|
1
|
Liu S, Liu C, He Y, Li J. Benign non-immune cells in tumor microenvironment. Front Immunol 2025; 16:1561577. [PMID: 40248695 PMCID: PMC12003390 DOI: 10.3389/fimmu.2025.1561577] [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: 01/20/2025] [Accepted: 02/24/2025] [Indexed: 04/19/2025] Open
Abstract
The tumor microenvironment (TME) is a highly complex and continuous evolving ecosystem, consisting of a diverse array of cellular and non-cellular components. Among these, benign non-immune cells, including cancer-associated fibroblasts (CAFs), adipocytes, endothelial cells (ECs), pericytes (PCs), Schwann cells (SCs) and others, are crucial factors for tumor development. Benign non-immune cells within the TME interact with both tumor cells and immune cells. These interactions contribute to tumor progression through both direct contact and indirect communication. Numerous studies have highlighted the role that benign non-immune cells exert on tumor progression and potential tumor-promoting mechanisms via multiple signaling pathways and factors. However, these benign non-immune cells may play different roles across cancer types. Therefore, it is important to understand the potential roles of benign non-immune cells within the TME based on tumor heterogeneity. A deep understanding allows us to develop novel cancer therapies by targeting these cells. In this review, we will introduce several types of benign non-immune cells that exert on different cancer types according to tumor heterogeneity and their roles in the TME.
Collapse
Affiliation(s)
- Shaowen Liu
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Chunhui Liu
- The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, China
| | - Yuan He
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jun Li
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, China
- Department of Molecular Pathology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| |
Collapse
|
|
2
|
Chen S, Zhou Z, Li Y, Du Y, Chen G. Application of single-cell sequencing to the research of tumor microenvironment. Front Immunol 2023; 14:1285540. [PMID: 37965341 PMCID: PMC10641410 DOI: 10.3389/fimmu.2023.1285540] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 10/17/2023] [Indexed: 11/16/2023] Open
Abstract
Single-cell sequencing is a technique for detecting and analyzing genomes, transcriptomes, and epigenomes at the single-cell level, which can detect cellular heterogeneity lost in conventional sequencing hybrid samples, and it has revolutionized our understanding of the genetic heterogeneity and complexity of tumor progression. Moreover, the tumor microenvironment (TME) plays a crucial role in the formation, development and response to treatment of tumors. The application of single-cell sequencing has ushered in a new age for the TME analysis, revealing not only the blueprint of the pan-cancer immune microenvironment, but also the heterogeneity and differentiation routes of immune cells, as well as predicting tumor prognosis. Thus, the combination of single-cell sequencing and the TME analysis provides a unique opportunity to unravel the molecular mechanisms underlying tumor development and progression. In this review, we summarize the recent advances in single-cell sequencing and the TME analysis, highlighting their potential applications in cancer research and clinical translation.
Collapse
Affiliation(s)
| | | | | | | | - Guoan Chen
- Department of Human Cell Biology and Genetics, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| |
Collapse
|
|
3
|
Badve SS, Gökmen-Polar Y. Targeting the Tumor-Tumor Microenvironment Crosstalk. Expert Opin Ther Targets 2023; 27:447-457. [PMID: 37395003 DOI: 10.1080/14728222.2023.2230362] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 06/23/2023] [Indexed: 07/04/2023]
Abstract
INTRODUCTION Cancer development and progression is a complex process influenced by co-evolution of the cancer cells and their microenvironment. However, traditional anti-cancer therapy is mostly targeted toward cancer cells. To improve the efficacy of cancer drugs, the complex interactions between the tumor (T) and the tumor microenvironment (TME) should be considered while developing therapeutics. AREAS COVERED The present review article will discuss the components of T-TME as well as the potential to co-target these two distinct elements. We document that these approaches have resulted in success in preventing tumor progression and metastasis, albeit in animal models in some cases. Lastly, it is important to consider the tissue context and tumor type as these could significantly modify the role of these molecules/pathways and hence the overall likelihood of response. Furthermore, we discuss the potential strategies to target the components of tumor microenvironment in anti-cancer therapy. PubMed and ClinicalTrials.gov was searched through May 2023. EXPERT OPINION The tumor-tumor microenvironment cross talk and heterogeneity are major mechanisms conferring resistance to standard of care. Better understanding of the tissue specific T-TME interactions and dual targeting has the promise of improving cancer control and clinical outcomes.
Collapse
Affiliation(s)
- Sunil S Badve
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
| | - Yesim Gökmen-Polar
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
| |
Collapse
|
|
4
|
Tang Q, Fang J, Lai W, Hu Y, Liu C, Hu X, Song C, Cheng T, Liu R, Huang X. Hippo pathway monomerizes STAT3 to regulate prostate cancer growth. Cancer Sci 2022; 113:2753-2762. [PMID: 35722967 PMCID: PMC9357639 DOI: 10.1111/cas.15463] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 04/25/2022] [Accepted: 06/09/2022] [Indexed: 02/05/2023] Open
Abstract
Prostate cancer ranks among the most commonly diagnosed malignancies for men, and has become a non-negligible threat for public health. Interplay between inflammatory factors and cancer cells renders inflammatory tissue environment as a predisposing condition for cancer development. The Hippo pathway is a conserved signaling pathway across multiple species during evolution that regulates tissue homeostasis and organ development. Nevertheless, whether Hippo pathway regulates cancer-related inflammatory factors remain elusive. Here we show that high cell density-mediated activation of Hippo pathway blunts STAT3 activity in prostate cancer cells. Hippo pathway component MST2 kinase phosphorylates STAT3 at T622, which is located in the SH2 domain of STAT3. This phosphorylation blocks SH2 domain in one STAT3 molecule to bind with the phosphorylated Y705 site in another STAT3 molecule, which further counteracts IL6-induced STAT3 dimerization and activation. Expression of a non-phosphoryable STAT3 T622A mutant enhances STAT3 activity and IL6 expression at high cell density, and promotes tumor growth in mice xenograft model. Our findings demonstrate that STAT3 is a novel phosphorylation substrate for MST2, and thereby highlight a regulatory cascade underlying the crosstalk between inflammation and Hippo pathway in prostate cancer cells.
