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A single targeted gamma-ray irradiation induced an acute modulation of immune cells and related cytokines in EMT6 mouse-bearing tumour model

Hasan N, Hasani NAH, Omar E, Sham FR, Fuad SBSA, Karim MKA, et al.

Cancer Biomark, 2023;38(1):61-75.
PMID: 37522193 DOI: 10.3233/CBM-220268

BACKGROUND: A complicated interplay between radiation doses, tumour microenvironment (TME), and host immune system is linked to the active participation of immune response.
OBJECTIVE: The effects of single targeted 2 Gy and 8 Gy gamma-ray irradiations on the immune cell population (lymphocytes, B-cells, T-cells, neutrophils, eosinophils, and macrophages) in EMT6 mouse-bearing tumour models was investigated.
METHODS: The effects of both irradiation doses in early (96 hours) and acute phase (5 to 11 days) post-irradiation on immune parameters were monitored in blood circulation and TME using flow cytometry. Simultaneously, selected cytokines related to immune cells within the TME were measured using multiplex ELISA.
RESULTS: A temporary reduction in systemic total white blood count (TWBC) resulted from an early phase (96 hours) of gamma-ray irradiation at 2 Gy and 8 Gy compared to sham control group. No difference was obtained in the acute phase. Neutrophils dominated among other immune cells in TME in sham control group. Eosinophils in TME was significantly increased after 8 Gy treatment in acute phase compared to sham control (p< 0.005). Furthermore, the increment of tumour necrosis (TNF)-α, eotaxin and interleukin (IL)-7 (p< 0.05) in both treatment groups and phases were associated with anti-tumour activities within TME by gamma-ray irradiation.
CONCLUSION: The temporary changes in immune cell populations within systemic circulation and TME induced by different doses of gamma-ray irradiation correlated with suppression of several pro-tumorigenic cytokines in mouse-bearing EMT6 tumour models.

Matched MeSH terms: Tumor Microenvironment
Fulltext The effect of environmental chemicals on the tumor microenvironment

Casey SC, Vaccari M, Al-Mulla F, Al-Temaimi R, Amedei A, Barcellos-Hoff MH, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1:S160-83.
PMID: 26106136 DOI: 10.1093/carcin/bgv035

Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.

Matched MeSH terms: Tumor Microenvironment/drug effects*
Beyond lipid-lowering: role of statins in endometrial cancer

Hafizz AMHA, Zin RRM, Aziz NHA, Kampan NC, Shafiee MN

Mol Biol Rep, 2020 Oct;47(10):8199-8207.
PMID: 32897522 DOI: 10.1007/s11033-020-05760-5

As the obesity rates dramatically increased across the globe, the risk of endometrial cancer (EC) has substantially increased. Measures to improve the EC outcome is utmost important, especially data have shown that women at their reproductive age are commonly affected. No doubt, surgical intervention is a standard treatment for EC. However, the fact that this cancer could arise from metabolic diseases, additional therapy by lipid-lowering agent could be utilized to change the tumour environment. We review available evidence to support the use of this agent in the clinical setting. We search available evidence on the use of statin in EC, in various settings including cell lines, animal and human study. The possible actions at different molecular pathways leading to cellular changes and proliferation of cell were evaluated. The venture in drug repositioning of statins as a chemo-preventive potential agent in EC has gained attention in gynaecological oncology practice worldwide. Lipid-lowering effect by statins may exerted a chemoprotective effect in EC, but there is still lack of evidence on statins use to improve prognosis and survival in EC. Through the cholesterol-lowering effect of statins; theoretically, it could inhibit cell growth, proliferation, migration, and lead to apoptosis. Epidemiological studies suggested that statins may improve survival rate among EC patients. However, some evidence revealed the effects were only more prominent in type II EC. Notwithstanding that several studies also showed no benefit of statins in EC. Hence we highlight the limitations of these studies in this review. In line with recent literature on the topic, statins may play a role in EC management. Future studies for a proper systematic review and randomized controlled study are needed to answer some uncertainties of statins effect in EC.

