH balance, regulation or sensing in a manner that enables growth and invasion outside normal constraints as part of oncogenic transformation. These cancer-supporting effects become more prominent when tumours develop an acidic microenvironment owing to metabolic reprogramming and disordered perfusion. The ensuing intracellular and extracellular pH disturbances affect multiple aspects of tumour biology, ranging from proliferation to immune surveillance, and can even facilitate further mutagenesis. As a selection pressure, extracellular acidosis accelerates disease progression by favouring acid-resistant cancer cells, which are typically associated with aggressive phenotypes. Although acid-base disturbances in tumours often occur alongside hypoxia and lactate accumulation, there is now ample evidence for a distinct role of H+-operated responses in key events underpinning cancer. The breadth of these actions presents therapeutic opportunities to change the trajectory of disease.
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Affiliation(s)
- Pawel Swietach
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
| | - Ebbe Boedtkjer
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.
| | - Stine Falsig Pedersen
- Department of Biology, University of Copenhagen, University of Copenhagen, Faculty of Science, København, Denmark.
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Ronco AL, Storz MA. Dietary Acid Load and Cancer Risk: A Review of the Uruguayan Experience. Nutrients 2023; 15:3098. [PMID: 37513516 PMCID: PMC10385454 DOI: 10.3390/nu15143098] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 07/07/2023] [Accepted: 07/08/2023] [Indexed: 07/30/2023] Open
Abstract
Dietary acid load (DAL) is recognized as a risk factor for several chronic disorders, including obesity, diabetes, and osteoporosis. Recent evidence suggests that an elevated DAL, as measured by the validated potential renal acid load (PRAL) and net endogenous acid production (NEAP) scores, could also increase the risk for several cancers. This narrative review summarizes the potential role of DAL in Uruguayan cancer patients and outlines the potentially involved pathophysiological pathways that mediate the role of DAL in both cancer development and growth. Although Uruguay is a developing country, its average diet is a heavily meat-based Western one, translating into a supraphysiological acid burden from diet. In recent years, we have published epidemiologic evidence based on ten case-control studies involving 3736 cancer cases and 9534 hospital-based controls. Odds ratios and 95% confidence intervals were estimated for each interest variable to analyze the association between the exposure levels of DAL scores and cancer, calculated by unconditional logistic regression. In a majority of the cases, the highest DAL scores tended to double the cancer risk as compared to the lowest category. We also found high risks for methionine intake, an acidifying amino acid found in higher concentrations in animal-based foods, which may increase cancer risks at least by a joint action based on the pH and the proliferation enhancing properties of the amino acid itself.
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Affiliation(s)
- Alvaro Luis Ronco
- Unit of Oncology and Radiotherapy, Pereira Rossell Women's Hospital, Bvard. Artigas 1590, Montevideo 11600, Uruguay
| | - Maximilian Andreas Storz
- Department of Internal Medicine II, Centre for Complementary Medicine, Freiburg University Hospital, Faculty of Medicine, University of Freiburg, 79106 Freiburg im Breisgau, Germany
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11
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Audero MM, Carvalho TMA, Ruffinatti FA, Loeck T, Yassine M, Chinigò G, Folcher A, Farfariello V, Amadori S, Vaghi C, Schwab A, Reshkin SJ, Cardone RA, Prevarskaya N, Fiorio Pla A. Acidic Growth Conditions Promote Epithelial-to-Mesenchymal Transition to Select More Aggressive PDAC Cell Phenotypes In Vitro. Cancers (Basel) 2023; 15:cancers15092572. [PMID: 37174038 PMCID: PMC10177299 DOI: 10.3390/cancers15092572] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 03/28/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by an acidic microenvironment, which contributes to therapeutic failure. So far there is a lack of knowledge with respect to the role of the acidic microenvironment in the invasive process. This work aimed to study the phenotypic and genetic response of PDAC cells to acidic stress along the different stages of selection. To this end, we subjected the cells to short- and long-term acidic pressure and recovery to pHe 7.4. This treatment aimed at mimicking PDAC edges and consequent cancer cell escape from the tumor. The impact of acidosis was assessed for cell morphology, proliferation, adhesion, migration, invasion, and epithelial-mesenchymal transition (EMT) via functional in vitro assays and RNA sequencing. Our results indicate that short acidic treatment limits growth, adhesion, invasion, and viability of PDAC cells. As the acid treatment progresses, it selects cancer cells with enhanced migration and invasion abilities induced by EMT, potentiating their metastatic potential when re-exposed to pHe 7.4. The RNA-seq analysis of PANC-1 cells exposed to short-term acidosis and pHe-selected recovered to pHe 7.4 revealed distinct transcriptome rewiring. We describe an enrichment of genes relevant to proliferation, migration, EMT, and invasion in acid-selected cells. Our work clearly demonstrates that upon acidosis stress, PDAC cells acquire more invasive cell phenotypes by promoting EMT and thus paving the way for more aggressive cell phenotypes.
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Affiliation(s)
- Madelaine Magalì Audero
- U1003-PHYCELL-Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, Villeneuve d'Ascq, 59000 Lille, France
- Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy
| | | | - Federico Alessandro Ruffinatti
- Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy
| | - Thorsten Loeck
- Institute of Physiology II, University of Münster, 48149 Münster, Germany
| | - Maya Yassine
- U1003-PHYCELL-Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, Villeneuve d'Ascq, 59000 Lille, France
| | - Giorgia Chinigò
- Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy
| | - Antoine Folcher
- U1003-PHYCELL-Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, Villeneuve d'Ascq, 59000 Lille, France
| | - Valerio Farfariello
- U1003-PHYCELL-Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, Villeneuve d'Ascq, 59000 Lille, France
| | - Samuele Amadori
- Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy
| | - Chiara Vaghi
- Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy
| | - Albrecht Schwab
- Institute of Physiology II, University of Münster, 48149 Münster, Germany
| | - Stephan J Reshkin
- Department of Biosciences, Biotechnologies and Environment, University of Bari, 70126 Bari, Italy
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Environment, University of Bari, 70126 Bari, Italy
| | - Natalia Prevarskaya
- U1003-PHYCELL-Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, Villeneuve d'Ascq, 59000 Lille, France
| | - Alessandra Fiorio Pla
- U1003-PHYCELL-Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, Villeneuve d'Ascq, 59000 Lille, France
- Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy
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12
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Rolver MG, Holland LKK, Ponniah M, Prasad NS, Yao J, Schnipper J, Kramer S, Elingaard‐Larsen L, Pedraz‐Cuesta E, Liu B, Pardo LA, Maeda K, Sandelin A, Pedersen SF. Chronic acidosis rewires cancer cell metabolism through PPARα signaling. Int J Cancer 2023; 152:1668-1684. [PMID: 36533672 PMCID: PMC10108231 DOI: 10.1002/ijc.34404] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/25/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022]
Abstract
The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Here, we used mammary, pancreatic, and colon cancer cells to show that adaptation to growth at an extracellular pH (pHe ) mimicking acidic tumor niches is associated with upregulated net acid extrusion capacity and elevated intracellular pH at physiological pHe , but not at acidic pHe . Using metabolic profiling, shotgun lipidomics, imaging and biochemical analyses, we show that the acid adaptation-induced phenotype is characterized by a shift toward oxidative metabolism, increased lipid droplet-, triacylglycerol-, peroxisome content and mitochondrial hyperfusion. Peroxisome proliferator-activated receptor-α (PPARA, PPARα) expression and activity are upregulated, at least in part by increased fatty acid uptake. PPARα upregulates genes driving increased mitochondrial and peroxisomal mass and β-oxidation capacity, including mitochondrial lipid import proteins CPT1A, CPT2 and SLC25A20, electron transport chain components, peroxisomal proteins PEX11A and ACOX1, and thioredoxin-interacting protein (TXNIP), a negative regulator of glycolysis. This endows acid-adapted cancer cells with increased capacity for utilizing fatty acids for metabolic needs, while limiting glycolysis. As a consequence, the acid-adapted cells exhibit increased sensitivity to PPARα inhibition. We conclude that PPARα is a key upstream regulator of metabolic changes favoring cancer cell survival in acidic tumor niches.