Collapse
Affiliation(s)
- Qingfeng Tang
- Department of Urology, Xindu district People's hospital of Chengdu, Chengdu, 610500, China
| | - Jing Fang
- Department of Nephrology, The sixth people's hospital of Chengdu, Chengdu, 610051, China
| | - Weiqi Lai
- Department of Urology, Xindu district People's hospital of Chengdu, Chengdu, 610500, China
| | - Yu Hu
- Department of Urology, Xindu district People's hospital of Chengdu, Chengdu, 610500, China
| | - Chengwan Liu
- Department of Urology, Xindu district People's hospital of Chengdu, Chengdu, 610500, China
| | - Xiaobo Hu
- Department of Urology, Xindu district People's hospital of Chengdu, Chengdu, 610500, China
| | - Caiyong Song
- Department of Urology, Xindu district People's hospital of Chengdu, Chengdu, 610500, China
| | - Tianmu Cheng
- Department of Urology, Xindu district People's hospital of Chengdu, Chengdu, 610500, China
| | - Rui Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P. R. China
| | - Xiaoke Huang
- Department of Urology, Xindu district People's hospital of Chengdu, Chengdu, 610500, China
| |
Collapse
|
|
5
|
Zhang H, Ma H, Yang X, Fan L, Tian S, Niu R, Yan M, Zheng M, Zhang S. Cell Fusion-Related Proteins and Signaling Pathways, and Their Roles in the Development and Progression of Cancer. Front Cell Dev Biol 2022; 9:809668. [PMID: 35178400 PMCID: PMC8846309 DOI: 10.3389/fcell.2021.809668] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 12/22/2021] [Indexed: 12/16/2022] Open
Abstract
Cell fusion is involved in many physiological and pathological processes, including gamete binding, and cancer development. The basic processes of cell fusion include membrane fusion, cytoplasmic mixing, and nuclear fusion. Cell fusion is regulated by different proteins and signaling pathways. Syncytin-1, syncytin-2, glial cell missing 1, galectin-1 and other proteins (annexins, myomaker, myomerger etc.) involved in cell fusion via the cyclic adenosine-dependent protein kinase A, mitogen-activated protein kinase, wingless/integrase-1, and c-Jun N-terminal kinase signaling pathways. In the progression of malignant tumors, cell fusion is essential during the organ-specific metastasis, epithelial-mesenchymal transformation, the formation of cancer stem cells (CSCs), cancer angiogenesis and cancer immunity. In addition, diploid cells can be induced to form polyploid giant cancer cells (PGCCs) via cell fusion under many kinds of stimuli, including cobalt chloride, chemotherapy, radiotherapy, and traditional Chinese medicine. PGCCs have CSC-like properties, and the daughter cells derived from PGCCs have a mesenchymal phenotype and exhibit strong migration, invasion, and proliferation abilities. Therefore, exploring the molecular mechanisms of cell fusion can enable us better understand the development of malignant tumors. In this review, the basic process of cell fusion and its significance in cancer is discussed.
Collapse
Affiliation(s)
- Hao Zhang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hong Ma
- Tianjin Union Medical Center, Nankai University, Tianjin, China
| | - Xiaohui Yang
- Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Linlin Fan
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Shifeng Tian
- Graduate School, Tianjin Medical University, Tianjin, China
| | - Rui Niu
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Man Yan
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Minying Zheng
- Tianjin Union Medical Center, Nankai University, Tianjin, China
| | - Shiwu Zhang
- Tianjin Union Medical Center, Nankai University, Tianjin, China
| |
Collapse
|
|
6
|
Nanoparticle-Based Modification of the DNA Methylome: A Therapeutic Tool for Atherosclerosis? CARDIOGENETICS 2022. [DOI: 10.3390/cardiogenetics12010002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Cardiovascular epigenomics is a relatively young field of research, yet it is providing novel insights into gene regulation in the atherosclerotic arterial wall. That information is already pointing to new avenues for atherosclerosis (AS) prevention and therapy. In parallel, advances in nanoparticle (NP) technology allow effective targeting of drugs and bioactive molecules to the vascular wall. The partnership of NP technology and epigenetics in AS is just beginning and promises to produce novel exciting candidate treatments. Here, we briefly discuss the most relevant recent advances in the two fields. We focus on AS and DNA methylation, as the DNA methylome of that condition is better understood in comparison with the rest of the cardiovascular disease field. In particular, we review the most recent advances in NP-based delivery systems and their use for DNA methylome modification in inflammation. We also address the promises of DNA methyltransferase inhibitors for prevention and therapy. Furthermore, we emphasize the unique challenges in designing therapies that target the cardiovascular epigenome. Lastly, we touch the issue of human exposure to industrial NPs and its impact on the epigenome as a reminder of the undesired effects that any NP-based therapy must avoid to be apt for secondary prevention of AS.
Collapse
|
|
7
|
Rawat K, Syeda S, Shrivastava A. Hyperactive neutrophils infiltrate vital organs of tumor bearing host and contribute to gradual systemic deterioration via upregulated NE, MPO and MMP-9 activity. Immunol Lett 2021; 241:35-48. [PMID: 34890699 DOI: 10.1016/j.imlet.2021.12.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/27/2021] [Accepted: 12/06/2021] [Indexed: 12/15/2022]
Abstract
Cancer is known to have systemic impact by targeting various organs that ultimately compromises the overall physiology of the host. Several reports have demonstrated the role of neutrophils in cancer wherein the focus has been drawn on the elevated neutrophil count in blood or at tumor loci. However, their role in mediating systemic effects during cancer progression has not been deciphered so far. Therefore, it is worthwhile to explore whether and how neutrophils contribute to systemic deterioration in cancer. To discern their systemic role, we evaluated neutrophil count and function at different stages of tumor growth in Dalton's Lymphoma mice model. Notably, our results displayed a gradual increase in Ly6G+ neutrophils in peripheral blood and their infiltration in vital organs including liver, lungs, spleen, kidney, lymph nodes and peritoneum of tumor bearing host. We showed remarkable alterations in histoarchitecture and serum enzyme levels that aggravated with tumor progression. We next examined neutrophil function by assessing its granular cargoes including neutrophil elastase (NE), myeloperoxidase (MPO), and matrix metalloproteinases (MMP-8 and MMP-9). Interestingly, blood neutrophils of tumor bearing mice exhibited a marked change in morphology with gradual increase in NE and MPO expression with tumor growth. In addition, we observed upregulated expression of NE, MPO, MMP-8 and MMP-9 in the vital organs of tumor bearing host. Taken together, our results demonstrate heightened infiltration and function of neutrophils in vital organs of tumor bearing host which possibly account for gradual systemic deterioration during cancer progression. Our findings thus implicate neutrophils as a potential therapeutic target that may help to reduce the overall fatality rate of cancer.
Collapse
Affiliation(s)
- Kavita Rawat
- Department of Zoology, University of Delhi, Delhi 110007, India
| | - Saima Syeda
- Department of Zoology, University of Delhi, Delhi 110007, India
| | - Anju Shrivastava
- Department of Zoology, University of Delhi, Delhi 110007, India.