Matched MeSH terms: Tumor Microenvironment/drug effects
Regulatory Role of Quiescence in the Biological Function of Cancer Stem Cells

Lee SH, Reed-Newman T, Anant S, Ramasamy TS

Stem Cell Rev Rep, 2020 12;16(6):1185-1207.
PMID: 32894403 DOI: 10.1007/s12015-020-10031-8

Quiescence in cancer cells is considered a therapeutic challenge as it confers dormancy in tumour, hence circumventing inherent anti-neoplastic surveillance system and standard-of-care cancer therapeutics including chemotherapy and radiotherapy. Since majority of the therapeutics target actively proliferating cancer cells, cancer cells eventually develop quiescent nature as mechanism of survival and cancer progression under both niche and therapeutic pressures. Quiescence state in cancer cells, eventually, confers resistant and aggressive nature to conventional cancer therapies, resulting in disease progression and relapse. Therefore, targeting quiescent cancer cells or cancer stem cells is a promising therapeutic approach, however an extensive review of the relevant information is needed in order to device an effective therapy. While the evidence of quiescence regulation in CSCs is rather a complex molecular and cellular network, herein, we aim to provide a comprehensive understanding of both intrinsic and extrinsic regulation in association with the function of CSCs. Findings on induction of quiescent state in CSCs population, its regulation at both cellular and molecular level, key molecular regulators, cellular events and processes including potential targets to develop therapeutics are extensively reviewed. This review also highlights the impact of CSC plasticity on quiescence which capturing the key challenge of targeting the cells in this state. Beyond understanding the mechanisms underlying quiescence nature of cancer cells, this review provides insightful perspective and future direction on insight in targeting these populations, hence collapse the tumour dormancy programme in order to eradicate tumour mass as a whole. Capability of CSCs to establish quiescent state as a mechanism of survival during unfavorable conditions, as well as its impact in cancer progression and subsequent relapse, including the potential therapeutic strategy to eradicate this CSCs sub-population in the tumor mass as an effective cancer therapy.

Matched MeSH terms: Tumor Microenvironment/drug effects
Molecular targeted therapy: Treating cancer with specificity

Lee YT, Tan YJ, Oon CE

Eur J Pharmacol, 2018 Sep 05;834:188-196.
PMID: 30031797 DOI: 10.1016/j.ejphar.2018.07.034

Molecular targeted therapies are revolutionized therapeutics which interfere with specific molecules to block cancer growth, progression, and metastasis. Many molecular targeted therapies approved by the Food and Drug Administration (FDA), have demonstrated remarkable clinical success in the treatment of a myriad of cancer types including breast, leukemia, colorectal, lung, and ovarian cancers. This review provides an update on the different types of molecular targeted therapies used in the treatment of cancer, focusing on the fundamentals of molecular targeted therapy, its mode of action in cancer treatment, as well as its advantages and limitations.

Matched MeSH terms: Tumor Microenvironment/drug effects
Parenchyma-stromal interleukin-1 alpha and interleukin-6 overexpressions in ameloblastoma correlate with the aggressive phenotype

