Displaying publications 1 - 20 of 91 in total

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  1. Fulltext 1'-Acetoxychavicol acetate inhibits growth of human oral carcinoma xenograft in mice and potentiates cisplatin effect via proinflammatory microenvironment alterations
    In LL, Arshad NM, Ibrahim H, Azmi MN, Awang K, Nagoor NH
    BMC Complement Altern Med, 2012;12:179.
    PMID: 23043547 DOI: 10.1186/1472-6882-12-179
    Oral cancers although preventable, possess a low five-year survival rate which has remained unchanged over the past three decades. In an attempt to find a more safe, affordable and effective treatment option, we describe here the use of 1'S-1'-acetoxychavicol acetate (ACA), a component of Malaysian ginger traditionally used for various medicinal purposes.
    Matched MeSH terms: Tumor Microenvironment/drug effects
  2. Fulltext 3D Microfluidic Bone Tumor Microenvironment Comprised of Hydroxyapatite/Fibrin Composite
    Ahn J, Lim J, Jusoh N, Lee J, Park TE, Kim Y, et al.
    Front Bioeng Biotechnol, 2019;7:168.
    PMID: 31380359 DOI: 10.3389/fbioe.2019.00168
    Bone is one of the most common sites of cancer metastasis, as its fertile microenvironment attracts tumor cells. The unique mechanical properties of bone extracellular matrix (ECM), mainly composed of hydroxyapatite (HA) affect a number of cellular responses in the tumor microenvironment (TME) such as proliferation, migration, viability, and morphology, as well as angiogenic activity, which is related to bone metastasis. In this study, we engineered a bone-mimetic microenvironment to investigate the interactions between the TME and HA using a microfluidic platform designed for culturing tumor cells in 3D bone-mimetic composite of HA and fibrin. We developed a bone metastasis TME model from colorectal cancer (SW620) and gastric cancer (MKN74) cells, which has very poor prognosis but rarely been investigated. The microfluidic platform enabled straightforward formation of 3D TME composed the hydrogel and multiple cell types. This facilitated monitoring of the effect of HA concentration and culture time on the TME. In 3D bone mimicking culture, we found that HA rich microenvironment affects cell viability, proliferation and cancer cell cytoplasmic volume in a manner dependent on the different metastatic cancer cell types and culture duration indicating the spatial heterogeneity (different origin of metastatic cancer) and temporal heterogeneity (growth time of cancer) of TME. We also found that both SW620 and MKN72 cells exhibited significantly reduced migration at higher HA concentration in our platform indicating inhibitory effect of HA in both cancer cells migration. Next, we quantitatively analyzed angiogenic sprouts induced by paracrine factors that secreted by TME and showed paracrine signals from tumor and stromal cell with a high HA concentration resulted in the formation of fewer sprouts. Finally we reconstituted vascularized TME allowing direct interaction between angiogenic sprouts and tumor-stroma microspheroids in a bone-mimicking microenvironment composing a tunable HA/fibrin composite. Our multifarious approach could be applied to drug screening and mechanistic studies of the metastasis, growth, and progression of bone tumors.
    Matched MeSH terms: Tumor Microenvironment
  3. 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
  4. 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
  5. Aberrant frequency of TNFR2-expressing CD4+ FoxP3+ regulatory T cells in nasopharyngeal carcinoma patients
    Engku Abd Rahman ENS, Irekeola AA, Shueb RH, Mat Lazim N, Mohamud R, Chen X, et al.
    Cytokine, 2023 Oct;170:156341.