| |
Collapse
|
|
8
|
Li Q, Yu L, Yang P, Hu Q. Prognostic Value of Inflammatory Markers in Nasopharyngeal Carcinoma Patients in the Intensity-Modulated Radiotherapy Era. Cancer Manag Res 2021; 13:6799-6810. [PMID: 34512020 PMCID: PMC8418375 DOI: 10.2147/cmar.s311094] [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: 03/14/2021] [Accepted: 07/23/2021] [Indexed: 12/12/2022] Open
Abstract
Purpose Inflammatory markers have been widely used in various cancers, but rarely in nasopharyngeal carcinoma (NPC). Here, we evaluated the prognostic value of pretreatment neutrophil-to-lymphocyte ratio (NLR), platelet-lymphocyte-ratio (PLR), systemic immune index (SII), and systemic inflammation response index (SIRI) on NPC in the intensity-modulated radiotherapy (IMRT) era. Methods We retrospectively analyzed data from NPC patients from the Renmin Hospital of Wuhan University, between January 2012 and July 2020. We used Chi-square test or Fisher’s exact test to compare the baseline characteristics, then applied Kaplan–Meier (K-M) survival analysis to compare the overall survival (OS) and progression-free survival (PFS) rates. Multivariate Cox proportional risk models were applied to identify independent prognostic factors. Results We enrolled a total of 342 NPC patients and found optimal cut-off values of 2.65, 184.91, 804.08, and 1.34 for NLR, PLR, SII, and SIRI, respectively. K-M survival analysis revealed that high NLR, PLR, SII, and SIRI were significantly associated with worse OS and PFS relative to those in the low groups. Results from univariate Cox analysis showed that clinical, T, and M stages, as well as NLR, PLR, SII, and SIRI were associated with OS, whereas age, alongside the aforementioned parameters, was associated with PFS. Moreover, multivariate Cox analysis showed that age ≥49 years (HR=2.48, 95% CI=1.21–5.05, P=0.013) and M1 stage (HR=3.84, 95% CI=1.52–9.73, P=0.013) were independent prognostic factors for OS, whereas SIRI ≥1.34 (HR=1.91, 95% CI=1.05–3.47, P=0.034) and M1 stage (HR=2.91, 95% CI=1.44–5.86, P=0.003) were independent prognostic factors for PFS. Conclusion Overall, our findings indicated that high NLR, PLR, SII, and SIRI were significantly associated with poor OS and PFS in NPC patients. High SIRI may be an independent risk factor for PFS of NPC patients in the IMRT era.
Collapse
Affiliation(s)
- Qian Li
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, People's Republic of China
| | - Lushi Yu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, People's Republic of China
| | - Pengcheng Yang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, People's Republic of China
| | - Qinyong Hu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, People's Republic of China
| |
Collapse
|
|
9
|
Barnabei L, Laplantine E, Mbongo W, Rieux-Laucat F, Weil R. NF-κB: At the Borders of Autoimmunity and Inflammation. Front Immunol 2021; 12:716469. [PMID: 34434197 PMCID: PMC8381650 DOI: 10.3389/fimmu.2021.716469] [Citation(s) in RCA: 340] [Impact Index Per Article: 85.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/22/2021] [Indexed: 12/18/2022] Open
Abstract
The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory response. In the first part of this review, we discuss the NF-κB inducers, signaling pathways, and regulators involved in immune homeostasis as well as detail the importance of post-translational regulation by ubiquitination in NF-κB function. We also indicate the stages of central and peripheral tolerance where NF-κB plays a fundamental role. With respect to central tolerance, we detail how NF-κB regulates medullary thymic epithelial cell (mTEC) development, homeostasis, and function. Moreover, we elaborate on its role in the migration of double-positive (DP) thymocytes from the thymic cortex to the medulla. With respect to peripheral tolerance, we outline how NF-κB contributes to the inactivation and destruction of autoreactive T and B lymphocytes as well as the differentiation of CD4+-T cell subsets that are implicated in immune tolerance. In the latter half of the review, we describe the contribution of NF-κB to the pathogenesis of autoimmunity and autoinflammation. The recent discovery of mutations involving components of the pathway has both deepened our understanding of autoimmune disease and informed new therapeutic approaches to treat these illnesses.
Collapse
Affiliation(s)
- Laura Barnabei
- INSERM UMR 1163, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute Paris Descartes Sorbonne Paris Cité University, Paris, France
| | - Emmanuel Laplantine
- Sorbonne Universités, Institut National de la Santé et de la Recherche Médicale (INSERM, UMR1135), Centre National de la Recherche Scientifique (CNRS, ERL8255), Centre d'Immunologie et des Maladies Infectieuses CMI, Paris, France
| | - William Mbongo
- Sorbonne Universités, Institut National de la Santé et de la Recherche Médicale (INSERM, UMR1135), Centre National de la Recherche Scientifique (CNRS, ERL8255), Centre d'Immunologie et des Maladies Infectieuses CMI, Paris, France
| | - Frédéric Rieux-Laucat
- INSERM UMR 1163, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute Paris Descartes Sorbonne Paris Cité University, Paris, France
| | - Robert Weil
- Sorbonne Universités, Institut National de la Santé et de la Recherche Médicale (INSERM, UMR1135), Centre National de la Recherche Scientifique (CNRS, ERL8255), Centre d'Immunologie et des Maladies Infectieuses CMI, Paris, France
| |
Collapse
|
|
10
|
Maia A, Wiemann S. Cancer-Associated Fibroblasts: Implications for Cancer Therapy. Cancers (Basel) 2021; 13:3526. [PMID: 34298736 PMCID: PMC8307167 DOI: 10.3390/cancers13143526] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/09/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022] Open
Abstract
Tumour cells do not exist as an isolated entity. Instead, they are surrounded by and closely interact with cells of the environment they are emerged in. The tumour microenvironment (TME) is not static and several factors, including cancer cells and therapies, have been described to modulate several of its components. Fibroblasts are key elements of the TME with the capacity to influence tumour progression, invasion and response to therapy, which makes them attractive targets in cancer treatment. In this review, we focus on fibroblasts and their numerous roles in the TME with a special attention to recent findings describing their heterogeneity and role in therapy response. Furthermore, we explore how different therapies can impact these cells and their communication with cancer cells. Finally, we highlight potential strategies targeting this cell type that can be employed for improving patient outcome.
Collapse
Affiliation(s)
- Ana Maia
- German Cancer Research Center (DKFZ), Division of Molecular Genome Analysis, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
| | - Stefan Wiemann
- German Cancer Research Center (DKFZ), Division of Molecular Genome Analysis, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
| |
Collapse
|
|
11
|
Epithelial Cell Transformation and Senescence as Indicators of Genome Aging: Current Advances and Unanswered Questions. Int J Mol Sci 2021; 22:ijms22147544. [PMID: 34299168 PMCID: PMC8303760 DOI: 10.3390/ijms22147544] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 07/08/2021] [Accepted: 07/09/2021] [Indexed: 02/06/2023] Open
Abstract
The recent advances in deciphering the human genome allow us to understand and evaluate the mechanisms of human genome age-associated transformations, which are largely unclear. Genome sequencing techniques assure comprehensive mapping of human genetics; however, understanding of gene functional interactions, specifically of time/age-dependent modifications, remain challenging. The age of the genome is defined by the sum of individual (inherited) and acquired genomic traits, based on internal and external factors that impact ontogenesis from the moment of egg fertilization and embryonic development. The biological part of genomic age opens a new perspective for intervention. The discovery of single cell-based mechanisms for genetic change indicates the possibility of influencing aging and associated disease burden, as well as metabolism. Cell populations with transformed genetic background were shown to serve as the origin of common diseases during extended life expectancy (superaging). Consequently, age-related cell transformation leads to cancer and cell degeneration (senescence). This article aims to describe current advances in the genomic mechanisms of senescence and its role in the spatiotemporal spread of epithelial clones and cell evolution.