Goh YC, Chan SW, Siar CH

Malays J Pathol, 2019 Dec;41(3):303-311.
PMID: 31901915

INTRODUCTION: Ameloblastoma is a benign but locally invasive odontogenic epithelial neoplasm with a high recurrence rate after treatment. The two main subsets encountered clinically are unicystic (UA) and solid/multicystic ameloblastoma (SMA). Currently neoplastic progression of many tumour types are believed to be related to parenchyma-stromal cell-cell interactions mediated by cytokines notably interleukins (IL). However their roles in ameloblastoma remain ill-understood.
MATERIALS AND METHODS: Thirty-nine formalin-fixed paraffin-embedded ameloblastoma cases comprising unicystic ameloblastoma (n=19) and solid/multicystic ameloblastoma (n=20) were subjected to IHC staining for IL-1α, IL-1β, IL-6 and IL-8. A semi-quantitative method was used to evaluate the expression levels of these cytokines according to cell types in the tumoural parenchyma and stroma.
RESULTS: Major findings were upregulations of IL-1α and IL-6 in SMA compared to UA. Both cytokines were heterogeneously detected in the tumoural parenchyma and stroma. Within the neoplastic epithelial compartment, IL-1α expression was more frequently detected in PA-like cells in UA whereas it was more frequently encountered in SR-like cells in SMA. IL-6 demonstrated higher expression levels in the stromal compartment of SMA. IL-1β and IL-8 were markedly underexpressed in both tumour subsets.
CONCLUSIONS: Overexpression of IL-1α in SMA suggests that this growth factor might play a role in promoting bone resorption and local invasiveness in this subtype. The expression levels of IL-1α and IL-6 in three cellular localizations indicate that parenchymal-stromal components of ameloblastoma interact reciprocally via IL-1α and IL-6 to create a microenvironment conducive for tumour progression.

Matched MeSH terms: Tumor Microenvironment/physiology
Fulltext The Adipokine Component in the Molecular Regulation of Cancer Cell Survival, Proliferation and Metastasis

Umar MI, Hassan W, Murtaza G, Buabeid M, Arafa E, Irfan HM, et al.

Pathol Oncol Res, 2021;27:1609828.
PMID: 34588926 DOI: 10.3389/pore.2021.1609828

A hormonal imbalance may disrupt the rigorously monitored cellular microenvironment by hampering the natural homeostatic mechanisms. The most common example of such hormonal glitch could be seen in obesity where the uprise in adipokine levels is in virtue of the expanding bulk of adipose tissue. Such aberrant endocrine signaling disrupts the regulation of cellular fate, rendering the cells to live in a tumor supportive microenvironment. Previously, it was believed that the adipokines support cancer proliferation and metastasis with no direct involvement in neoplastic transformations and tumorigenesis. However, the recent studies have reported discrete mechanisms that establish the direct involvement of adipokine signaling in tumorigenesis. Moreover, the individual adipokine profile of the patients has never been considered in the prognosis and staging of the disease. Hence, the present manuscript has focused on the reported extensive mechanisms that culminate the basis of poor prognosis and diminished survival rate in obese cancer patients.

Matched MeSH terms: Tumor Microenvironment/physiology
A miRNA-145/TGF-β1 negative feedback loop regulates the cancer-associated fibroblast phenotype

Melling GE, Flannery SE, Abidin SA, Clemmens H, Prajapati P, Hinsley EE, et al.

Carcinogenesis, 2018 05 28;39(6):798-807.
PMID: 29506142 DOI: 10.1093/carcin/bgy032

The dissemination of cancer cells to local and distant sites depends on a complex and poorly understood interplay between malignant cells and the cellular and non-cellular components surrounding them, collectively termed the tumour microenvironment. One of the most abundant cell types of the tumour microenvironment is the fibroblast, which becomes corrupted by locally derived cues such as TGF-β1 and acquires an altered, heterogeneous phenotype (cancer-associated fibroblasts, CAF) supportive of tumour cell invasion and metastasis. Efforts to develop new treatments targeting the tumour mesenchyme are hampered by a poor understanding of the mechanisms underlying the development of CAF. Here, we examine the contribution of microRNA to the development of experimentally-derived CAF and correlate this with changes observed in CAF derived from tumours. Exposure of primary normal human fibroblasts to TGF-β1 resulted in the acquisition of a myofibroblastic CAF-like phenotype. This was associated with increased expression of miR-145, a miRNA predicted in silico to target multiple components of the TGF-β signalling pathway. miR-145 was also overexpressed in CAF derived from oral cancers. Overexpression of miR-145 blocked TGF-β1-induced myofibroblastic differentiation and reverted CAF towards a normal fibroblast phenotype. We conclude that miR-145 is a key regulator of the CAF phenotype, acting in a negative feedback loop to dampen acquisition of myofibroblastic traits, a key feature of CAF associated with poor disease outcome.