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Affiliation(s)
- Michala G. Rolver
- Section for Cell Biology and Physiology, Department of BiologyUniversity of CopenhagenCopenhagenDenmark
| | - Lya K. K. Holland
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research CenterCopenhagenDenmark
| | - Muthulakshmi Ponniah
- Section for Cell Biology and Physiology, Department of BiologyUniversity of CopenhagenCopenhagenDenmark
| | - Nanditha S. Prasad
- Section for Cell Biology and Physiology, Department of BiologyUniversity of CopenhagenCopenhagenDenmark
| | - Jiayi Yao
- The Bioinformatics Center, Department of BiologyUniversity of CopenhagenCopenhagenDenmark
- Biotech Research and Innovation Center, University of CopenhagenCopenhagenDenmark
| | - Julie Schnipper
- Laboratory of Cellular and Molecular Physiology, University of Picardie Jules VerneAmiensFrance
| | - Signe Kramer
- Section for Cell Biology and Physiology, Department of BiologyUniversity of CopenhagenCopenhagenDenmark
| | | | - Elena Pedraz‐Cuesta
- Section for Cell Biology and Physiology, Department of BiologyUniversity of CopenhagenCopenhagenDenmark
| | - Bin Liu
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research CenterCopenhagenDenmark
| | - Luis A. Pardo
- Oncophysiology Group, Max‐Planck‐Institute for Multidisciplinary SciencesGöttingenGermany
| | - Kenji Maeda
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research CenterCopenhagenDenmark
| | - Albin Sandelin
- The Bioinformatics Center, Department of BiologyUniversity of CopenhagenCopenhagenDenmark
- Biotech Research and Innovation Center, University of CopenhagenCopenhagenDenmark
| | - Stine Falsig Pedersen
- Section for Cell Biology and Physiology, Department of BiologyUniversity of CopenhagenCopenhagenDenmark
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13
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Czaplinska D, Ialchina R, Andersen HB, Yao J, Stigliani A, Dannesboe J, Flinck M, Chen X, Mitrega J, Gnosa SP, Dmytriyeva O, Alves F, Napp J, Sandelin A, Pedersen SF. Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness. Int J Cancer 2023; 152:1210-1225. [PMID: 36408933 PMCID: PMC10108304 DOI: 10.1002/ijc.34367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 10/14/2022] [Accepted: 11/07/2022] [Indexed: 11/22/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with minimal treatment options and a global rise in prevalence. PDAC is characterized by frequent driver mutations including KRAS and TP53 (p53), and a dense, acidic tumor microenvironment (TME). The relation between genotype and TME in PDAC development is unknown. Strikingly, when wild type (WT) Panc02 PDAC cells were adapted to growth in an acidic TME and returned to normal pH to mimic invasive cells escaping acidic regions, they displayed a strong increase of aggressive traits such as increased growth in 3-dimensional (3D) culture, adhesion-independent colony formation and invasive outgrowth. This pattern of acidosis-induced aggressiveness was observed in 3D spheroid culture as well as upon organotypic growth in matrigel, collagen-I and combination thereof, mimicking early and later stages of PDAC development. Acid-adaptation-induced gain of cancerous traits was further increased by p53 knockout (KO), but only in specific extracellular matrix (ECM) compositions. Akt- and Transforming growth factor-β (TGFβ) signaling, as well as expression of the Na+ /H+ exchanger NHE1, were increased by acid adaptation. Whereas Akt inhibition decreased spheroid growth regardless of treatment and genotype, stimulation with TGFβI increased growth of WT control spheroids, and inhibition of TGFβ signaling tended to limit growth under acidic conditions only. Our results indicate that a complex crosstalk between tumor acidosis, ECM composition and genotype contributes to PDAC development. The findings may guide future strategies for acidosis-targeted therapies.
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Affiliation(s)
- Dominika Czaplinska
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Renata Ialchina
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Henriette Berg Andersen
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Jiayi Yao
- Section for Computational and RNA Biology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), Faculty of Health, University of Copenhagen, Copenhagen, Denmark
| | - Arnaud Stigliani
- Section for Computational and RNA Biology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), Faculty of Health, University of Copenhagen, Copenhagen, Denmark
| | - Johs Dannesboe
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Mette Flinck
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Xiaoming Chen
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Jakub Mitrega
- Max-Planck-Institute for Multidisciplinary Sciences, Goettingen, Germany.,Institute for Diagnostic and Interventional Radiology, University Medical Center Goettingen, Goettingen, Germany
| | - Sebastian Peter Gnosa
- Biotech Research and Innovation Centre (BRIC), Faculty of Health, University of Copenhagen, Copenhagen, Denmark
| | - Oksana Dmytriyeva
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health, University of Copenhagen, Copenhagen, Denmark
| | - Frauke Alves
- Max-Planck-Institute for Multidisciplinary Sciences, Goettingen, Germany.,Institute for Diagnostic and Interventional Radiology, University Medical Center Goettingen, Goettingen, Germany.,Clinic of Haematology and Medical Oncology, University Medical Center Goettingen, Goettingen, Germany
| | - Joanna Napp
- Max-Planck-Institute for Multidisciplinary Sciences, Goettingen, Germany.,Institute for Diagnostic and Interventional Radiology, University Medical Center Goettingen, Goettingen, Germany.,Clinic of Haematology and Medical Oncology, University Medical Center Goettingen, Goettingen, Germany
| | - Albin Sandelin
- Section for Computational and RNA Biology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.,Biotech Research and Innovation Centre (BRIC), Faculty of Health, University of Copenhagen, Copenhagen, Denmark
| | - Stine Falsig Pedersen
- Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
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14
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Zhang Q, Liu N, Wang J, Liu Y, Wang K, Zhang J, Pan X. The Recent Advance of Cell-Penetrating and Tumor-Targeting Peptides as Drug Delivery Systems Based on Tumor Microenvironment. Mol Pharm 2023; 20:789-809. [PMID: 36598861 DOI: 10.1021/acs.molpharmaceut.2c00629] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Cancer has become the primary reason for industrial countries death. Although first-line treatments have achieved remarkable results in inhibiting tumors, they could have serious side effects because of insufficient selectivity. Therefore, specific localization of tumor cells is currently the main desire for cancer treatment. In recent years, cell-penetrating peptides (CPPs), as a kind of promising delivery vehicle, have attracted much attention because they mediate the high-efficiency import of large quantities of cargos in vivo and vitro. Unfortunately, the poor targeting of CPPs is still a barrier to their clinical application. In order to solve this problem, researchers use the various characteristics of tumor microenvironment and multiple receptors to improve the specificity toward tumors. This review focuses on the characteristics of the tumor microenvironment, and introduces the development of strategies and peptides based on these characteristics as drug delivery system in the tumor-targeted therapy.
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Affiliation(s)
- Qingqing Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Nanxin Liu
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Jin Wang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Yuying Liu
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Kai Wang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Jie Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Xiaoyan Pan
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China
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15
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Luo X, Wu S, Xiao M, Gu H, Zhang H, Chen J, Liu Y, Zhang C, Zhang J. Advances and Prospects of Prolamine Corn Protein Zein as Promising Multifunctional Drug Delivery System for Cancer Treatment. Int J Nanomedicine 2023; 18:2589-2621. [PMID: 37213352 PMCID: PMC10198181 DOI: 10.2147/ijn.s402891] [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: 12/28/2022] [Accepted: 05/06/2023] [Indexed: 05/23/2023] Open
Abstract
Zein is a type of prolamine protein that is derived from corn, and it has been recognized by the US FDA as one of the safest biological materials available. Zein possesses valuable characteristics that have made it a popular choice for the preparation of drug carriers, which can be administered through various routes to improve the therapeutic effect of antitumor drugs. Additionally, zein contains free hydroxyl and amino groups that offer numerous modification sites, enabling it to be hybridized with other materials to create functionalized drug delivery systems. However, despite its potential, the clinical translation of drug-loaded zein-based carriers remains challenging due to insufficient basic research and relatively strong hydrophobicity. In this paper, we aim to systematically introduce the main interactions between loaded drugs and zein, administration routes, and the functionalization of zein-based antitumor drug delivery systems, in order to demonstrate its development potential and promote their further application. We also provide perspectives and future directions for this promising area of research.
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Affiliation(s)
- Xi Luo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Sudan Wu
- Blood Purification Center, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
| | - Meng Xiao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Huan Gu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Huan Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Jianping Chen
- Lika Shing Faculty of Medicine, School of Chinese Medicine, the University of Hong KOng, Hong Kong, People’s Republic of China
| | - Yang Liu
- Department of Vascular Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
- Correspondence: Yang Liu, Hospital of Chengdu University of Traditional Chinese Medicine, No. 37, Shierqiao Road, Jinniu District, Chengdu, Sichuan, People’s Republic of China, Email
| | - Chen Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Jinming Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
- Jinming Zhang, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, No.1166, Liutai Avenue, Wenjiang District, Chengdu, Sichuan, People’s Republic of China, Email
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16
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Lee D, Hong JH. Activated PyK2 and Its Associated Molecules Transduce Cellular Signaling from the Cancerous Milieu for Cancer Metastasis. Int J Mol Sci 2022; 23:ijms232415475. [PMID: 36555115 PMCID: PMC9779422 DOI: 10.3390/ijms232415475] [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: 11/08/2022] [Revised: 11/28/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022] Open
Abstract
PyK2 is a member of the proline-rich tyrosine kinase and focal adhesion kinase families and is ubiquitously expressed. PyK2 is mainly activated by stimuli, such as activated Src kinases and intracellular acidic pH. The mechanism of PyK2 activation in cancer cells has been addressed extensively. The up-regulation of PyK2 through overexpression and enhanced phosphorylation is a key feature of tumorigenesis and cancer migration. In this review, we summarized the cancer milieu, including acidification and cancer-associated molecules, such as chemical reagents, interactive proteins, chemokine-related molecules, calcium channels/transporters, and oxidative molecules that affect the fate of PyK2. The inhibition of PyK2 leads to a beneficial strategy to attenuate cancer cell development, including metastasis. Thus, we highlighted the effect of PyK2 on various cancer cell types and the distribution of molecules that affect PyK2 activation. In particular, we underlined the relationship between PyK2 and cancer metastasis and its potential to treat cancer cells.
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Abstract
Significance: Cancer-associated tissue-specific lactic acidosis stimulates and mediates tumor invasion and metastasis and is druggable. Rarely, malignancy causes systemic lactic acidosis, the role of which is poorly understood. Recent Advances: The understanding of the role of lactate has shifted dramatically since its discovery. Long recognized as only a waste product, lactate has become known as an alternative metabolism substrate and a secreted nutrient that is exchanged between the tumor and the microenvironment. Tissue-specific lactic acidosis is targeted to improve the host body's anticancer defense and serves as a tool that allows the targeting of anticancer compounds. Systemic lactic acidosis is associated with poor survival. In patients with solid cancer, systemic lactic acidosis is associated with an extremely poor prognosis, as revealed by the analysis of 57 published cases in this study. Although it is considered a pathology worth treating, targeting systemic lactic acidosis in patients with solid cancer is usually inefficient. Critical Issues: Research gaps include simple questions, such as the unknown nuclear pH of the cancer cells and its effects on chemotherapy outcomes, pH sensitivity of glycosylation in cancer cells, in vivo mechanisms of response to acidosis in the absence of lactate, and overinterpretation of in vitro results that were obtained by using cells that were not preadapted to acidic environments. Future Directions: Numerous metabolism-targeting anticancer compounds induce lactatemia, lactic acidosis, or other types of acidosis. Their potential to induce acidic environments is largely overlooked, although the acidosis might contribute to a substantial portion of the observed clinical effects. Antioxid. Redox Signal. 37, 1130-1152.