Collapse
|
|
12
|
Armstrong H, Bording-Jorgensen M, Wine E. The Multifaceted Roles of Diet, Microbes, and Metabolites in Cancer. Cancers (Basel) 2021; 13:cancers13040767. [PMID: 33673140 PMCID: PMC7917909 DOI: 10.3390/cancers13040767] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/05/2021] [Accepted: 02/09/2021] [Indexed: 02/07/2023] Open
Abstract
Many studies performed to date have implicated select microbes and dietary factors in a variety of cancers, yet the complexity of both these diseases and the relationship between these factors has limited the ability to translate findings into therapies and preventative guidelines. Here we begin by discussing recently published studies relating to dietary factors, such as vitamins and chemical compounds used as ingredients, and their contribution to cancer development. We further review recent studies, which display evidence of the microbial-diet interaction in the context of cancer. The field continues to advance our understanding of the development of select cancers and how dietary factors are related to the development, prevention, and treatment of these cancers. Finally, we highlight the science available in the discussion of common misconceptions with regards to cancer and diet. We conclude this review with thoughts on where we believe future research should focus in order to provide the greatest impact towards human health and preventative medicine.
Collapse
Affiliation(s)
- Heather Armstrong
- CEGIIR, University of Alberta, Edmonton, AB T6G 2X8, Canada;
- Department of Pediatrics, University of Alberta, Edmonton, AB T6G 1C9, Canada
- Correspondence: (H.A.); (E.W.)
| | - Michael Bording-Jorgensen
- CEGIIR, University of Alberta, Edmonton, AB T6G 2X8, Canada;
- Department of Pediatrics, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Eytan Wine
- CEGIIR, University of Alberta, Edmonton, AB T6G 2X8, Canada;
- Department of Pediatrics, University of Alberta, Edmonton, AB T6G 1C9, Canada
- Department of Physiology, University of Alberta, Edmonton, AB T6G 1C9, Canada
- Correspondence: (H.A.); (E.W.)
| |
Collapse
|
|
13
|
Akhtar W, Marella A, Alam MM, Khan MF, Akhtar M, Anwer T, Khan F, Naematullah M, Azam F, Rizvi MA, Shaquiquzzaman M. Design and synthesis of pyrazole-pyrazoline hybrids as cancer-associated selective COX-2 inhibitors. Arch Pharm (Weinheim) 2020; 354:e2000116. [PMID: 33015829 DOI: 10.1002/ardp.202000116] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 08/22/2020] [Accepted: 09/11/2020] [Indexed: 12/25/2022]
Abstract
In continuation of our previous work on cancer and inflammation, 15 novel pyrazole-pyrazoline hybrids (WSPP1-15) were synthesized and fully characterized. The formation of the pyrazoline ring was confirmed by the appearance of three doublets of doublets in 1 H nuclear magnetic resonance spectra exhibiting an AMX pattern for three protons (HA , HM , and HX ) of the pyrazoline ring. All the synthesized compounds were screened for their in vitro anticancer activity against five cell lines, that is, MCF-7, A549, SiHa, COLO205, and HepG2 cells, using the MTT growth inhibition assay. 5-Fluorouracil was taken as the positive control in the study. It was observed that, among them, WSPP11 was found to be active against A549, SiHa, COLO205, and HepG2 cells, with IC50 values of 4.94, 4.54, 4.86, and 2.09 µM. All the derivatives were also evaluated for their cytotoxicity against HaCaT cells. WSPP11 was also found to be nontoxic against normal cells (cell line HaCaT), with an IC50 value of more than 50 µM. The derivatives were also evaluated for their in vitro anti-inflammatory activity by the protein (egg albumin) denaturation assay and the red blood cell membrane stabilizing assay, using diclofenac sodium and celecoxib as standard. Compounds that showed significant anticancer and anti-inflammatory activities were further studied for COX-2 inhibition. The manifestation of a higher COX-2 selectivity index of WSPP11 as compared with other derivatives and an in vitro anticancer activity against four cell lines further established that compounds that were more selective toward COX-2 also exhibited a better spectrum of activity against various cancer cell lines.
Collapse
Affiliation(s)
- Wasim Akhtar
- Drug Design and Medicinal Chemistry Laboratory, Jamia Hamdard, New Delhi, India
| | - Akranth Marella
- Fryer Global Regulatory Solutions and Services, Hyderabad, Telangana, India
| | | | - Mohemmed F Khan
- Drug Design and Medicinal Chemistry Laboratory, Jamia Hamdard, New Delhi, India
| | - Mymoona Akhtar
- Drug Design and Medicinal Chemistry Laboratory, Jamia Hamdard, New Delhi, India
| | - Tariq Anwer
- Department of Pharmacology, College of Pharmacy, Jazan University, Gizan, Saudi Arabia
| | - Farah Khan
- Department of Biochemistry, Jamia Hamdard, New Delhi, India
| | - Md Naematullah
- Department of Biochemistry, Jamia Hamdard, New Delhi, India
| | - Faizul Azam
- Department of Pharmaceutical Chemistry & Pharmacognosy, Unaizah College of Pharmacy, Qassim University, Unaizah, Saudi Arabia
| | | | | |
Collapse
|
|
14
|
Piotrowski I, Kulcenty K, Suchorska W. Interplay between inflammation and cancer. Rep Pract Oncol Radiother 2020; 25:422-427. [PMID: 32372882 PMCID: PMC7191124 DOI: 10.1016/j.rpor.2020.04.004] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 02/20/2020] [Accepted: 04/02/2020] [Indexed: 02/07/2023] Open
Abstract
Tumor-promoting inflammation is one of the hallmarks of cancer. It has been shown that cancer development is strongly influenced by both chronic and acute inflammation process. Progress in research on inflammation revealed a connection between inflammatory processes and neoplastic transformation, the progression of tumour, and the development of metastases and recurrences. Moreover, the tumour invasive procedures (both surgery and biopsy) affect the remaining tumour cells by increasing their survival, proliferation and migration. One of the concepts explaining this phenomena is an induction of a wound healing response. While in normal tissue it is necessary for tissue repair, in tumour tissue, induction of adaptive and innate immune response related to wound healing, stimulates tumour cell survival, angiogenesis and extravasation of circulating tumour cells. It has become evident that certain types of immune response and immune cells can promote tumour progression more than others. In this review, we focus on current knowledge on carcinogenesis and promotion of cancer growth induced by inflammatory processes.