    PMID: 37657236 DOI: 10.1016/j.cyto.2023.156341
    TNFR2 is a surface marker of highly suppressive subset of CD4+ FoxP3+ regulatory T cells (Tregs) in humans and mice. This study examined the TNFR2 expression by Tregs of nasopharyngeal carcinoma (NPC) patients and healthy controls. The proliferation, migration, survival of TNFR2+ Tregs, and association with clinicopathological characteristics were assessed. The expression levels of selected cytokines were also determined. The results demonstrated that in both peripheral blood (PB) (10.45 ± 5.71%) and tumour microenvironment (TME) (54.38 ± 16.15%) of NPC patients, Tregs expressed TNFR2 at noticeably greater levels than conventional T cells (Tconvs) (3.91 ± 2.62%, p  0.05), the proportions of PB and TME TNFR2+ Tregs in NPC patients showed more proliferative, higher migration capacity, and better survival ability, as compared to those in healthy controls. Furthermore, TNFR2+ Tregs from NPC patients expressed significantly higher amounts of IL-6 (p = 0.0077), IL-10 (p = 0.0001), IFN-γ (p = 0.0105) and TNF-α (p 
    Matched MeSH terms: Tumor Microenvironment
  6. Adenosine Receptors as Novel Targets for the Treatment of Various Cancers
    Gorain B, Choudhury H, Yee GS, Bhattamisra SK
    Curr Pharm Des, 2019;25(26):2828-2841.
    PMID: 31333092 DOI: 10.2174/1381612825666190716102037
    Adenosine is a ubiquitous signaling nucleoside molecule, released from different cells within the body to act on vasculature and immunoescape. The physiological action on the proliferation of tumour cell has been reported by the presence of high concentration of adenosine within the tumour microenvironment, which results in the progression of the tumour, even leading to metastases. The activity of adenosine exclusively depends upon the interaction with four subtypes of heterodimeric G-protein-coupled adenosine receptors (AR), A1, A2A, A2B, and A3-ARs on the cell surface. Research evidence supports that the activation of those receptors via specific agonist or antagonist can modulate the proliferation of tumour cells. The first category of AR, A1 is known to play an antitumour activity via tumour-associated microglial cells to prevent the development of glioblastomas. A2AAR are found in melanoma, lung, and breast cancer cells, where tumour proliferation is stimulated due to inhibition of the immune response via inhibition of natural killer cells cytotoxicity, T cell activity, and tumourspecific CD4+/CD8+ activity. Alternatively, A2BAR helps in the development of tumour upon activation via upregulation of angiogenin factor in the microvascular endothelial cells, inhibition of MAPK and ERK 1/2 phosphorylation activity. Lastly, A3AR is expressed in low levels in normal cells whereas the expression is upregulated in tumour cells, however, agonists to this receptor inhibit tumour proliferation through modulation of Wnt and NF-κB signaling pathways. Several researchers are in search for potential agents to modulate the overexpressed ARs to control cancer. Active components of A2AAR antagonists and A3AR agonists have already entered in Phase-I clinical research to prove their safety in human. This review focused on novel research targets towards the prevention of cancer progression through stimulation of the overexpressed ARs with the hope to protect lives and advance human health.
    Matched MeSH terms: Tumor Microenvironment
  7. Fulltext Analysis of octamer-binding transcription factor-4 expression in oral leukoplakia
    Tegginamani AS, Shivakumar VH, Kallarakkal TG, Ismail SM, Abraham MT, Bin Zamzuri AT
    J Oral Maxillofac Pathol, 2020 09 09;24(2):400.
    PMID: 33456258 DOI: 10.4103/jomfp.JOMFP_272_19
    Background: Oral potentially malignant disorders have a risk for malignant transformation but are difficult to reliably identify and predict which patients are at the risk for malignant transformation. OCT4 has been hypothesized to play a key oncogenic driver in a variety of solid tumors. A deeper understanding of the aberrant molecular pathways which lead to carcinogenesis needs to be identified by the potential markers.

    Aims: To assess the OCT4 stemness factor in oral leukoplakia for its potential risk to malignant transformation.

    Settings and Design: 20 cases of oral leukoplakia were obtained from archives at Oral Cancer Research & Coordinating center (OCRCC) Malaysia Subjects and Methods: 20 cases of oral leukoplakia were assessed by OCT4 immunohistochemically. Oral squamous cell carcinoma was used as a control.

    Result: no expression of OCT 4 was observed in any cases of oral leukoplakia.