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Affiliation(s)
- Petr Heneberg
- Third Faculty of Medicine, Charles University, Prague, Czech Republic
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18
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Nanomodulation and nanotherapeutics of tumor-microenvironment. OPENNANO 2022. [DOI: 10.1016/j.onano.2022.100099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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19
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Observational and clinical evidence that plant-based nutrition reduces dietary acid load. J Nutr Sci 2022; 11:e93. [PMID: 36405093 PMCID: PMC9641522 DOI: 10.1017/jns.2022.93] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 09/29/2022] [Indexed: 12/14/2022] Open
Abstract
Contemporary diets in Western countries are largely acid-inducing and deficient in potassium alkali salts, resulting in low-grade metabolic acidosis. The chronic consumption of acidogenic diets abundant in animal-based foods (meats, dairy, cheese and eggs) poses a substantial challenge to the human body's buffering capacities and chronic retention of acid wherein the progressive loss of bicarbonate stores can cause cellular and tissue damage. An elevated dietary acid load (DAL) has been associated with systemic inflammation and other adverse metabolic conditions. In this narrative review, we examine DAL quantification methods and index observational and clinical evidence on the role of plant-based diets, chiefly vegetarian and vegan, in reducing DAL. Quantitation of protein and amino acid composition and of intake of alkalising organic potassium salts and magnesium show that plant-based diets are most effective at reducing DAL. Results from clinical studies and recommendations in the form of expert committee opinions suggest that for a number of common illnesses, wherein metabolic acidosis is a contributing factor, the regular inclusion of plant-based foods offers measurable benefits for disease prevention and management. Based on available evidence, dietary shifts toward plant-based nutrition effectively reduces dietary-induced, low-grade metabolic acidosis.
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20
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Acid Adaptation Promotes TRPC1 Plasma Membrane Localization Leading to Pancreatic Ductal Adenocarcinoma Cell Proliferation and Migration through Ca 2+ Entry and Interaction with PI3K/CaM. Cancers (Basel) 2022; 14:cancers14194946. [PMID: 36230869 PMCID: PMC9563726 DOI: 10.3390/cancers14194946] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/03/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers globally, with a 5-year overall survival of less than 10%. The development and progression of PDAC are linked to its fluctuating acidic tumor microenvironment. Ion channels act as important sensors of this acidic tumor microenvironment. They transduce extracellular signals and regulate signaling pathways involved in all hallmarks of cancer. In this study, we evaluated the interplay between a pH-sensitive ion channel, the calcium (Ca2+) channel transient receptor potential C1 (TRPC1), and three different stages of the tumor microenvironment, normal pH, acid adaptation, and acid recovery, and its impact on PDAC cell migration, proliferation, and cell cycle progression. In acid adaptation and recovery conditions, TRPC1 localizes to the plasma membrane, where it interacts with PI3K and calmodulin, and permits Ca2+ entry, which results in downstream signaling, leading to proliferation and migration. Thus, TRPC1 exerts a more aggressive role after adaptation to the acidic tumor microenvironment. Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a low overall survival rate of less than 10% and limited therapeutic options. Fluctuations in tumor microenvironment pH are a hallmark of PDAC development and progression. Many ion channels are bona fide cellular sensors of changes in pH. Yet, the interplay between the acidic tumor microenvironment and ion channel regulation in PDAC is poorly understood. In this study, we show that acid adaption increases PANC-1 cell migration but attenuates proliferation and spheroid growth, which are restored upon recovery. Moreover, acid adaptation and recovery conditions favor the plasma membrane localization of the pH-sensitive calcium (Ca2+) channel transient receptor potential C1 (TRPC1), TRPC1-mediated Ca2+ influx, channel interaction with the PI3K p85α subunit and calmodulin (CaM), and AKT and ERK1/2 activation. Knockdown (KD) of TRPC1 suppresses cell migration, proliferation, and spheroid growth, notably in acid-recovered cells. KD of TRPC1 causes the accumulation of cells in G0/G1 and G2/M phases, along with reduced expression of CDK6, −2, and −1, and cyclin A, and increased expression of p21CIP1. TRPC1 silencing decreases the basal Ca2+ influx in acid-adapted and -recovered cells, but not in normal pH conditions, and Ca2+ chelation reduces cell migration and proliferation solely in acid adaptation and recovery conditions. In conclusion, acid adaptation and recovery reinforce the involvement of TRPC1 in migration, proliferation, and cell cycle progression by permitting Ca2+ entry and forming a complex with the PI3K p85α subunit and CaM.
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21
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Proposal to Consider Chemical/Physical Microenvironment as a New Therapeutic Off-Target Approach. Pharmaceutics 2022; 14:pharmaceutics14102084. [PMID: 36297518 PMCID: PMC9611316 DOI: 10.3390/pharmaceutics14102084] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/26/2022] [Accepted: 09/28/2022] [Indexed: 11/22/2022] Open
Abstract
The molecular revolution could lead drug discovery from chance observation to the rational design of new classes of drugs that could simultaneously be more effective and less toxic. Unfortunately, we are witnessing some failure in this sense, and the causes of the crisis involve a wide range of epistemological and scientific aspects. In pharmacology, one key point is the crisis of the paradigm the “magic bullet”, which is to design therapies based on specific molecular targets. Drug repurposing is one of the proposed ways out of the crisis and is based on the off-target effects of known drugs. Here, we propose the microenvironment as the ideal place to direct the off-targeting of known drugs. While it has been extensively investigated in tumors, the generation of a harsh microenvironment is also a phenotype of the vast majority of chronic diseases. The hostile microenvironment, on the one hand, reduces the efficacy of both chemical and biological drugs; on the other hand, it dictates a sort of “Darwinian” selection of those cells armed to survive in such hostile conditions. This opens the way to the consideration of the microenvironment as a convenient target for pharmacological action, with a clear example in proton pump inhibitors.
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22
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Ronco AL, Martínez-López W, Calderón JM, Storz MA. Dietary acid load and esophageal cancer risk: A case-control study. Thorac Cancer 2022; 13:2759-2766. [PMID: 36054595 PMCID: PMC9527162 DOI: 10.1111/1759-7714.14612] [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: 05/19/2022] [Revised: 07/31/2022] [Accepted: 08/01/2022] [Indexed: 12/02/2022] Open
Abstract
Background A high dietary acid load (DAL) can produce metabolic acidosis, which is linked to cancer development through mechanisms of inflammation and cell transformation. There is limited epidemiological evidence linking DAL and cancer risk; however, none of the published studies focused on DAL and esophageal cancer (EC) risk in particular. Therefore, we sought to explore this association in the present study. Methods A case‐control study was performed in 1295 male patients (185 squamous cell EC cases and 1110 age‐frequency and urban/rural residence matched controls) through a multitopic inquiry, including a food frequency questionnaire. Food‐derived nutrients were calculated from available databases. The DAL was calculated based on two validated measures: Potential renal acid load (PRAL) score and net endogenous acid production (NEAP) score. Odds ratios (OR) and their 95% confidence intervals (95% CI) were estimated by unconditional logistic regression, adjusting for confounders. Results We found direct, significant associations between dietary acid load and EC risk: (OR = 2.28, 95% CI: 1.44–3.61, ptrend <0.0001) and (OR = 2.17, 95% CI: 1.38–3.41, ptrend <0.0001) for highest PRAL and NEAP tertiles, respectively. Our data raise the possibility that a high DAL may contribute to EC development. Both acid load scores were directly associated with animal‐based foods (mainly meat) and inversely associated with the intake of plant‐based foods. Conclusion To the best of our knowledge, this is the first epidemiological case–control study analyzing associations of DAL and squamous cell EC risk. Further research is warranted to confirm our findings.
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Affiliation(s)
- Alvaro Luis Ronco
- Unit of Oncology and Radiotherapy, Pereira Rossell Women's Hospital, Montevideo, Uruguay
| | - Wilner Martínez-López
- Academic Unit on Radiation Protection, Faculty of Medicine, University of the Republic, Montevideo, Uruguay
| | - Juan M Calderón
- Biomedical Sciences Center, University of Montevideo, Montevideo, Uruguay
| | - Maximilian Andreas Storz
- Department of Internal Medicine II, Center for Complementary Medicine, Freiburg Medical Center - Faculty of Medicine, University of Freiburg, Freiburg, Germany
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23
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Russell S, Xu L, Kam Y, Abrahams D, Ordway B, Lopez AS, Bui MM, Johnson J, Epstein T, Ruiz E, Lloyd MC, Swietach P, Verduzco D, Wojtkowiak J, Gillies RJ. Proton export upregulates aerobic glycolysis. BMC Biol 2022; 20:163. [PMID: 35840963 PMCID: PMC9287933 DOI: 10.1186/s12915-022-01340-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 05/30/2022] [Indexed: 01/06/2023] Open
Abstract
INTRODUCTION Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the "Warburg Effect." It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolytic pathway, including the terminal step of exporting H+ equivalents from the cytoplasm. Proton exporters maintain an alkaline cytoplasmic pH, which can enhance all glycolytic enzyme activities, even in the absence of oncogene-related expression changes. Based on this observation, we hypothesized that increased uptake and fermentative metabolism of glucose could be driven by the expulsion of H+ equivalents from the cell. RESULTS To test this hypothesis, we stably transfected lowly glycolytic MCF-7, U2-OS, and glycolytic HEK293 cells to express proton-exporting systems: either PMA1 (plasma membrane ATPase 1, a yeast H+-ATPase) or CA-IX (carbonic anhydrase 9). The expression of either exporter in vitro enhanced aerobic glycolysis as measured by glucose consumption, lactate production, and extracellular acidification rate. This resulted in an increased intracellular pH, and metabolomic analyses indicated that this was associated with an increased flux of all glycolytic enzymes upstream of pyruvate kinase. These cells also demonstrated increased migratory and invasive phenotypes in vitro, and these were recapitulated in vivo by more aggressive behavior, whereby the acid-producing cells formed higher-grade tumors with higher rates of metastases. Neutralizing tumor acidity with oral buffers reduced the metastatic burden. CONCLUSIONS Therefore, cancer cells which increase export of H+ equivalents subsequently increase intracellular alkalization, even without oncogenic driver mutations, and this is sufficient to alter cancer metabolism towards an upregulation of aerobic glycolysis, a Warburg phenotype. Overall, we have shown that the traditional understanding of cancer cells favoring glycolysis and the subsequent extracellular acidification is not always linear. Cells which can, independent of metabolism, acidify through proton exporter activity can sufficiently drive their metabolism towards glycolysis providing an important fitness advantage for survival.