Collapse
Key Words
- ANGPTL4, angiopoietin-like 4
- CDH1, cadherin 1
- COX, cyclooxygenase
- Cancer
- EMT, epithelail to mesenchymal transition
- EP, receptor - prostaglandin receptor
- GI, gastrointensinal cancer
- IL-6, interleukin 6
- Inflammation
- MPO, myeloperoxidase
- NADPH, nicotynamide adenine dinucleotide phosphate hydrogen
- NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells
- NK, natural killer cells
- NO, nitric oxide
- NSAIDs, non-steroidal anti-inflammatory drugs
- PGE2, prostaglandin E2
- PTHrP, parathyroid hormone related protein
- RNS, reactive nitrogen species
- ROS, reactive oxigen species
- STAT3, signal transducer and activator of transcription 3
- TGF-β, transforming growth factor β
- TGFBRII, transforming growth factor, beta receptor II
- TNF-α, tumour necrosis factor α
- TNFR1, Tumor necrosis factor receptor 1
- TNFR2, Tumor necrosis factor receptor 2
- Tumor reccurence
- VEGF, vascular endothelail growth factor
- bFGF, fibroblast growth factor
- iNOS, inducible nitric oxide synthase
Collapse
Affiliation(s)
- Igor Piotrowski
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, Garbary 15 Street, 61-866 Poznań, Poland.,Department of Electroradiology, University of Medical Sciences, Garbary 15 Street, 61-866 Poznań, Poland
| | - Katarzyna Kulcenty
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, Garbary 15 Street, 61-866 Poznań, Poland.,Department of Electroradiology, University of Medical Sciences, Garbary 15 Street, 61-866 Poznań, Poland
| | - Wiktoria Suchorska
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, Garbary 15 Street, 61-866 Poznań, Poland.,Department of Medical Physics, Greater Poland Cancer Centre, Garbary 15 Street, 61-866 Poznań, Poland
| |
Collapse
|
|
15
|
De Almeida CV, de Camargo MR, Russo E, Amedei A. Role of diet and gut microbiota on colorectal cancer immunomodulation. World J Gastroenterol 2019; 25:151-162. [PMID: 30670906 PMCID: PMC6337022 DOI: 10.3748/wjg.v25.i2.151] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 12/20/2018] [Accepted: 12/27/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers, and it is characterized by genetic and epigenetic alterations, as well as by inflammatory cell infiltration among malignant and stromal cells. However, this dynamic infiltration can be influenced by the microenvironment to promote tumor proliferation, survival and metastasis or cancer inhibition. In particular, the cancer microenvironment metabolites can regulate the inflammatory cells to induce a chronic inflammatory response that can be a predisposing condition for CRC retention. In addition, some nutritional components might contribute to a chronic inflammatory condition by regulating various immune and inflammatory pathways. Besides that, diet strongly modulates the gut microbiota composition, which has a key role in maintaining gut homeostasis and is associated with the modulation of host inflammatory and immune responses. Therefore, diet has a fundamental role in CRC initiation, progression and prevention. In particular, functional foods such as probiotics, prebiotics and symbiotics can have a potentially positive effect on health beyond basic nutrition and have anti-inflammatory effects. In this review, we discuss the influence of diet on gut microbiota composition, focusing on its role on gut inflammation and immunity. Finally, we describe the potential benefits of using probiotics and prebiotics to modulate the host inflammatory response, as well as its application in CRC prevention and treatment.
Collapse
Affiliation(s)
| | - Marcela Rodrigues de Camargo
- Department of Surgery, Stomatology, Pathology and Radiology, Bauru School of Dentistry, São Paulo University, Bauru-Sao Paulo 17012901, Brazil
| | - Edda Russo
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50139, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence and Department of Biomedicine, Azienda Ospedaliera Universitaria Careggi (AOUC), Florence 50139, Italy
| |
Collapse
|
|
16
|
Litmanovich A, Khazim K, Cohen I. The Role of Interleukin-1 in the Pathogenesis of Cancer and its Potential as a Therapeutic Target in Clinical Practice. Oncol Ther 2018; 6:109-127. [PMID: 32700032 PMCID: PMC7359982 DOI: 10.1007/s40487-018-0089-z] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Indexed: 02/07/2023] Open
Abstract
Interleukin-1 (IL-1) has long been known to be a key mediator of immunity and inflammation. Its dysregulation has been implicated in recent years in tumorigenesis and tumor progression, and its upregulation is thought to be associated with many tumors. Overexpression of the IL-1 agonists IL-1α and IL-1β has been shown to promote tumor invasiveness and metastasis by inducing the expression of angiogenic genes and growth factors. IL-1 blockers such as anakinra and canakinumab are already approved and widely used for the treatment of some autoimmune and autoinflammatory diseases and are currently being tested in preclinical and human clinical trials for cancer therapy. In this paper we review the most recent discoveries regarding the association between IL-1 dysregulation and cancer and present the novel IL-1 blockers currently being tested in cancer therapy and their corresponding clinical trials.
Collapse
Affiliation(s)
- Adi Litmanovich
- The Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
- Research Institute, Galilee Medical Center, Nahariya, Israel
| | - Khaled Khazim
- The Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
- Research Institute, Galilee Medical Center, Nahariya, Israel
- Department of Nephrology and Hypertension, Galilee Medical Center, Nahariya, Israel
| | - Idan Cohen
- The Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel.
- Research Institute, Galilee Medical Center, Nahariya, Israel.
| |
Collapse
|
|
17
|
Hussein K, Panning B. [Reconstruction of the examination of the laryngeal carcinoma of Emperor Frederick III by Rudolf Virchow]. DER PATHOLOGE 2017; 39:172-177. [PMID: 29147845 DOI: 10.1007/s00292-017-0392-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Rudolf Virchow is one of the founders of modern pathology, and many of his ideas on inflammatory and neoplastic diseases are still valid today. Even for Virchow, determination of malignancy was not always easy. As an example, the laryngeal disease of Crown Prince Frederick William, the later Emperor Frederick III, is presented.The clinical findings at the beginning of the disease were suggestive of a carcinoma, though an inflammatory lesion was also discussed. Several attempts were made to remove the lesion bioptically, but local recurrences occurred and the first tissue samples were not examined histopathologically. Since laryngeal tumour operations had a high mortality at that time, histopathologic examinations were made in order to decide for or against an operation. The samples taken after pre-treatment did not meet Virchow's criteria for determining a carcinoma. Contrary to the present concept of a carcinoma in situ-carcinoma sequence, Virchow's concept was based on the assumption that carcinomas are not derived from the epithelium, but arise from a mesenchymal-epithelial transformation from the connective tissue. The clinical suspicion of a laryngeal carcinoma was confirmed only shortly before the patient's death and later by a post-mortem examination.The question repeatedly asked is whether Virchow should have diagnosed a carcinoma at the beginning of the disease. The answer has been the same for more than a hundred years: the clinician is dissatisfied with the histopathological diagnosis, so the pathologist is to blame.
Collapse
Affiliation(s)
- K Hussein
- Institut für Pathologie, Medizinische Hochschule Hannover (MHH), Carl-Neuberg-Straße 1, 30625, Hannover, Deutschland.
| | - B Panning
- Klinik für Anästhesiologie und Intensivmedizin, Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| |
Collapse
|
|
18
|
Machairas N, Kostakis ID, Prodromidou A, Stamopoulos P, Feretis T, Garoufalia Z, Damaskos C, Tsourouflis G, Kouraklis G. Trends in white blood cell and platelet indices in a comparison of patients with papillary thyroid carcinoma and multinodular goiter do not permit differentiation between the conditions. Endocr Res 2017; 42:311-317. [PMID: 28506088 DOI: 10.1080/07435800.2017.1319859] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
AIM Carcinogenesis has been related to systematic inflammatory response. Our aim was to study white blood cell and platelet indices as markers of this inflammatory response in thyroid cancer and to associate them with various clinicopathological parameters. METHODS We included 228 patients who underwent thyroidectomy within a period of 54 months, 89 with papillary thyroid carcinoma and 139 with multinodular hyperplasia. We examined potential links between white blood cell and platelet indices on the one hand and the type thyroid pathology and various clinicopathological parameters on the other. RESULTS No significant differences were detected between thyroid cancer and multinodular hyperplasia and no significant associations were detected with regard to lymphovascular invasion and tumor size. However, the mean platelet volume was higher in multifocal tumors, while the platelet count, plateletcrit, and platelet-to-lymphocyte ratio were increased in cases with extrathyroidal extension and in T3 tumors. Additionally, T3 tumors had lower platelet distribution width. These associations demonstrated low accuracy in predicting these pathological features, but they were found to provide a satisfying negative predictive value, with the exception of the mean platelet volume. CONCLUSIONS White blood cell and platelet indices cannot assist in distinguishing benign goiter from thyroid cancer. However, they can provide information about tumor multifocality, extrathyroidal extension, and presence of a T3 tumor, and they may be used as a means to exclude these pathological characteristics, especially the last two, in papillary thyroid carcinoma.