Matched MeSH terms: Tumor Microenvironment/physiology
Fulltext Cancer stem cells as key drivers of tumour progression

Ayob AZ, Ramasamy TS

J Biomed Sci, 2018 Mar 06;25(1):20.
PMID: 29506506 DOI: 10.1186/s12929-018-0426-4

BACKGROUND: Cancer stem cells (CSCs) are subpopulations of cancer cells sharing similar characteristics as normal stem or progenitor cells such as self-renewal ability and multi-lineage differentiation to drive tumour growth and heterogeneity. Throughout the cancer progression, CSC can further be induced from differentiated cancer cells via the adaptation and cross-talks with the tumour microenvironment as well as a response from therapeutic pressures, therefore contributes to their heterogeneous phenotypes. Challengingly, conventional cancer treatments target the bulk of the tumour and are unable to target CSCs due to their highly resistance nature, leading to metastasis and tumour recurrence.
MAIN BODY: This review highlights the roles of CSCs in tumour initiation, progression and metastasis with a focus on the cellular and molecular regulators that influence their phenotypical changes and behaviours in the different stages of cancer progression. We delineate the cross-talks between CSCs with the tumour microenvironment that support their intrinsic properties including survival, stemness, quiescence and their cellular and molecular adaptation in response to therapeutic pressure. An insight into the distinct roles of CSCs in promoting angiogenesis and metastasis has been captured based on in vitro and in vivo evidences.
CONCLUSION: Given dynamic cellular events along the cancer progression and contributions of resistance nature by CSCs, understanding their molecular and cellular regulatory mechanism in a heterogeneous nature, provides significant cornerstone for the development of CSC-specific therapeutics.

Matched MeSH terms: Tumor Microenvironment/physiology*
In human invasive breast ductal carcinoma, tumor stromal macrophages and tumor nest macrophages have distinct relationships with clinicopathological parameters and tumor angiogenesis

Ch'ng ES, Tuan Sharif SE, Jaafar H

Virchows Arch, 2013 Mar;462(3):257-67.
PMID: 23283409 DOI: 10.1007/s00428-012-1362-4

Tumor-associated macrophages play a crucial role in breast cancer progression and tumor angiogenesis. However, evaluation of tumor-associated macrophages incorporating their histological locations is lacking. The aim of this study was to clarify whether macrophages in tumor stroma and macrophages in tumor cell nests have distinctive properties in relation to pertinent breast cancer clinicopathological parameters and tumor angiogenesis. In 94 human invasive breast ductal carcinomas, tumor-associated macrophages were immunostained with anti-CD68 antibody and counted or graded according to these histological locations. Microvessels were immunostained with anti-CD34 antibody and counted for microvessel density. We found that the presence of tumor stromal and tumor nest macrophages was closely correlated (p = 0.001). Both tumor stromal and tumor nest macrophages were associated with mitotic count (p = 0.001 and p = 0.037, respectively). However, only higher tumor stromal macrophage grades were associated with higher tumor grades (p = 0.004) and negative estrogen receptor status (p = 0.007). Multivariate analysis showed that tumors with a high mitotic count score (score 3 vs. scores 1 and 2) had a higher tumor stromal macrophage density (Grades III and IV) when adjusted for tumor size, tubule formation, and estrogen receptor status (odds ratio 3.41, p = 0.010). The tumor nest macrophage count significantly correlated with the microvessel density (p tumor stromal macrophages and tumor nest macrophages residing in different tumor microenvironments have distinctive roles.