    Conclusion: The molecular mechanisms of Oct4 regulation and in particular of its switch on and off in tissues depends upon its microenvironment, which makes it challenging in fundamental and applied research fields of regenerative medicine and cancer therapy. It's better that patients should undergo multiple biopsies for the early detection of malignant transformation with close follow-up during the first two to three years, a large amount of work remains to be done with multi-marker panel investigation, as cure rates have remained constant over three decades.

    Matched MeSH terms: Tumor Microenvironment
  8. Fulltext Association of BRCA1- and BRCA2-deficiency with mutation burden, expression of PD-L1/PD-1, immune infiltrates, and T cell-inflamed signature in breast cancer
    Wen WX, Leong CO
    PLoS One, 2019;14(4):e0215381.
    PMID: 31022191 DOI: 10.1371/journal.pone.0215381
    Immune checkpoint inhibitors have demonstrated effective anti-tumour response in cancer types with high mutation burden (e.g. melanoma) and in subset of cancers with features of genomic instability (e.g. mismatch-repair deficiency). One possible explanation for this effect is the increased expression of immune checkpoint molecules and pre-existing adaptive immune response in these cancers. Given that BRCA1 and BRCA2 are integral in maintaining genomic integrity, we hypothesise that the inactivation of these genes may give rise to breast cancers with such immunogenic phenotype. Therefore, using two large series of publicly available breast cancer datasets, namely that from The Cancer Genome Atlas and Wellcome Trust Institute, we sought to investigate the association between BRCA1- and BRCA2-deficiency with features of genomic instability, expression of PD-L1 and PD-1, landscape of inferred tumour-infiltrating immune cells, and T-cell inflamed signature in breast cancers. Here, we report that BRCA1 and BRCA2-deficient breast cancers were associated with features of genomic instability including increased mutation burden. Interestingly, BRCA1-, but not BRCA2-, deficient breast cancers were associated with increased expression of PD-L1 and PD-1, higher abundance of tumour-infiltrating immune cells, and enrichment of T cell-inflamed signature. The differences in immunophenotype between BRCA1- and BRCA2-deficient breast cancers can be attributed, in part, to PTEN gene mutation. Therefore, features of genomic instability such as that mediated by BRCA1- and BRCA2- deficiency in breast cancer were necessary, but not always sufficient, for yielding T cell-inflamed tumour microenvironment, and by extension, predicting clinical benefit from immunotherapy.
    Matched MeSH terms: Tumor Microenvironment/genetics; Tumor Microenvironment/immunology
  9. 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
  10. Fulltext Bioengineered siRNA-Based Nanoplatforms Targeting Molecular Signaling Pathways for the Treatment of Triple Negative Breast Cancer: Preclinical and Clinical Advancements
    Hattab D, Bakhtiar A
    Pharmaceutics, 2020 Sep 29;12(10).
    PMID: 33003468 DOI: 10.3390/pharmaceutics12100929
    Triple negative breast cancer (TNBC) is one of the most aggressive types of breast cancer. Owing to the absenteeism of hormonal receptors expressed at the cancerous breast cells, hormonal therapies and other medications targeting human epidermal growth factor receptor 2 (HER2) are ineffective in TNBC patients, making traditional chemotherapeutic agents the only current appropriate regimen. Patients' predisposition to relapse and metastasis, chemotherapeutics' cytotoxicity and resistance and poor prognosis of TNBC necessitates researchers to investigate different novel-targeted therapeutics. The role of small interfering RNA (siRNA) in silencing the genes/proteins that are aberrantly overexpressed in carcinoma cells showed great potential as part of TNBC therapeutic regimen. However, targeting specificity, siRNA stability, and delivery efficiency cause challenges in the progression of this application clinically. Nanotechnology was highlighted as a promising approach for encapsulating and transporting siRNA with high efficiency-low toxicity profile. Advances in preclinical and clinical studies utilizing engineered siRNA-loaded nanotherapeutics for treatment of TNBC were discussed. Specific and selective targeting of diverse signaling molecules/pathways at the level of tumor proliferation and cell cycle, tumor invasion and metastasis, angiogenesis and tumor microenvironment, and chemotherapeutics' resistance demonstrated greater activity via integration of siRNA-complexed nanoparticles.