Collapse
MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Algorithms
- Biomarkers/blood
- Carcinoma, Papillary/blood
- Carcinoma, Papillary/diagnosis
- Carcinoma, Papillary/immunology
- Carcinoma, Papillary/pathology
- Diagnosis, Differential
- Goiter, Nodular/blood
- Goiter, Nodular/diagnosis
- Goiter, Nodular/immunology
- Goiter, Nodular/pathology
- Humans
- Leukocyte Count
- Mean Platelet Volume
- Middle Aged
- Platelet Count
- Predictive Value of Tests
- ROC Curve
- Retrospective Studies
- Thyroid Cancer, Papillary
- Thyroid Gland/immunology
- Thyroid Gland/pathology
- Thyroid Neoplasms/blood
- Thyroid Neoplasms/diagnosis
- Thyroid Neoplasms/immunology
- Thyroid Neoplasms/pathology
- Tumor Burden
- Young Adult
Collapse
Affiliation(s)
- Nikolaos Machairas
- a Second Department of Propedeutic Surgery , " Laiko" General Hospital, National and Kapodistrian University of Athens, Medical School , Athens , Greece
| | - Ioannis D Kostakis
- a Second Department of Propedeutic Surgery , " Laiko" General Hospital, National and Kapodistrian University of Athens, Medical School , Athens , Greece
| | - Anastasia Prodromidou
- a Second Department of Propedeutic Surgery , " Laiko" General Hospital, National and Kapodistrian University of Athens, Medical School , Athens , Greece
| | - Paraskevas Stamopoulos
- a Second Department of Propedeutic Surgery , " Laiko" General Hospital, National and Kapodistrian University of Athens, Medical School , Athens , Greece
| | - Themistoklis Feretis
- a Second Department of Propedeutic Surgery , " Laiko" General Hospital, National and Kapodistrian University of Athens, Medical School , Athens , Greece
| | - Zoe Garoufalia
- a Second Department of Propedeutic Surgery , " Laiko" General Hospital, National and Kapodistrian University of Athens, Medical School , Athens , Greece
| | - Christos Damaskos
- a Second Department of Propedeutic Surgery , " Laiko" General Hospital, National and Kapodistrian University of Athens, Medical School , Athens , Greece
| | - Gerasimos Tsourouflis
- a Second Department of Propedeutic Surgery , " Laiko" General Hospital, National and Kapodistrian University of Athens, Medical School , Athens , Greece
| | - Gregory Kouraklis
- a Second Department of Propedeutic Surgery , " Laiko" General Hospital, National and Kapodistrian University of Athens, Medical School , Athens , Greece
| |
Collapse
|
|
19
|
Divella R, De Luca R, Abbate I, Naglieri E, Daniele A. Obesity and cancer: the role of adipose tissue and adipo-cytokines-induced chronic inflammation. J Cancer 2016; 7:2346-2359. [PMID: 27994674 PMCID: PMC5166547 DOI: 10.7150/jca.16884] [Citation(s) in RCA: 211] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 09/19/2016] [Indexed: 12/12/2022] Open
Abstract
Adipose tissue in addition to its ability to keep lipids is now recognized as a real organ with both metabolic and endocrine functions. Recent studies demonstrated that in obese animals is established a status of adipocyte hypoxia and in this hypoxic state interaction between adipocytes and stromal vascular cells contribute to tumor development and progression. In several tumors such as breast, colon, liver and prostate, obesity represents a poor predictor of clinical outcomes. Dysfunctional adipose tissue in obesity releases a disturbed profile of adipokines with elevated levels of pro-inflammatory factors and a consequent alteration of key signaling mediators which may be an active local player in establishing the peritumoral environment promoting tumor growth and progression. Therefore, adipose tissue hypoxia might contribute to cancer risk in the obese population. To date the precise mechanisms behind this obesity-cancer link is not yet fully understood. In the light of information provided in this review that aims to identify the key mechanisms underlying the link between obesity and cancer we support that inflammatory state specific of obesity may be important in obesity-cancer link.
Collapse
Affiliation(s)
- Rosa Divella
- Clinical Pathology Laboratory, Department of Experimental Oncology. Giovanni Paolo II National Cancer Institute, V.Le Orazio Flacco 65, 70124 -Bari, Italy
| | - Raffaele De Luca
- Department of Surgery Oncology. Giovanni Paolo II National Cancer Institute, V.Le Orazio Flacco 65, 70124 -Bari, Italy
| | - Ines Abbate
- Clinical Pathology Laboratory, Department of Experimental Oncology. Giovanni Paolo II National Cancer Institute, V.Le Orazio Flacco 65, 70124 -Bari, Italy
| | - Emanuele Naglieri
- Department of Medical Oncology, Giovanni Paolo II National Cancer Institute, V.Le Orazio Flacco 65, 70124 -Bari, Italy
| | - Antonella Daniele
- Clinical Pathology Laboratory, Department of Experimental Oncology. Giovanni Paolo II National Cancer Institute, V.Le Orazio Flacco 65, 70124 -Bari, Italy
| |
Collapse
|
|
20
|
Todoric J, Antonucci L, Karin M. Targeting Inflammation in Cancer Prevention and Therapy. Cancer Prev Res (Phila) 2016; 9:895-905. [PMID: 27913448 DOI: 10.1158/1940-6207.capr-16-0209] [Citation(s) in RCA: 273] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 10/03/2016] [Indexed: 12/14/2022]
Abstract
Inflammation is associated with the development and malignant progression of most cancers. As most of the cell types involved in cancer-associated inflammation are genetically stable and thus are not subjected to rapid emergence of drug resistance, the targeting of inflammation represents an attractive strategy both for cancer prevention and for cancer therapy. Tumor-extrinsic inflammation is caused by many factors, including bacterial and viral infections, autoimmune diseases, obesity, tobacco smoking, asbestos exposure, and excessive alcohol consumption, all of which increase cancer risk and stimulate malignant progression. In contrast, cancer-intrinsic or cancer-elicited inflammation can be triggered by cancer-initiating mutations and can contribute to malignant progression through the recruitment and activation of inflammatory cells. Both extrinsic and intrinsic inflammation can result in immunosuppression, thereby providing a preferred background for tumor development. In clinical trials, lifestyle modifications including healthy diet, exercise, alcohol, and smoking cessation have proven effective in ameliorating inflammation and reducing the risk of cancer-related deaths. In addition, consumption of certain anti-inflammatory drugs, including aspirin, can significantly reduce cancer risk, suggesting that common nonsteroidal anti-inflammatory drugs (NSAID) and more specific COX2 inhibitors can be used in cancer prevention. In addition to being examined for their preventative potential, both NSAIDs and more potent anti-inflammatory antibody-based drugs need to be tested for their ability to augment the efficacy of more conventional therapeutic approaches on the basis of tumor resection, radiation, and cytotoxic chemicals. Cancer Prev Res; 9(12); 895-905. ©2016 AACR.