Matched MeSH terms: Tumor Microenvironment/immunology
Fulltext Small Molecules Targeting Programmed Cell Death in Breast Cancer Cells

Maniam S, Maniam S

Int J Mol Sci, 2021 Sep 08;22(18).
PMID: 34575883 DOI: 10.3390/ijms22189722

Targeted chemotherapy has become the forefront for cancer treatment in recent years. The selective and specific features allow more effective treatment with reduced side effects. Most targeted therapies, which include small molecules, act on specific molecular targets that are altered in tumour cells, mainly in cancers such as breast, lung, colorectal, lymphoma and leukaemia. With the recent exponential progress in drug development, programmed cell death, which includes apoptosis and autophagy, has become a promising therapeutic target. The research in identifying effective small molecules that target compensatory mechanisms in tumour cells alleviates the emergence of drug resistance. Due to the heterogenous nature of breast cancer, various attempts were made to overcome chemoresistance. Amongst breast cancers, triple negative breast cancer (TNBC) is of particular interest due to its heterogeneous nature in response to chemotherapy. TNBC represents approximately 15% of all breast tumours, however, and still has a poor prognosis. Unlike other breast tumours, signature targets lack for TNBCs, causing high morbidity and mortality. This review highlights several small molecules with promising preclinical data that target autophagy and apoptosis to induce cell death in TNBC cells.

Matched MeSH terms: Tumor Microenvironment/drug effects; Tumor Microenvironment/genetics
Fulltext Toll-like receptors and cancer, particularly oral squamous cell carcinoma

Rich AM, Hussaini HM, Parachuru VP, Seymour GJ

Front Immunol, 2014;5:464.
PMID: 25309546 DOI: 10.3389/fimmu.2014.00464

It is becoming increasingly apparent that the tumor microenvironment plays an important role in the progression of cancer. The microenvironment may promote tumor cell survival and proliferation or, alternatively may induce tumor cell apoptosis. Toll-like receptors (TLRs) are transmembrane proteins, expressed on immune cells and epithelial cells, that recognize exogenous and endogenous macromolecules. Once activated, they initiate signaling pathways leading to the release of cytokines and chemokines, which recruit immune cells inducing further cytokine production, the production of angiogenic mediators and growth factors, all of which may influence tumor progression. This paper examines the actions of TLRs in carcinogenesis with particular emphasis on their role in oral squamous cell carcinoma.

Matched MeSH terms: Tumor Microenvironment
Fulltext Is targeting autophagy mechanism in cancer a good approach? The possible double-edge sword effect

Lim SM, Mohamad Hanif EA, Chin SF

Cell Biosci, 2021 Mar 20;11(1):56.
PMID: 33743781 DOI: 10.1186/s13578-021-00570-z

Autophagy is a conserved cellular process required to maintain homeostasis. The hallmark of autophagy is the formation of a phagophore that engulfs cytosolic materials for degradation and recycling to synthesize essential components. Basal autophagy is constitutively active under normal conditions and it could be further induced by physiological stimuli such as hypoxia, nutrient starvation, endoplasmic reticulum stress,energy depletion, hormonal stimulation and pharmacological treatment. In cancer, autophagy is highly context-specific depending on the cell type, tumour microenvironment, disease stage and external stimuli. Recently, the emerging role of autophagy as a double-edged sword in cancer has gained much attention. On one hand, autophagy suppresses malignant transformation by limiting the production of reactive oxygen species and DNA damage during tumour development. Subsequently, autophagy evolved to support the survival of cancer cells and promotes the tumourigenicity of cancer stem cells at established sites. Hence, autophagy is an attractive target for cancer therapeutics and researchers have been exploiting the use of autophagy modulators as adjuvant therapy. In this review, we present a summary of autophagy mechanism and controlling pathways, with emphasis on the dual-role of autophagy (double-edged sword) in cancer. This is followed by an overview of the autophagy modulation for cancer treatment and is concluded by a discussion on the current perspectives and future outlook of autophagy exploitation for precision medicine.