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Affiliation(s)
- Shonagh Russell
- Cancer Physiology, Moffitt Cancer Center, 12902 USF Magnolia Dr, Tampa, FL 33612 USA
- Graduate School, University of South Florida, 4202 E Fowler Ave, Tampa, FL 33620 USA
| | - Liping Xu
- Cancer Physiology, Moffitt Cancer Center, 12902 USF Magnolia Dr, Tampa, FL 33612 USA
| | - Yoonseok Kam
- Agilent Technologies, 5301 Stevens Creek Blvd, Santa Clara, CA 9505 USA
| | - Dominique Abrahams
- Cancer Physiology, Moffitt Cancer Center, 12902 USF Magnolia Dr, Tampa, FL 33612 USA
| | - Bryce Ordway
- Cancer Physiology, Moffitt Cancer Center, 12902 USF Magnolia Dr, Tampa, FL 33612 USA
- Graduate School, University of South Florida, 4202 E Fowler Ave, Tampa, FL 33620 USA
| | - Alex S. Lopez
- Anatomic Pathology, Moffitt Cancer Center, 12902 USF Magnolia Dr, Tampa, FL 33612 USA
| | - Marilyn M. Bui
- Anatomic Pathology, Moffitt Cancer Center, 12902 USF Magnolia Dr, Tampa, FL 33612 USA
- Analytic Microscopy Core, Moffitt Cancer Center, 12902 USF Magnolia Dr, Tampa, FL 33612 USA
| | - Joseph Johnson
- Analytic Microscopy Core, Moffitt Cancer Center, 12902 USF Magnolia Dr, Tampa, FL 33612 USA
| | | | - Epifanio Ruiz
- Small Animal Imaging Department, Moffitt Cancer Center, 12902 USF Magnolia Dr, Tampa, FL 33612 USA
| | - Mark C. Lloyd
- Inspirata, Inc., One North Dale Mabry Hwy. Suite 600, Tampa, FL 33609 USA
| | - Pawel Swietach
- Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT UK
| | - Daniel Verduzco
- Cancer Physiology, Moffitt Cancer Center, 12902 USF Magnolia Dr, Tampa, FL 33612 USA
| | - Jonathan Wojtkowiak
- Cancer Physiology, Moffitt Cancer Center, 12902 USF Magnolia Dr, Tampa, FL 33612 USA
| | - Robert J. Gillies
- Cancer Physiology, Moffitt Cancer Center, 12902 USF Magnolia Dr, Tampa, FL 33612 USA
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Zhang L, Zheng L, Yang X, Yao S, Wang H, An J, Jin H, Wen G, Tuo B. Pathology and physiology of acid‑sensitive ion channels in the digestive system (Review). Int J Mol Med 2022; 50:94. [PMID: 35616162 PMCID: PMC9170189 DOI: 10.3892/ijmm.2022.5150] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 05/11/2022] [Indexed: 11/16/2022] Open
Abstract
As a major proton-gated cation channel, acid-sensitive ion channels (ASICs) can perceive large extracellular pH changes. ASICs play an important role in the occurrence and development of diseases of various organs and tissues including in the heart, brain, and gastrointestinal tract, as well as in tumor proliferation, invasion, and metastasis in acidosis and regulation of an acidic microenvironment. The permeability of ASICs to sodium and calcium ions is the basis of their physiological and pathological roles in the body. This review summarizes the physiological and pathological mechanisms of ASICs in digestive system diseases, which plays an important role in the early diagnosis, treatment, and prognosis of digestive system diseases related to ASIC expression.
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Affiliation(s)
- Li Zhang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Liming Zheng
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Xingyue Yang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Shun Yao
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Hui Wang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Jiaxing An
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Hai Jin
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Guorong Wen
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Biguang Tuo
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
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25
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The risk of increasing tumor malignancy after PET diagnosis. CURRENT ISSUES IN PHARMACY AND MEDICAL SCIENCES 2022. [DOI: 10.2478/cipms-2022-0007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
This manuscript reviews evidences underlying the estimation of risk of malignancy enhancement of advanced aggressive cancers as a result of the gamma radiation emitted by tracers used in PET diagnostics. We conclude that among many cancers, such a phenomenon likely occurs, particularly in tumor cells with an aggressive biology in the advanced stages of their development, e.g. prostate cancer, melanoma and colorectal cancer. Moreover, we surmise based on gathered evidence that fluorine -18 (18F) labeled pharmaceuticals (18F-deoxyglucose and 18F-choline), commonly used in positron emission tomography (PET) can lead to malignancy enhancement of diagnosed cancer, manifesting as accelerated infiltration of the neighboring tissue, accelerated metastasis and/or radio- and chemotherapy resistance. In this review, some suggestions on future studies verifying this concept are also proposed. If our concerns are justified, it might be appropriate in the future to consider this assumption at the stage of deciding whether to undertake PET monitoring in some patients with advanced aggressive cancer.
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26
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Storz MA, Ronco AL. Quantifying dietary acid load in U.S. cancer survivors: an exploratory study using NHANES data. BMC Nutr 2022; 8:43. [PMID: 35505426 PMCID: PMC9063047 DOI: 10.1186/s40795-022-00537-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 04/26/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Diet is an important determinant of systemic pH and acid-base regulation. A frequent consumption of acid-inducing foods (including processed meats and cheese) combined with a low intake of base-inducing foods (such as fruits, legumes and vegetables) increases Dietary Acid Load (DAL), which has been associated with an increased risk for certain cancers. DAL also appears to be of paramount importance in cancer survivors, in whom it was associated with increased mortality and poor overall physical health. Literature on DAL in cancer survivors, however, is scarce and limited to a few studies. METHODS Using cross-sectional data from the National Health and Nutrition Examination Surveys (NHANES), we sought to quantify DAL in U.S. cancer survivors and contrasted the results to the general population. DAL was estimated using established formulas (Potential Renal Acid Load (PRAL) and Net Endogenous Acid Production (NEAP)). RESULTS Our study comprised 19,413 participants, of which 1444 were self-reported cancer survivors. Almost 63% of cancer survivors were female (weighted proportion) with a mean age of 61.75 (0.51) years. DAL scores were consistently higher in cancer survivors (as compared to the general population) after adjustment for confounders in multivariate regression models. These differences, however, were not statistically significant (p = 0.506 for NEAPF, 0.768 for PRALR and 0.468 for NEAPR, respectively). Notably, DAL scores were positive throughout (> 0 mEq/d) in cancer survivors, suggesting an acidifying diet. Specific examples include mean PRALR scores > 11 mEq/d in cancer survivors aged 55 years and mean NEAPF scores > 50 mEq/d in cancer survivors aged 40-60 years). CONCLUSIONS The acidifying diet in this sample of cancer survivors warrants caution and requires further investigation. Comparably high DAL scores have been associated with adverse health outcomes and an increased mortality in previous studies in breast cancer survivors. Thus, increased awareness as well as additional clinical trials in this field are urgently warranted.
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Affiliation(s)
- Maximilian Andreas Storz
- Department of Internal Medicine II, Center for Complementary Medicine, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
| | - Alvaro Luis Ronco
- Unit of Oncology and Radiotherapy, Pereira Rossell Women's Hospital, Bvard. Artigas 1590, 11600, Montevideo, Uruguay
- School of Medicine, CLAEH University, Prado and Salt Lake, 20100, Maldonado, Uruguay
- Biomedical Sciences Center, University of Montevideo, Puntas de Santiago 1604, 11500, Montevideo, Uruguay
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The role of tumor acidification in aggressiveness, cell dissemination and treatment resistance of oral squamous cell carcinoma. Life Sci 2022; 288:120163. [PMID: 34822797 DOI: 10.1016/j.lfs.2021.120163] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 11/10/2021] [Accepted: 11/16/2021] [Indexed: 12/30/2022]
Abstract
AIMS To investigate the role of tumor acidification in cell behavior, migration, and treatment resistance of oral squamous cell carcinoma (OSCC). MAIN METHODS The SCC4 and SCC25 cell lines were exposed to acidified (pH 6.8) cell culture medium for 7 days. Alternatively, a long-term acidosis was induced for 21 days. In addition, to mimic dynamic pH fluctuation of the tumor microenvironment, cells were reconditioned to neutral pH after experimental acidosis. This study assessed cell proliferation and viability by sulforhodamine B and flow cytometry. Individual and collective cell migration was analyzed by wound healing, time lapse, and transwell assays. Modifications of cell phenotype, EMT induction and stemness potential were investigated by qRT-PCR, western blot, and immunofluorescence. Finally, resistance to chemo- and radiotherapy of OSCC when exposed to acidified environmental conditions (pH 6.8) was determined. KEY FINDINGS The exposure to an acidic microenvironment caused an initial reduction of OSCC cells viability, followed by an adaptation process. Acidic adapted cells acquired a mesenchymal-like phenotype along with increased migration and motility indexes. Moreover, tumoral extracellular acidity was capable to induce cellular stemness and to increase chemo- and radioresistance of oral cancer cells. SIGNIFICANCE In summary, the results showed that the acidic microenvironment leads to a more aggressive and treatment resistant OSCC cell population.