Collapse
Affiliation(s)
- Jelena Todoric
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California.,Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Laura Antonucci
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California. .,Department of Pathology, School of Medicine, University of California San Diego, La Jolla, California
| |
Collapse
|
|
21
|
Tanaka T, Shimizu M, Kochi T, Shirakami Y, Mori T, Watanabe N, Naiki T, Moriwaki H, Yoshimi K, Serikawa T, Kuramoto T. Apc-Mutant Kyoto Apc Delta (KAD) Rats Are Susceptible to 4-NQO-Induced Tongue Carcinogenesis. Cancers (Basel) 2014; 6:1522-39. [PMID: 25050571 PMCID: PMC4190553 DOI: 10.3390/cancers6031522] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Revised: 06/26/2014] [Accepted: 07/01/2014] [Indexed: 12/21/2022] Open
Abstract
Despite widening interest in the possible association between infection/inflammation and cancer development, knowledge of this issue in relation to oral cancer remains inadequate. This study aimed to determine the susceptibility of Apc-mutant Kyoto Apc Delta (KAD) rats, which are vulnerable to developing inflammation-associated colorectal carcinogenesis, to 4-nitroquinoline 1-oxide (4-NQO)-induced tongue carcinogenesis in order to clarify the role of inflammation in oral cancer. KAD (20 males and 22 females) and F344/NS1c (22 males and 23 females) rats received drinking water with or without 4-NQO (20 ppm) for eight weeks. Histopathological and immunohistochemical analyses of the tongue were performed at week 20. Additionally, the mRNA expression of inflammatory cytokines in the tongue mucosa was determined at week 8. Tongue squamous cell carcinoma (SCC) developed in the KAD and F344/NS1c rats that received 4-NQO. Regardless of gender, the incidence and multiplicity of tongue SCC were greater in the KAD rats than in the F344/NS1c rats. In addition, the multiplicity of tongue SCC in the female KAD rats was significantly greater than that observed in the male KAD (p < 0.01) and female F344/NS1c rats (p < 0.05). The levels of inflammation and the mRNA expression of inflammatory cytokines in the tongue in the 4-NQO-treated female KAD rats were the highest among the rats given 4-NQO. These results show that KAD rats, particularly females, are susceptible to 4-NQO-induced tongue carcinogenesis, suggesting the utility of models employing KAD rats for investigating the pathobiology of oral (tongue) carcinogenesis associated with inflammation.
Collapse
Affiliation(s)
- Takuji Tanaka
- Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1 Kashima-Cho, Gifu 500-8513, Japan.
| | - Masahito Shimizu
- Department of Internal Medicine/Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
| | - Takahiro Kochi
- Department of Internal Medicine/Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
| | - Yohei Shirakami
- Department of Internal Medicine/Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
| | - Takayuki Mori
- Department of Pharmacy, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki 503-8502, Japan.
| | - Naoki Watanabe
- Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1 Kashima-Cho, Gifu 500-8513, Japan.
| | - Takafumi Naiki
- Department of Clinical Laboratory, Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu 500-8513, Japan.
| | - Hisataka Moriwaki
- Department of Internal Medicine/Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
| | - Kazuto Yoshimi
- The Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
| | - Tadao Serikawa
- The Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
| | - Takashi Kuramoto
- The Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
| |
Collapse
|
|
22
|
Theruvathu JA, Yin YW, Pettitt BM, Sowers LC. Comparison of the structural and dynamic effects of 5-methylcytosine and 5-chlorocytosine in a CpG dinucleotide sequence. Biochemistry 2013; 52:8590-8. [PMID: 24147911 DOI: 10.1021/bi400980c] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Inflammation-mediated reactive molecules can result in an array of oxidized and halogenated DNA-damage products, including 5-chlorocytosine ((Cl)C). Previous studies have shown that (Cl)C can mimic 5-methylcytosine ((m)C) and act as a fraudulent epigenetic signal, promoting the methylation of previously unmethylated DNA sequences. Although the 5-halouracils are good substrates for base-excision repair, no repair activity has yet been identified for (Cl)C. Because of the apparent biochemical similarities of (m)C and (Cl)C, we have investigated the effects of (m)C and (Cl)C substitution on oligonucleotide structure and dynamics. In this study, we have constructed oligonucleotide duplexes containing C, (Cl)C, and (m)C within a CpG dinucleotide. The thermal and thermodynamic stability of these duplexes were found to be experimentally indistinguishable. Crystallographic structures of duplex oligonucleotides containing (m)C or (Cl)C were determined to 1.2 and 1.9 Å resolution, respectively. Both duplexes are B-form and are superimposable on a previously determined structure of a cytosine-containing duplex with a rmsd of approximately 0.25 Å. NMR solution studies indicate that all duplexes containing cytosine or the cytosine analogues are normal B-form and that no structural perturbations are observed surrounding the site of each substitution. The magnitude of the base-stacking-induced upfield shifts for nonexchangeable base proton resonances are similar for each of the duplexes examined, indicating that neither (m)C nor (Cl)C significantly alter base-stacking interactions. The (Cl)C analogue is paired with G in an apparently normal geometry; however, the G-imino proton of the (Cl)C-G base pair resonates to higher field relative to (m)C-G or C-G, indicating a weaker imino hydrogen bond. Using selective ¹⁵N-enrichment and isotope-edited NMR, we observe that the amino group of (Cl)C rotates at roughly half of the rate of the corresponding amino groups of the C-G and (m)C-G base pairs. The altered chemical shifts of hydrogen-bonding proton resonances for the (Cl)C-G base pair as well as the slower rotation of the (Cl)C amino group can be attributed to the electron-withdrawing inductive property of the 5-chloro substituent. The apparent similarity of duplexes containing (m)C and (Cl)C demonstrated here is in accord with results of previous biochemical studies and further suggests that (Cl)C is likely to be an unusually persistent form of DNA damage.
Collapse
Affiliation(s)
- Jacob A Theruvathu
- Department of Pharmacology & Toxicology, The University of Texas Medical Branch , 3.330 Basic Science Building, 301 University Boulevard, Galveston, Texas 77555, United States
| | | | | | | |
Collapse
|
|
23
|
Hefetz-Sela S, Scherer PE. Adipocytes: impact on tumor growth and potential sites for therapeutic intervention. Pharmacol Ther 2013; 138:197-210. [PMID: 23353703 DOI: 10.1016/j.pharmthera.2013.01.008] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2013] [Accepted: 01/10/2013] [Indexed: 12/12/2022]
Abstract
The prevalence of obesity has increased dramatically in recent decades, reaching epidemic proportions. It is becoming clear that obesity is associated not only with type 2 diabetes mellitus and cardiovascular disease, but also with multiple types of cancer. Obesity is characterized by impaired adipose tissue function, leading to adipocyte hypertrophy, inflammation, hypoxia and induced angiogenesis, extracellular matrix remodeling and fibrosis as well as additional stress responses. While epidemiological data indicate that obesity is a well-established risk factor for certain malignancies, the molecular mechanisms underlying the link between obesity and cancer are still poorly understood. Recent data implicates systemic and paracrine factors secreted from adipose tissue during the obese state, promoting cancer development and progression. Here, we focus on the obesity-associated adipose tissue remodeling that may not only lead to metabolic complications, but also to a permissive pro-tumorigenic environment. Particular attention is given to the local pro-tumorigenic effects derived from adipocytes that present an important part of the tumor microenvironment of at least some cancers, in an attempt to describe the nature of the major players of the adipocyte-cancer cell crosstalk that dictates to a large extent tumor progression.