Matched MeSH terms: Tumor Microenvironment
Role of therapeutic agents on repolarisation of tumour-associated macrophage to halt lung cancer progression

Aldawsari HM, Gorain B, Alhakamy NA, Md S

J Drug Target, 2020 02;28(2):166-175.
PMID: 31339380 DOI: 10.1080/1061186X.2019.1648478

Tumour-associated macrophages (TAMs) represent as much as 50% of the solid mass in different types of human solid tumours including lung, breast, ovarian and pancreatic adenocarcinomas. The tumour microenvironment (TME) plays an important role in the polarisation of macrophages into the M1 phenotype, which is tumour-suppressive, or M2 phenotype, which is tumour promoting. Preclinical and clinical evidences suggest that TAMs are predominantly of the M2 phenotype that supports immune suppression, tumour growth, angiogenesis, metastasis and therapeutic resistance. Hence, significant attention has been focussed on the development of strategies for the modification of TAMs to halt lung cancer progression. The promotion of repolarisation from the M2 to the M1 subtype, or the prevention of M2 polarisation of TAMs in the stromal environment is potential approaches to reduce progression and metastasis of lung cancer. The focus of this article is an introduction to the development and evaluation of therapeutic agents that may halt lung cancer progression via the manipulation of macrophage polarisation. This article will address recent advances in the therapeutic efficacy of nanomedicine exploiting surface functionalisation of nanoparticles and will also consider future perspectives.

Matched MeSH terms: Tumor Microenvironment
Fulltext Gut Dysbiosis and Intestinal Barrier Dysfunction: Potential Explanation for Early-Onset Colorectal Cancer

Ahmad Kendong SM, Raja Ali RA, Nawawi KNM, Ahmad HF, Mokhtar NM

Front Cell Infect Microbiol, 2021;11:744606.
PMID: 34966694 DOI: 10.3389/fcimb.2021.744606

Colorectal cancer (CRC) is a heterogeneous disease that commonly affects individuals aged more than 50 years old globally. Regular colorectal screening, which is recommended for individuals aged 50 and above, has decreased the number of cancer death toll over the years. However, CRC incidence has increased among younger population (below 50 years old). Environmental factors, such as smoking, dietary factor, urbanization, sedentary lifestyle, and obesity, may contribute to the rising trend of early-onset colorectal cancer (EOCRC) because of the lack of genetic susceptibility. Research has focused on the role of gut microbiota and its interaction with epithelial barrier genes in sporadic CRC. Population with increased consumption of grain and vegetables showed high abundance of Prevotella, which reduces the risk of CRC. Microbes, such as Fusobacterium nucleatum, Bacteroides fragilis and Escherichia coli deteriorate in the intestinal barrier, which leads to the infiltration of inflammatory mediators and chemokines. Gut dysbiosis may also occur following inflammation as clearly observed in animal model. Both gut dysbiosis pre- or post-inflammatory process may cause major alteration in the morphology and functional properties of the gut tissue and explain the pathological outcome of EOCRC. The precise mechanism of disease progression from an early stage until cancer establishment is not fully understood. We hypothesized that gut dysbiosis, which may be influenced by environmental factors, may induce changes in the genome, metabolome, and immunome that could destruct the intestinal barrier function. Also, the possible underlying inflammation may give impact microbial community leading to disruption of physical and functional role of intestinal barrier. This review explains the potential role of the interaction among host factors, gut microenvironment, and gut microbiota, which may provide an answer to EOCRC.