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28
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Blaszczak W, Swietach P. What do cellular responses to acidity tell us about cancer? Cancer Metastasis Rev 2021; 40:1159-1176. [PMID: 34850320 PMCID: PMC8825410 DOI: 10.1007/s10555-021-10005-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/22/2021] [Indexed: 12/20/2022]
Abstract
The notion that invasive cancer is a product of somatic evolution is a well-established theory that can be modelled mathematically and demonstrated empirically from therapeutic responses. Somatic evolution is by no means deterministic, and ample opportunities exist to steer its trajectory towards cancer cell extinction. One such strategy is to alter the chemical microenvironment shared between host and cancer cells in a way that no longer favours the latter. Ever since the first description of the Warburg effect, acidosis has been recognised as a key chemical signature of the tumour microenvironment. Recent findings have suggested that responses to acidosis, arising through a process of selection and adaptation, give cancer cells a competitive advantage over the host. A surge of research efforts has attempted to understand the basis of this advantage and seek ways of exploiting it therapeutically. Here, we review key findings and place these in the context of a mathematical framework. Looking ahead, we highlight areas relating to cellular adaptation, selection, and heterogeneity that merit more research efforts in order to close in on the goal of exploiting tumour acidity in future therapies.
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Affiliation(s)
- Wiktoria Blaszczak
- Department of Physiology, Anatomy & Genetics, Parks Road, Oxford, OX1 3PT, England
| | - Pawel Swietach
- Department of Physiology, Anatomy & Genetics, Parks Road, Oxford, OX1 3PT, England.
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29
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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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30
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Park Y, Jeong J, Seong S, Kim W. In Silico Evaluation of Natural Compounds for an Acidic Extracellular Environment in Human Breast Cancer. Cells 2021; 10:2673. [PMID: 34685653 PMCID: PMC8534855 DOI: 10.3390/cells10102673] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/01/2021] [Accepted: 10/03/2021] [Indexed: 12/11/2022] Open
Abstract
The survival rates for breast cancer (BC) have improved in recent years, but resistance, metastasis, and recurrence still remain major therapeutic challenges for BC. The acidic tumor microenvironment (TME) has attracted attention because of its association with tumorigenesis, metastasis, drug resistance, and immune surveillance. In this study, we evaluated natural compounds from traditional herbal medicine used to treat cancer that selectively target genes regulated by extracellular acidosis. We integrated four transcriptomic data including BC prognostic data from The Cancer Genome Atlas database, gene expression profiles of MCF-7 cells treated with 102 natural compounds, patterns of gene profiles by acidic condition, and single-cell RNA-sequencing from BC patient samples. Bruceine D (BD) was predicted as having the highest therapeutic potential, having an information gain (IG) score of 0.24, to regulate reprogrammed genes driven by acidosis affecting the survival of BC patients. BD showed the highest IG on EMT (IG score: 0.11) and invasion (IG score: 0.1) compared to the other phenotypes with the CancerSEA database. BD also demonstrated therapeutic potential by interfering with the tumor cell-TME interactions by reducing the amyloid beta precursor protein and CD44 expression. Therefore, BD is a potential candidate to target the acidic TME induced metastatic process in BC.
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Affiliation(s)
- YoungJoon Park
- Cnh Center for Cancer Research, Cnh Corporation, Gangnam-gu, Seoul 06154, Korea;
| | - Jaekwang Jeong
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA;
| | - Shin Seong
- Soram Korean Medicine Hospital, Gangnam-gu, Seoul 06154, Korea;
| | - Wonnam Kim
- Cnh Center for Cancer Research, Cnh Corporation, Gangnam-gu, Seoul 06154, Korea;
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31
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Recent advances in active targeting of nanomaterials for anticancer drug delivery. Adv Colloid Interface Sci 2021; 296:102509. [PMID: 34455211 DOI: 10.1016/j.cis.2021.102509] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 07/24/2021] [Accepted: 08/15/2021] [Indexed: 12/15/2022]
Abstract
One of the challenges in cancer chemotherapy is the low target to non-target ratio of therapeutic agents which incur severe adverse effect on the healthy tissues. In this regard, nanomaterials have tremendous potential for impacting cancer therapy by altering the toxicity profile of the drug. Some of the striking advantages provided by the nanocarriers mediated targeted drug delivery are relatively high build-up of drug concentration at the tumor site, improved drug content in the formulation and enhanced colloidal stability. Further, nanocarriers with tumor-specific moieties can be targeted to the cancer cell through cell surface receptors, tumor antigens and tumor vasculatures with high affinity and accuracy. Moreover, it overcomes the bottleneck of aimless drug biodistribution, undesired toxicity and heavy dosage of administration. This review discusses the recent developments in active targeting of nanomaterials for anticancer drug delivery through cancer cell surface targeting, organelle specific targeting and tumor microenvironment targeting strategies. Special emphasis has been given towards cancer cell surface and organelle specific targeting as delivery of anticancer drugs through these routes have made paradigm change in cancer management. Further, the current challenges and future prospects of nanocarriers mediated active drug targeting are also demonstrated.
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Bychkov ML, Kirichenko AV, Shulepko MA, Mikhaylova IN, Kirpichnikov MP, Lyukmanova EN. Mambalgin-2 Inhibits Growth, Migration, and Invasion of Metastatic Melanoma Cells by Targeting the Channels Containing an ASIC1a Subunit Whose Up-Regulation Correlates with Poor Survival Prognosis. Biomedicines 2021; 9:1324. [PMID: 34680442 PMCID: PMC8533404 DOI: 10.3390/biomedicines9101324] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 02/04/2023] Open
Abstract
Melanoma is an aggressive cancer characterized by the acidification of the extracellular environment. Here, we showed for the first time that extracellular media acidification increases proliferation, migration, and invasion of patient-derived metastatic melanoma cells and up-regulates cell-surface expression of acid-sensitive channels containing the ASIC1a, α-ENaC, and γ-ENaC subunits. No influence of media acidification on these processes was found in normal keratinocytes. To control metastatic melanoma progression associated with the ASIC1a up-regulation, we proposed the ASIC1a inhibitor, -mambalgin-2 from Dendpoaspis polylepis venom. Recombinant analog of mambalgin-2 cancelled acidification-induced proliferation, migration, and invasion of metastatic melanoma cells, promoted apoptosis, and down-regulated cell-surface expression of prooncogenic factors CD44 and Frizzled 4 and phosphorylation of transcription factor SNAI. Confocal microscopy and affinity purification revealed that mambalgin-2 interacts with heterotrimeric ASIC1a/α-ENaC/γ-ENaC channels on the surface of metastatic melanoma cells. Using the mutant variant of mambalgin-2 with reduced activity toward ASIC1a, we confirmed that the principal molecular target of mambalgin-2 in melanoma cells is the ASIC1a subunit. Bioinformatic analysis confirmed up-regulation of the ASIC1 expression as a marker of poor survival prognosis for patients with metastatic melanoma. Thus, targeting ASIC1a by drugs such as mambalgin-2 could be a promising strategy for metastatic melanoma treatment.
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Affiliation(s)
- Maxim L. Bychkov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 119997 Moscow, Russia; (M.L.B.); (A.V.K.); (M.A.S.); (M.P.K.)
| | - Artem V. Kirichenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 119997 Moscow, Russia; (M.L.B.); (A.V.K.); (M.A.S.); (M.P.K.)
- Moscow Institute of Physics and Technology (State University), 141701 Dolgoprudny, Russia
| | - Mikhail A. Shulepko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 119997 Moscow, Russia; (M.L.B.); (A.V.K.); (M.A.S.); (M.P.K.)
| | - Irina N. Mikhaylova
- Federal State Budgetary Institution “N.N. Blokhin National Medical Research Center of Oncology”, Ministry of Health of Russia, 115548 Moscow, Russia;
| | - Mikhail P. Kirpichnikov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 119997 Moscow, Russia; (M.L.B.); (A.V.K.); (M.A.S.); (M.P.K.)
- Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Ekaterina N. Lyukmanova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 119997 Moscow, Russia; (M.L.B.); (A.V.K.); (M.A.S.); (M.P.K.)
- Moscow Institute of Physics and Technology (State University), 141701 Dolgoprudny, Russia
- Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
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Ion Channels, Transporters, and Sensors Interact with the Acidic Tumor Microenvironment to Modify Cancer Progression. Rev Physiol Biochem Pharmacol 2021; 182:39-84. [PMID: 34291319 DOI: 10.1007/112_2021_63] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Solid tumors, including breast carcinomas, are heterogeneous but typically characterized by elevated cellular turnover and metabolism, diffusion limitations based on the complex tumor architecture, and abnormal intra- and extracellular ion compositions particularly as regards acid-base equivalents. Carcinogenesis-related alterations in expression and function of ion channels and transporters, cellular energy levels, and organellar H+ sequestration further modify the acid-base composition within tumors and influence cancer cell functions, including cell proliferation, migration, and survival. Cancer cells defend their cytosolic pH and HCO3- concentrations better than normal cells when challenged with the marked deviations in extracellular H+, HCO3-, and lactate concentrations typical of the tumor microenvironment. Ionic gradients determine the driving forces for ion transporters and channels and influence the membrane potential. Cancer and stromal cells also sense abnormal ion concentrations via intra- and extracellular receptors that modify cancer progression and prognosis. With emphasis on breast cancer, the current review first addresses the altered ion composition and the changes in expression and functional activity of ion channels and transporters in solid cancer tissue. It then discusses how ion channels, transporters, and cellular sensors under influence of the acidic tumor microenvironment shape cancer development and progression and affect the potential of cancer therapies.