Collapse
Affiliation(s)
- Simona Hefetz-Sela
- Touchstone Diabetes Center, Departments of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | | |
Collapse
|
|
24
|
Mamlouk S, Wielockx B. Hypoxia-inducible factors as key regulators of tumor inflammation. Int J Cancer 2012; 132:2721-9. [PMID: 23055435 DOI: 10.1002/ijc.27901] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Accepted: 09/25/2012] [Indexed: 12/23/2022]
Abstract
Low levels of oxygen or hypoxia is often an obstacle in health, particularly in pathological disorders like cancer. The main family of transcription factors responsible for cell survival and adaptation under strenuous conditions of hypoxia are the "hypoxia-inducible factors" (HIFs). Together with prolyl hydroxylase domain enzymes (PHDs), HIFs regulates tumor angiogenesis, proliferation, invasion, metastasis, in addition to resistance to radiation and chemotherapy. Additionally, the entire HIF transcription cascade is involved in the "seventh" hallmark of cancer; inflammation. Studies have shown that hypoxia can influence tumor associated immune cells toward assisting in tumor proliferation, differentiation, vessel growth, distant metastasis and suppression of the immune response via cytokine expression alterations. These changes are not necessarily analogous to HIF's role in non-cancer immune responses, where hypoxia often encourages a strong inflammatory response.
Collapse
Affiliation(s)
- Soulafa Mamlouk
- Emmy Noether Research Group and Institute of Pathology, University of Technology, Dresden, Germany
| | | |
Collapse
|
|
25
|
Witz IP. The tumor microenvironment: the making of a paradigm. CANCER MICROENVIRONMENT 2009; 2 Suppl 1:9-17. [PMID: 19701697 PMCID: PMC2756342 DOI: 10.1007/s12307-009-0025-8] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2009] [Accepted: 08/06/2009] [Indexed: 12/17/2022]
Abstract
What has been will be again, what has been done will be done again; there is nothing new under the sun (Ecclesiastes 1:9) Stephen Paget was the conceptual father of the role played by the Tumor Microenvironment (TME) in tumor progression. The focus of this essay is the developmental phase of the post Paget TME research. Attempts will be made to highlight some of the pioneering work of scientists from the late sixties through the eighties of last century who laid the foundations for the contemporary scientific achievements of TME research but whose ground breaking studies are rarely cited. This review should serve as a small tribute to their great work.
Collapse
Affiliation(s)
- Isaac P Witz
- Faculty of Life Sciences, Department of Cell Research & Immunology, Tel Aviv University, Ramat Aviv, Tel Aviv, 69978, Israel,
| |
Collapse
|
|
26
|
Geiger TR, Peeper DS. Metastasis mechanisms. Biochim Biophys Acta Rev Cancer 2009; 1796:293-308. [PMID: 19683560 DOI: 10.1016/j.bbcan.2009.07.006] [Citation(s) in RCA: 224] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2009] [Revised: 07/23/2009] [Accepted: 07/31/2009] [Indexed: 12/22/2022]
Abstract
Metastasis, the spread of malignant cells from a primary tumor to distant sites, poses the biggest problem to cancer treatment and is the main cause of death of cancer patients. It occurs in a series of discrete steps, which have been modeled into a "metastatic cascade". In this review, we comprehensively describe the molecular and cellular mechanisms underlying the different steps, including Epithelial-Mesenchymal Transition (EMT), invasion, anoikis, angiogenesis, transport through vessels and outgrowth of secondary tumors. Furthermore, we implement recent findings that have broadened and challenged the classical view on the metastatic cascade, for example the establishment of a "premetastatic niche", the requirement of stem cell-like properties, the role of the tumor stroma and paracrine interactions of the tumor with cells in distant anatomical sites. A better understanding of the molecular processes underlying metastasis will conceivably present us with novel targets for therapeutic intervention.
Collapse
Affiliation(s)
- Thomas R Geiger
- Division of Molecular Genetics, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
| | | |
Collapse
|
|
27
|
Horch RE, Pepescu LM, Vacanti C, Maio G. Ethical issues in cellular and molecular medicine and tissue engineering. J Cell Mol Med 2009; 12:1785-93. [PMID: 19145705 PMCID: PMC4506149 DOI: 10.1111/j.1582-4934.2008.00460.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Affiliation(s)
- Raymund E Horch
- Department of Plastic and Hand Surgery, University Hospital Erlangen, University of Erlangen-Nuernberg, Krankenhausstrasse 12, D-91054 Erlangen, Germany.
| | | | | | | |
Collapse
|
|
28
|
Affiliation(s)
- Isaac P Witz
- Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
| |
Collapse
|
|
29
|
Widera D, Kaus A, Kaltschmidt C, Kaltschmidt B. Neural stem cells, inflammation and NF-kappaB: basic principle of maintenance and repair or origin of brain tumours? J Cell Mol Med 2007; 12:459-70. [PMID: 18182066 PMCID: PMC3822535 DOI: 10.1111/j.1582-4934.2007.00208.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Several recent reports suggest that inflammatory signals play a decisive role in the self-renewal, migration and differentiation of multipotent neural stem cells (NSCs). NSCs are believed to be able to ameliorate the symptoms of several brain pathologies through proliferation, migration into the area of the lesion and either differentiation into the appropriate cell type or secretion of anti-inflammatory cytokines. Although NSCs have beneficial roles, current evidence indicates that brain tumours, such as astrogliomas or ependymomas are also caused by tumour-initiating cells with stem-like properties. However, little is known about the cellular and molecular processes potentially generating tumours from NSCs. Most pro-inflammatory conditions are considered to activate the transcription factor NF-kappaB in various cell types. Strong inductive effects of NF-kappaB on proliferation and migration of NSCs have been described. Moreover, NF-kappaB is constitutively active in most tumour cells described so far. Chronic inflammation is also known to initiate cancer. Thus, NF-kappaB might provide a novel mechanistic link between chronic inflammation, stem cells and cancer. This review discusses the apparently ambivalent role of NF-kappaB: physiological maintenance and repair of the brain via NSCs, and a potential role in tumour initiation. Furthermore, it reveals a possible mechanism of brain tumour formation based on inflammation and NF-kappaB activity in NSCs.
Collapse
Affiliation(s)
- D Widera
- Institut für Zellbiologie der Tiere, Fakultät für Biologie, Universität Bielefeld, Bielefeld, Germany
| | | | | | | |
Collapse
|
|
30
|
Okada F, Fujii J. Molecular Mechanisms of Inflammation-Induced Carcinogenesis. J Clin Biochem Nutr 2006. [DOI: 10.3164/jcbn.39.103] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Futoshi Okada
- Department of Biomolecular Function, Graduate School of Medical Science, Yamagata University
| | - Junichi Fujii
- Department of Biomolecular Function, Graduate School of Medical Science, Yamagata University
| |
Collapse
|