Matched MeSH terms: Tumor Microenvironment
Fulltext Virus like particles as a platform for cancer vaccine development

Ong HK, Tan WS, Ho KL

PeerJ, 2017;5:e4053.
PMID: 29158984 DOI: 10.7717/peerj.4053

Cancers have killed millions of people in human history and are still posing a serious health problem worldwide. Therefore, there is an urgent need for developing preventive and therapeutic cancer vaccines. Among various cancer vaccine development platforms, virus-like particles (VLPs) offer several advantages. VLPs are multimeric nanostructures with morphology resembling that of native viruses and are mainly composed of surface structural proteins of viruses but are devoid of viral genetic materials rendering them neither infective nor replicative. In addition, they can be engineered to display multiple, highly ordered heterologous epitopes or peptides in order to optimize the antigenicity and immunogenicity of the displayed entities. Like native viruses, specific epitopes displayed on VLPs can be taken up, processed, and presented by antigen-presenting cells to elicit potent specific humoral and cell-mediated immune responses. Several studies also indicated that VLPs could overcome the immunosuppressive state of the tumor microenvironment and break self-tolerance to elicit strong cytotoxic lymphocyte activity, which is crucial for both virus clearance and destruction of cancerous cells. Collectively, these unique characteristics of VLPs make them optimal cancer vaccine candidates. This review discusses current progress in the development of VLP-based cancer vaccines and some potential drawbacks of VLPs in cancer vaccine development. Extracellular vesicles with close resembling to viral particles are also discussed and compared with VLPs as a platform in cancer vaccine developments.

Matched MeSH terms: Tumor Microenvironment
CD4+ Foxp3+ Regulatory T-cells in Modulating Inflammatory Microenvironment in Chronic Rhinosinusitis with Nasal Polyps: Progress and Future Prospect

M Yusoff NNF, Ahmad S, Wan Abdul Rahman WF, Mohamud R, C Boer J, Plebanski M, et al.

Cytokine, 2024 Jun;178:156557.
PMID: 38452440 DOI: 10.1016/j.cyto.2024.156557

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a subtype of chronic rhinosinusitis (CRS) characterized by the presence of nasal polyps (NP) in the paranasal mucosa. Despite the complex etiology, NP is believed to result from chronic inflammation. The long-term aftermath of the type 2 response is responsible for symptoms seen in NP patients, i.e. rhinorrhea, hyposmia, and nasal obstruction. Immune cellular tolerogenic mechanisms, particularly CD4 + Foxp3 + regulatory T cells (Tregs), are crucial to curtail inflammatory responses. Current evidence suggests impaired Treg activity is the main reason underlying the compromise of self-tolerance, contributing to the onset of CRSwNP. There is compelling evidence that tumor necrosis factor 2 (TNFR2) is preferentially expressed by Tregs, and TNFR2 is able to identify the most potent suppressive subset of Tregs. Tumor necrosis factor (TNF)-TNFR2 interaction plays a decisive role in the activation and expansion of Tregs. This review summarizes current understanding of Tregs biology, focusing on the discussion of the recent advances in the study of TNF-TNFR2 axis in the upregulation of Treg function as a negative feedback mechanism in the control of chronic inflammation. The role of dysregulation of Tregs in the immunopathogenesis of CRSwNP will be analyzed. The future perspective on the harnessing Tregs-mediated self-tolerant mechanism in the management of CRSwNP will be introduced.

Matched MeSH terms: Tumor Microenvironment
Linking Benzene, in Utero Carcinogenicity and Fetal Hematopoietic Stem Cell Niches: A Mechanistic Review