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34
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Gillies RJ. Cancer heterogeneity and metastasis: life at the edge. Clin Exp Metastasis 2021; 39:15-19. [PMID: 33999364 DOI: 10.1007/s10585-021-10101-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 04/28/2021] [Indexed: 01/05/2023]
Abstract
There is abundant evidence that the phenotype of cells the tumor at the stromal interface is distinct from the tumor cells that are within the core. Molecular phenotyping of cells at the edge show that they express higher levels of proteins associated with elevated glycolytic metabolism, including GLUT-1, HIF-1, and CA-IX. An end product of glycolysis is the production of acid, and acidosis of tumors is strongly associated with increased metastatic potential across a wide variety of tumor types. The molecular machinery promoting this export of acid is being defined, with close collaboration between carbonic anhydrases, sodium dependent bicarbonate and monocarboxylate transporters. Neutralization of this acidity can prevent local invasion and metastasis, and this has led to the "acid-mediated invasion hypothesis" wherein export of acid from the tumor into the stroma leads to matrix remodeling, which can promote local invasion.
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Affiliation(s)
- Robert J Gillies
- Department of Cancer Physiology, Moffitt Cancer Center, Tampa, FL, USA.
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Hypoxia and Extracellular Acidification as Drivers of Melanoma Progression and Drug Resistance. Cells 2021; 10:cells10040862. [PMID: 33918883 PMCID: PMC8070386 DOI: 10.3390/cells10040862] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 03/31/2021] [Accepted: 04/07/2021] [Indexed: 12/15/2022] Open
Abstract
Hypoxia and elevated extracellular acidification are prevalent features of solid tumors and they are often shown to facilitate cancer progression and drug resistance. In this review, we have compiled recent and most relevant research pertaining to the role of hypoxia and acidification in melanoma growth, invasiveness, and response to therapy. Melanoma represents a highly aggressive and heterogeneous type of skin cancer. Currently employed treatments, including BRAF V600E inhibitors and immune therapy, often are not effective due to a rapidly developing drug resistance. A variety of intracellular mechanisms impeding the treatment were discovered. However, the tumor microenvironment encompassing stromal and immune cells, extracellular matrix, and physicochemical conditions such as oxygen level or acidity, may also influence the therapy effectiveness. Hypoxia and acidification are able to reprogram the metabolism of melanoma cells, enhance their survival and invasiveness, as well as promote the immunosuppressive environment. For this reason, these physicochemical features of the melanoma niche and signaling pathways related to them emerge as potential therapeutic targets.
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Izci M, Maksoudian C, Manshian BB, Soenen SJ. The Use of Alternative Strategies for Enhanced Nanoparticle Delivery to Solid Tumors. Chem Rev 2021; 121:1746-1803. [PMID: 33445874 PMCID: PMC7883342 DOI: 10.1021/acs.chemrev.0c00779] [Citation(s) in RCA: 256] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Indexed: 02/08/2023]
Abstract
Nanomaterial (NM) delivery to solid tumors has been the focus of intense research for over a decade. Classically, scientists have tried to improve NM delivery by employing passive or active targeting strategies, making use of the so-called enhanced permeability and retention (EPR) effect. This phenomenon is made possible due to the leaky tumor vasculature through which NMs can leave the bloodstream, traverse through the gaps in the endothelial lining of the vessels, and enter the tumor. Recent studies have shown that despite many efforts to employ the EPR effect, this process remains very poor. Furthermore, the role of the EPR effect has been called into question, where it has been suggested that NMs enter the tumor via active mechanisms and not through the endothelial gaps. In this review, we provide a short overview of the EPR and mechanisms to enhance it, after which we focus on alternative delivery strategies that do not solely rely on EPR in itself but can offer interesting pharmacological, physical, and biological solutions for enhanced delivery. We discuss the strengths and shortcomings of these different strategies and suggest combinatorial approaches as the ideal path forward.
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Affiliation(s)
- Mukaddes Izci
- NanoHealth
and Optical Imaging Group, Translational Cell and Tissue Research
Unit, Department of Imaging and Pathology, KU Leuven, Herestraat 49, B3000 Leuven, Belgium
| | - Christy Maksoudian
- NanoHealth
and Optical Imaging Group, Translational Cell and Tissue Research
Unit, Department of Imaging and Pathology, KU Leuven, Herestraat 49, B3000 Leuven, Belgium
| | - Bella B. Manshian
- Translational
Cell and Tissue Research Unit, Department of Imaging and Pathology, KU Leuven, Herestraat 49, B3000 Leuven, Belgium
| | - Stefaan J. Soenen
- NanoHealth
and Optical Imaging Group, Translational Cell and Tissue Research
Unit, Department of Imaging and Pathology, KU Leuven, Herestraat 49, B3000 Leuven, Belgium
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Halcrow PW, Geiger JD, Chen X. Overcoming Chemoresistance: Altering pH of Cellular Compartments by Chloroquine and Hydroxychloroquine. Front Cell Dev Biol 2021; 9:627639. [PMID: 33634129 PMCID: PMC7900406 DOI: 10.3389/fcell.2021.627639] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 01/18/2021] [Indexed: 12/12/2022] Open
Abstract
Resistance to the anti-cancer effects of chemotherapeutic agents (chemoresistance) is a major issue for people living with cancer and their providers. A diverse set of cellular and inter-organellar signaling changes have been implicated in chemoresistance, but it is still unclear what processes lead to chemoresistance and effective strategies to overcome chemoresistance are lacking. The anti-malaria drugs, chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) are being used for the treatment of various cancers and CQ and HCQ are used in combination with chemotherapeutic drugs to enhance their anti-cancer effects. The widely accepted anti-cancer effect of CQ and HCQ is their ability to inhibit autophagic flux. As diprotic weak bases, CQ and HCQ preferentially accumulate in acidic organelles and neutralize their luminal pH. In addition, CQ and HCQ acidify the cytosolic and extracellular environments; processes implicated in tumorigenesis and cancer. Thus, the anti-cancer effects of CQ and HCQ extend beyond autophagy inhibition. The present review summarizes effects of CQ, HCQ and proton pump inhibitors on pH of various cellular compartments and discuss potential mechanisms underlying their pH-dependent anti-cancer effects. The mechanisms considered here include their ability to de-acidify lysosomes and inhibit autophagosome lysosome fusion, to de-acidify Golgi apparatus and secretory vesicles thus affecting secretion, and to acidify cytoplasm thus disturbing aerobic metabolism. Further, we review the ability of these agents to prevent chemotherapeutic drugs from accumulating in acidic organelles and altering their cytosolic concentrations.
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Affiliation(s)
| | | | - Xuesong Chen
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, United States
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38
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Anemone A, Consolino L, Conti L, Irrera P, Hsu MY, Villano D, Dastrù W, Porporato PE, Cavallo F, Longo DL. Tumour acidosis evaluated in vivo by MRI-CEST pH imaging reveals breast cancer metastatic potential. Br J Cancer 2021; 124:207-216. [PMID: 33257841 PMCID: PMC7782702 DOI: 10.1038/s41416-020-01173-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 10/07/2020] [Accepted: 10/28/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Tumour acidosis is considered to play a central role in promoting cancer invasion and migration, but few studies have investigated in vivo how tumour pH correlates with cancer invasion. This study aims to determine in vivo whether tumour acidity is associated with cancer metastatic potential. METHODS Breast cancer cell lines with different metastatic potentials have been characterised for several markers of aggressiveness and invasiveness. Murine tumour models have been developed and assessed for lung metastases and tumour acidosis has been assessed in vivo by a magnetic resonance imaging-based chemical exchange saturation transfer (CEST) pH imaging approach. RESULTS The higher metastatic potential of 4T1 and TS/A primary tumours, in comparison to the less aggressive TUBO and BALB-neuT ones, was confirmed by the highest expression of cancer cell stem markers (CD44+CD24-), highlighting their propensity to migrate and invade, coinciding with the measurement obtained by in vitro assays. MRI-CEST pH imaging successfully discriminated the more aggressive 4T1 and TS/A tumours that displayed a more acidic pH. Moreover, the observed higher tumour acidity was significantly correlated with an increased number of lung metastases. CONCLUSIONS The findings of this study indicate that the extracellular acidification is associated with the metastatic potential.
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Affiliation(s)
- Annasofia Anemone
- Department of Molecular Biotechnology and Health Sciences, Molecular Imaging Center, University of Torino, Via Nizza 52, Torino, Italy
| | - Lorena Consolino
- Department of Molecular Biotechnology and Health Sciences, Molecular Imaging Center, University of Torino, Via Nizza 52, Torino, Italy
| | - Laura Conti
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, Torino, Italy
| | - Pietro Irrera
- University of Campania "Luigi Vanvitelli", Viale Abramo Lincoln, 5, Caserta, Italy
| | - Myriam Y Hsu
- Department of Molecular Biotechnology and Health Sciences, Molecular Imaging Center, University of Torino, Via Nizza 52, Torino, Italy
| | - Daisy Villano
- Department of Molecular Biotechnology and Health Sciences, Molecular Imaging Center, University of Torino, Via Nizza 52, Torino, Italy
| | - Walter Dastrù
- Department of Molecular Biotechnology and Health Sciences, Molecular Imaging Center, University of Torino, Via Nizza 52, Torino, Italy
| | - Paolo E Porporato
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, Torino, Italy
| | - Federica Cavallo
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, Torino, Italy
| | - Dario Livio Longo
- Institute of Biostructures and Bioimaging (IBB), Italian National Research Council (CNR), Via Nizza 52, Torino, Italy.
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39
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Quade BN, Parker MD, Occhipinti R. The therapeutic importance of acid-base balance. Biochem Pharmacol 2021; 183:114278. [PMID: 33039418 PMCID: PMC7544731 DOI: 10.1016/j.bcp.2020.114278] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 10/06/2020] [Indexed: 02/06/2023]
Abstract
Baking soda and vinegar have been used as home remedies for generations and today we are only a mouse-click away from claims that baking soda, lemon juice, and apple cider vinegar are miracles cures for everything from cancer to COVID-19. Despite these specious claims, the therapeutic value of controlling acid-base balance is indisputable and is the basis of Food and Drug Administration-approved treatments for constipation, epilepsy, metabolic acidosis, and peptic ulcers. In this narrative review, we present evidence in support of the current and potential therapeutic value of countering local and systemic acid-base imbalances, several of which do in fact involve the administration of baking soda (sodium bicarbonate). Furthermore, we discuss the side effects of pharmaceuticals on acid-base balance as well as the influence of acid-base status on the pharmacokinetic properties of drugs. Our review considers all major organ systems as well as information relevant to several clinical specialties such as anesthesiology, infectious disease, oncology, dentistry, and surgery.
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Affiliation(s)
- Bianca N Quade
- Department of Physiology and Biophysics, The State University of New York, The University at Buffalo, Buffalo, NY 14203, USA
| | - Mark D Parker
- Department of Physiology and Biophysics, The State University of New York, The University at Buffalo, Buffalo, NY 14203, USA; Department of Ophthalmology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA; State University of New York Eye Institute, University at Buffalo, The State University of New York, Buffalo, NY, USA
| | - Rossana Occhipinti
- Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
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40
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Urbanelli L, Buratta S, Logozzi M, Mitro N, Sagini K, Raimo RD, Caruso D, Fais S, Emiliani C. Lipidomic analysis of cancer cells cultivated at acidic pH reveals phospholipid fatty acids remodelling associated with transcriptional reprogramming. J Enzyme Inhib Med Chem 2020; 35:963-973. [PMID: 32308048 PMCID: PMC7191909 DOI: 10.1080/14756366.2020.1748025] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Cancer cells need to modulate the biosynthesis of membrane lipids and fatty acids to adapt themselves to an accelerated rate of cell division and survive into an extracellular environment characterised by a low pH. To gain insight this crucial survival process, we investigated the lipid composition of Mel 501 melanoma cells cultured at either physiological or acidic pH and observed the remodelling of phospholipids towards longer and more unsaturated acyl chains at low pH. This modification was related to changes in gene expression profile, as we observed an up-regulation of genes involved in acyl chain desaturation, elongation and transfer to phospholipids. PC3 prostate and MCF7 breast cancer cells adapted at acidic pH also demonstrated phospholipid fatty acid remodelling related to gene expression changes. Overall findings clearly indicate that low extracellular pH impresses a specific lipid signature to cells, associated with transcriptional reprogramming.
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Affiliation(s)
- Lorena Urbanelli
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy
| | - Sandra Buratta
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy
| | - Mariantonia Logozzi
- Department of Oncology and Molecular Medicine, National Institute of Health, Rome, Italy
| | - Nico Mitro
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Krizia Sagini
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy
| | - Rossella Di Raimo
- Department of Oncology and Molecular Medicine, National Institute of Health, Rome, Italy
| | - Donatella Caruso
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Stefano Fais
- Department of Oncology and Molecular Medicine, National Institute of Health, Rome, Italy
| | - Carla Emiliani
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.,CEMIN-Center of Excellence for Innovative Nanostructured Material, University of Perugia, Perugia, Italy
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41
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Kudriaeva AA, Saratov GA, Kaminskaya AN, Vladimirov VI, Barzilovich PY, Belogurov AA. Polyamines Counteract Carbonate-Driven Proteasome Stalling in Alkaline Conditions. Biomolecules 2020; 10:biom10121597. [PMID: 33255475 PMCID: PMC7760842 DOI: 10.3390/biom10121597] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/13/2020] [Accepted: 11/16/2020] [Indexed: 02/04/2023] Open
Abstract
Cancer cells tend to increase intracellular pH and, at the same time, are known to intensively produce and uptake polyamines such as spermine. Here, we show that various amines, including biogenic polyamines, boost the activity of proteasomes in a dose-dependent manner. Proteasome activity in the classical amine-containing buffers, such as 2-(N-morpholino)ethanesulfonic acid (MES), Tris, (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), glycylglycine, bis-Tris propane, and bicine, has a skewed distribution with a maximum at pH of 7.0–8.0. The activity of proteasomes in buffers containing imidazole and bis-Tris is maintained almost on the same level, in the pH range of 6.5–8.5. The third type of activation is observed in buffers based on the amino acids arginine and ornithine, as well as the natural polyamines spermine and spermidine. Proteasome activity in these buffers is dramatically increased at pH values greater than 7.5. Anionic buffers such as phosphate or carbonate, in contrast, inhibit proteasome activity during alkalization. Importantly, supplementation of a carbonate–phosphate buffer with spermine counteracts carbonate-driven proteasome stalling in alkaline conditions, predicting an additional physiological role of polyamines in maintaining the metabolism and survival of cancer cells.
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Affiliation(s)
- Anna A. Kudriaeva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (A.A.K.); (G.A.S.); (A.N.K.); (P.Y.B.)
| | - George A. Saratov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (A.A.K.); (G.A.S.); (A.N.K.); (P.Y.B.)
- Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology (National Research University), 141701 Dolgoprudny, Russia
| | - Alena N. Kaminskaya
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (A.A.K.); (G.A.S.); (A.N.K.); (P.Y.B.)
| | - Vasiliy I. Vladimirov
- Pushchino Branch of Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 142290 Pushchino, Russia;
| | - Petro Yu Barzilovich
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (A.A.K.); (G.A.S.); (A.N.K.); (P.Y.B.)
| | - Alexey A. Belogurov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (A.A.K.); (G.A.S.); (A.N.K.); (P.Y.B.)
- Faculty of Fundamental Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia
- Correspondence:
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42
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Boussadia Z, Zanetti C, Parolini I. Role of microenvironmental acidity and tumor exosomes in cancer immunomodulation. Transl Cancer Res 2020; 9:5775-5786. [PMID: 35117938 PMCID: PMC8798230 DOI: 10.21037/tcr.2020.03.69] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 03/13/2020] [Indexed: 12/12/2022]
Abstract
Tumor microenvironment (TME) is a complex milieu in which tumor grows, develops and progresses through a complex bi-directional cross-talk with immune-, stromal cells, and the extracellular matrix (ECM). In this context, tumor-derived exosomes (TE) drive the fate of tumor cells through a stimulatory or inhibitory role on immune system. In fact, TE can induce the apoptosis of cells of the immune surveillance, and enhance the proliferation and survival of stromal cells that sustain tumor development. However, depending on the molecular cargo, TE are also able to stimulate anti-tumor immune response. TME is mainly characterized by the acidic pH that contributes to tumor development, through multiple mechanisms. Among these, the impairment of tumor immune surveillance does occur within acidic TME, and is directly mediated by acidic pH or by molecular cargo carried by TE. Little is known about the role of TE in immunomodulation in acidic conditions. The present review summarizes the studies describing the role of microenvironmental acidity and TE in immune system modulation.
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Affiliation(s)
- Zaira Boussadia
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Roma, Italy
| | - Cristiana Zanetti
- Deparment of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Roma, Italy
| | - Isabella Parolini
- Deparment of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Roma, Italy
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43
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Yao J, Czaplinska D, Ialchina R, Schnipper J, Liu B, Sandelin A, Pedersen SF. Cancer Cell Acid Adaptation Gene Expression Response Is Correlated to Tumor-Specific Tissue Expression Profiles and Patient Survival. Cancers (Basel) 2020; 12:cancers12082183. [PMID: 32764426 PMCID: PMC7463722 DOI: 10.3390/cancers12082183] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/21/2020] [Accepted: 07/31/2020] [Indexed: 12/13/2022] Open
Abstract
The acidic pH of the tumor microenvironment plays a critical role in driving cancer development toward a more aggressive phenotype, but the underlying mechanisms are unclear. To this end, phenotypic and genotypic changes induced by adaptation of cancer cells to chronic acidosis have been studied. However, the generality of acid adaptation patterns across cell models and their correlation to the molecular phenotypes and aggressiveness of human cancers are essentially unknown. Here, we define an acid adaptation expression response shared across three cancer cell models, dominated by metabolic rewiring, extracellular matrix remodeling, and altered cell cycle regulation and DNA damage response. We find that many genes which are upregulated by acid adaptation are significantly correlated to patient survival, and more generally, that there are clear correlations between acid adaptation expression response and gene expression change between normal and tumor tissues, for a large subset of cancer patients. Our data support the notion that tumor microenvironment acidity is one of the key factors driving the selection of aggressive cancer cells in human patient tumors, yet it also induces a growth-limiting genotype that likely limits cancer cell growth until the cells are released from acidosis, for instance during invasion.
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Affiliation(s)
- Jiayi Yao
- The Bioinformatics Centre, Department of Biology, University of Copenhagen, DK2200 Copenhagen, Denmark;
- Biotech Research and Innovation Centre, University of Copenhagen, DK2200 Copenhagen, Denmark
| | - Dominika Czaplinska
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, DK2100 Copenhagen, Denmark; (D.C.); (R.I.); (J.S.)
| | - Renata Ialchina
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, DK2100 Copenhagen, Denmark; (D.C.); (R.I.); (J.S.)
| | - Julie Schnipper
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, DK2100 Copenhagen, Denmark; (D.C.); (R.I.); (J.S.)
| | - Bin Liu
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, DK2100 Copenhagen, Denmark;
| | - Albin Sandelin
- The Bioinformatics Centre, Department of Biology, University of Copenhagen, DK2200 Copenhagen, Denmark;
- Biotech Research and Innovation Centre, University of Copenhagen, DK2200 Copenhagen, Denmark
- Correspondence: (A.S.); (S.F.P.)
| | - Stine Falsig Pedersen
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, DK2100 Copenhagen, Denmark; (D.C.); (R.I.); (J.S.)
- Correspondence: (A.S.); (S.F.P.)