Yusoff NA, Abd Hamid Z, Budin SB, Taib IS

Int J Mol Sci, 2023 Mar 28;24(7).
PMID: 37047305 DOI: 10.3390/ijms24076335

Previous research reported that prolonged benzene exposure during in utero fetal development causes greater fetal abnormalities than in adult-stage exposure. This phenomenon increases the risk for disease development at the fetal stage, particularly carcinogenesis, which is mainly associated with hematological malignancies. Benzene has been reported to potentially act via multiple modes of action that target the hematopoietic stem cell (HSCs) niche, a complex microenvironment in which HSCs and multilineage hematopoietic stem and progenitor cells (HSPCs) reside. Oxidative stress, chromosomal aberration and epigenetic modification are among the known mechanisms mediating benzene-induced genetic and epigenetic modification in fetal stem cells leading to in utero carcinogenesis. Hence, it is crucial to monitor exposure to carcinogenic benzene via environmental, occupational or lifestyle factors among pregnant women. Benzene is a well-known cause of adult leukemia. However, proof of benzene involvement with childhood leukemia remains scarce despite previously reported research linking incidences of hematological disorders and maternal benzene exposure. Furthermore, accumulating evidence has shown that maternal benzene exposure is able to alter the developmental and functional properties of HSPCs, leading to hematological disorders in fetus and children. Since HSPCs are parental blood cells that regulate hematopoiesis during the fetal and adult stages, benzene exposure that targets HSPCs may induce damage to the population and trigger the development of hematological diseases. Therefore, the mechanism of in utero carcinogenicity by benzene in targeting fetal HSPCs is the primary focus of this review.

Matched MeSH terms: Tumor Microenvironment
Fulltext Role of Cytokines and Chemokines in NSCLC Immune Navigation and Proliferation

Ramachandran S, Verma AK, Dev K, Goyal Y, Bhatt D, Alsahli MA, et al.

Oxid Med Cell Longev, 2021;2021:5563746.
PMID: 34336101 DOI: 10.1155/2021/5563746

With over a million deaths every year around the world, lung cancer is found to be the most recurrent cancer among all types. Nonsmall cell lung carcinoma (NSCLC) amounts to about 85% of the entire cases. The other 15% owes it to small cell lung carcinoma (SCLC). Despite decades of research, the prognosis for NSCLC patients is poorly understood with treatment options limited. First, this article emphasises on the part that tumour microenvironment (TME) and its constituents play in lung cancer progression. This review also highlights the inflammatory (pro- or anti-) roles of different cytokines (ILs, TGF-β, and TNF-α) and chemokine (CC, CXC, C, and CX3C) families in the lung TME, provoking tumour growth and subsequent metastasis. The write-up also pinpoints recent developments in the field of chemokine biology. Additionally, it covers the role of extracellular vesicles (EVs), as alternate carriers of cytokines and chemokines. This allows the cytokines/chemokines to modulate the EVs for their secretion, trafficking, and aid in cancer proliferation. In the end, this review also stresses on the role of these factors as prognostic biomarkers for lung immunotherapy, apart from focusing on inflammatory actions of these chemoattractants.

Matched MeSH terms: Tumor Microenvironment
Modeling nasopharyngeal carcinoma in three dimensions

Siva Sankar P, Che Mat MF, Muniandy K, Xiang BLS, Ling PS, Hoe SLL, et al.

Oncol Lett, 2017 Apr;13(4):2034-2044.
PMID: 28454359 DOI: 10.3892/ol.2017.5697

Nasopharyngeal carcinoma (NPC) is a type of cancer endemic in Asia, including Malaysia, Southern China, Hong Kong and Taiwan. Treatment resistance, particularly in recurring cases, remains a challenge. Thus, studies to develop novel therapeutic agents are important. Potential therapeutic compounds may be effectively examined using two-dimensional (2D) cell culture models, three-dimensional (3D) spheroid models or in vivo animal models. The majority of drug assessments for cancers, including for NPC, are currently performed with 2D cell culture models. This model offers economical and high-throughput screening advantages. However, 2D cell culture models cannot recapitulate the architecture and the microenvironment of a tumor. In vivo models may recapitulate certain architectural and microenvironmental conditions of a tumor, however, these are not feasible for the screening of large numbers of compounds. By contrast, 3D spheroid models may be able to recapitulate a physiological microenvironment not observed in 2D cell culture models, in addition to avoiding the impediments of in vivo animal models. Thus, the 3D spheroid model offers a more representative model for the study of NPC growth, invasion and drug response, which may be cost-effective without forgoing quality.

Matched MeSH terms: Tumor Microenvironment

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