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44
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Targeting the Acidic Tumor Microenvironment: Unexpected Pro-Neoplastic Effects of Oral NaHCO 3 Therapy in Murine Breast Tissue. Cancers (Basel) 2020; 12:cancers12040891. [PMID: 32268614 PMCID: PMC7226235 DOI: 10.3390/cancers12040891] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/31/2020] [Accepted: 03/31/2020] [Indexed: 11/16/2022] Open
Abstract
The acidic tumor microenvironment modifies malignant cell behavior. Here, we study consequences of the microenvironment in breast carcinomas. Beginning at carcinogen-based breast cancer induction, we supply either regular or NaHCO3-containing drinking water to female C57BL/6j mice. We evaluate urine and blood acid-base status, tumor metabolism (microdialysis sampling), and tumor pH (pH-sensitive microelectrodes) in vivo. Based on freshly isolated epithelial organoids from breast carcinomas and normal breast tissue, we assess protein expression (immunoblotting, mass spectrometry), intracellular pH (fluorescence microscopy), and cell proliferation (bromodeoxyuridine incorporation). Oral NaHCO3 therapy increases breast tumor pH in vivo from 6.68 ± 0.04 to 7.04 ± 0.09 and intracellular pH in breast epithelial organoids by ~0.15. Breast tumors develop with median latency of 85.5 ± 8.2 days in NaHCO3-treated mice vs. 82 ± 7.5 days in control mice. Oral NaHCO3 therapy does not affect tumor growth, histopathology or glycolytic metabolism. The capacity for cellular net acid extrusion is increased in NaHCO3-treated mice and correlates negatively with breast tumor latency. Oral NaHCO3 therapy elevates proliferative activity in organoids from breast carcinomas. Changes in protein expression patterns-observed by high-throughput proteomics analyses-between cancer and normal breast tissue and in response to oral NaHCO3 therapy reveal complex influences on metabolism, cytoskeleton, cell-cell and cell-matrix interaction, and cell signaling pathways. We conclude that oral NaHCO3 therapy neutralizes the microenvironment of breast carcinomas, elevates the cellular net acid extrusion capacity, and accelerates proliferation without net effect on breast cancer development or tumor growth. We demonstrate unexpected pro-neoplastic consequences of oral NaHCO3 therapy that in breast tissue cancel out previously reported anti-neoplastic effects.
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Rebecca VW, Herlyn M. Nongenetic Mechanisms of Drug Resistance in Melanoma. ANNUAL REVIEW OF CANCER BIOLOGY 2020. [DOI: 10.1146/annurev-cancerbio-030419-033533] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Resistance to targeted and immune-based therapies limits cures in patients with metastatic melanoma. A growing number of reports have identified nongenetic primary resistance mechanisms including intrinsic microenvironment- and lineage plasticity–mediated processes serving critical functions in the persistence of disease throughout therapy. There is a temporally shifting spectrum of cellular identities fluidly occupied by therapy-persisting melanoma cells responsible for driving therapeutic resistance and metastasis. The key epigenetic, metabolic, and phenotypic reprogramming events requisite for the manifestation and maintenance of so-called persister melanoma populations remain poorly understood and underscore the need to comprehensively investigate actionable vulnerabilities. Here we attempt to integrate the field's observations on nongenetic mechanisms of drug resistance in melanoma. We postulate that the future design of therapeutic strategies specifically addressing therapy-persisting subpopulations of melanoma will improve the curative potential of therapy for patients with metastatic disease.
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Affiliation(s)
- Vito W. Rebecca
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA
| | - Meenhard Herlyn
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA
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46
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Abstract
The microenvironment of solid tumors is often acidic due to poor vascular perfusion, regional hypoxia, and increased glycolytic activity of tumor cells. Although acidosis is harmful to most types of cells, tumor cells seem well adapted to such harsh conditions. Moreover, overwhelming evidence indicates that tumor cells are more invasive and more aggressive in acidic conditions by a cascade of cell signaling and upregulation of oncogenic gene expression. Therefore, how extracellular acidic signals are transduced to the cytoplasm and then into the nucleus is an interesting topic to many cancer researchers. In this review, we update on the recent advances in acidosis-induced tumorigenesis through the acid-sensing ion channels (ASICs) and activation of cell signaling.
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Affiliation(s)
- Liu Yang
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, P.R. China
| | - Xiaoge Hu
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang, P.R. China.,Cancer Institute and Department of Pharmacology/Toxicology, University of Mississippi Medical Center, Jackson, MS, USA
| | - Yin-Yuan Mo
- Cancer Institute and Department of Pharmacology/Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.
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47
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Abstract
Acidic metabolic waste products accumulate in the tumor microenvironment because of high metabolic activity and insufficient perfusion. In tumors, the acidity of the interstitial space and the relatively well-maintained intracellular pH influence cancer and stromal cell function, their mutual interplay, and their interactions with the extracellular matrix. Tumor pH is spatially and temporally heterogeneous, and the fitness advantage of cancer cells adapted to extracellular acidity is likely particularly evident when they encounter less acidic tumor regions, for instance, during invasion. Through complex effects on genetic stability, epigenetics, cellular metabolism, proliferation, and survival, the compartmentalized pH microenvironment favors cancer development. Cellular selection exacerbates the malignant phenotype, which is further enhanced by acid-induced cell motility, extracellular matrix degradation, attenuated immune responses, and modified cellular and intercellular signaling. In this review, we discuss how the acidity of the tumor microenvironment influences each stage in cancer development, from dysplasia to full-blown metastatic disease.
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Affiliation(s)
- Ebbe Boedtkjer
- Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark
| | - Stine F. Pedersen
- Department of Biology, University of Copenhagen, DK-2100 Copenhagen, Denmark
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Abstract
PURPOSE OF REVIEW A strong association between diabetes mellitus and carcinogenesis has been reported in different organs. The purpose of this review is to summarize the new evidences in relation to diabetes mellitus and its association with the development, prognosis, and therapeutic strategies of head and neck squamous cell carcinomas (HNSCC). RECENT FINDINGS Recent publications suggest that glycemic metabolism is altered in HNSCC. Elevated blood glucose levels, before or around the time of diagnosis, have been reported to reduce survival rates in HNSCC. Also, the homeostasis model assessment-insulin resistance has been independently associated with disease-free survival, suggesting that improving the glycemic control may improve the prognosis in this group of patients.Epidemiological studies revealed that cancer patients with diabetes mellitus have less cancer-related mortality after antiglycemic treatment, opening the option to include antiglycolytic agents, such as metformin, in the therapeutic plan. This finding is in accordance with in-vitro studies that demonstrated a decrease in tumor-cell proliferation with antidiabetic medications. SUMMARY Recent findings highlight the importance of glucose metabolism in the pathogenesis and progression of cancer cells. The knowledge of these altered pathways gives us an opportunity to design target treatments aimed to modulate glucose catabolism.
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Serpa J. Metabolic Remodeling as a Way of Adapting to Tumor Microenvironment (TME), a Job of Several Holders. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1219:1-34. [PMID: 32130691 DOI: 10.1007/978-3-030-34025-4_1] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The microenvironment depends and generates dependence on all the cells and structures that share the same niche, the biotope. The contemporaneous view of the tumor microenvironment (TME) agrees with this idea. The cells that make up the tumor, whether malignant or not, behave similarly to classes of elements within a living community. These elements inhabit, modify and benefit from all the facilities the microenvironment has to offer and that will contribute to the survival and growth of the tumor and the progression of the disease.The metabolic adaptation to microenvironment is a crucial process conducting to an established tumor able to grow locally, invade and metastasized. The metastatic cancer cells are reasonable more plastic than non-metastatic cancer cells, because the previous ones must survive in the microenvironment where the primary tumor develops and in addition, they must prosper in the microenvironment in the metastasized organ.The metabolic remodeling requires not only the adjustment of metabolic pathways per se but also the readjustment of signaling pathways that will receive and obey to the extracellular instructions, commanding the metabolic adaptation. Many diverse players are pivotal in cancer metabolic fitness from the initial signaling stimuli, going through the activation or repression of genes, until the phenotype display. The new phenotype will permit the import and consumption of organic compounds, useful for energy and biomass production, and the export of metabolic products that are useless or must be secreted for a further recycling or controlled uptake. In the metabolic network, three subsets of players are pivotal: (1) the organic compounds; (2) the transmembrane transporters, and (3) the enzymes.This chapter will present the "Pharaonic" intent of diagraming the interplay between these three elements in an attempt of simplifying and, at the same time, of showing the complex sight of cancer metabolism, addressing the orchestrating role of microenvironment and highlighting the influence of non-cancerous cells.
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Affiliation(s)
- Jacinta Serpa
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal.
- Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisbon, Portugal.
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Dunne M, Regenold M, Allen C. Hyperthermia can alter tumor physiology and improve chemo- and radio-therapy efficacy. Adv Drug Deliv Rev 2020; 163-164:98-124. [PMID: 32681862 DOI: 10.1016/j.addr.2020.07.007] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 07/07/2020] [Accepted: 07/10/2020] [Indexed: 12/20/2022]
Abstract
Hyperthermia has demonstrated clinical success in improving the efficacy of both chemo- and radio-therapy in solid tumors. Pre-clinical and clinical research studies have demonstrated that targeted hyperthermia can increase tumor blood flow and increase the perfused fraction of the tumor in a temperature and time dependent manner. Changes in tumor blood circulation can produce significant physiological changes including enhanced vascular permeability, increased oxygenation, decreased interstitial fluid pressure, and reestablishment of normal physiological pH conditions. These alterations in tumor physiology can positively impact both small molecule and nanomedicine chemotherapy accumulation and distribution within the tumor, as well as the fraction of the tumor susceptible to radiation therapy. Hyperthermia can trigger drug release from thermosensitive formulations and further improve the accumulation, distribution, and efficacy of chemotherapy.
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