    Matched MeSH terms: Tumor Microenvironment
  11. Fulltext CD36-Fatty Acid-Mediated Metastasis via the Bidirectional Interactions of Cancer Cells and Macrophages
    Zaidi NE, Shazali NAH, Leow TC, Osman MA, Ibrahim K, Cheng WH, et al.
    Cells, 2022 Nov 10;11(22).
    PMID: 36428985 DOI: 10.3390/cells11223556
    Tumour heterogeneity refers to the complexity of cell subpopulations coexisting within the tumour microenvironment (TME), such as proliferating tumour cells, tumour stromal cells and infiltrating immune cells. The bidirectional interactions between cancer and the surrounding microenvironment mark the tumour survival and promotion functions, which allow the cancer cells to become invasive and initiate the metastatic cascade. Importantly, these interactions have been closely associated with metabolic reprogramming, which can modulate the differentiation and functions of immune cells and thus initiate the antitumour response. The purpose of this report is to review the CD36 receptor, a prominent cell receptor in metabolic activity specifically in fatty acid (FA) uptake, for the metabolic symbiosis of cancer-macrophage. In this review, we provide an update on metabolic communication between tumour cells and macrophages, as well as how the immunometabolism indirectly orchestrates the tumour metastasis.
    Matched MeSH terms: Tumor Microenvironment
  12. 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
  13. 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*
  14. Cancer-associated fibroblasts of colorectal cancer and their markers: updates, challenges and translational outlook
    Musa M, Ali A
    Future Oncol, 2020 Oct;16(29):2329-2344.
    PMID: 32687721 DOI: 10.2217/fon-2020-0384
    Accumulation of cancer-associated fibroblasts (CAFs) in the tumor microenvironment is associated with poor prognosis and recurrence of colorectal cancer (CRC). Despite their prominent roles in colorectal carcinogenesis, there is a lack of robust and specific markers to classify the heterogeneous and highly complex CAF populations. This has resulted in confusing and misleading definitions of CAFs in cancer niche. Advancements in molecular biology approaches have open doors to reliable CAF marker detection methods in various solid tumors. These discoveries would contribute to more efficient screening, monitoring and targeted therapy of CRC thus potentially will reduce cancer morbidity and mortality rates. This review highlights current scenarios, dilemma, translational potentials of CAF biomarker and future therapeutic applications involving CAF marker identification in CRC.
    Matched MeSH terms: Tumor Microenvironment*
  15. Cell membrane cloaked nanomedicines for bio-imaging and immunotherapy of cancer: Improved pharmacokinetics, cell internalization and anticancer efficacy
    Hussain Z, Rahim MA, Jan N, Shah H, Rawas-Qalaji M, Khan S, et al.
    J Control Release, 2021 07 10;335:130-157.
    PMID: 34015400 DOI: 10.1016/j.jconrel.2021.05.018
    Despite enormous advancements in the field of oncology, the innocuous and effectual treatment of various types of malignancies remained a colossal challenge. The conventional modalities such as chemotherapy, radiotherapy, and surgery have been remained the most viable options for cancer treatment, but lacking of target-specificity, optimum safety and efficacy, and pharmacokinetic disparities are their impliable shortcomings. Though, in recent decades, numerous encroachments in the field of onco-targeted drug delivery have been adapted but several limitations (i.e., short plasma half-life, early clearance by reticuloendothelial system, immunogenicity, inadequate internalization and localization into the onco-tissues, chemoresistance, and deficient therapeutic efficacy) associated with these onco-targeted delivery systems limits their clinical viability. To abolish the aforementioned inadequacies, a promising approach has been emerged in which stealthing of synthetic nanocarriers has been attained by cloaking them into the natural cell membranes. These biomimetic nanomedicines not only retain characteristics features of the synthetic nanocarriers but also inherit the cell-membrane intrinsic functionalities. In this review, we have summarized preparation methods, mechanism of cloaking, and pharmaceutical and therapeutic superiority of cell-membrane camouflaged nanomedicines in improving the bio-imaging and immunotherapy against various types of malignancies. These pliable adaptations have revolutionized the current drug delivery strategies by optimizing the plasma circulation time, improving the permeation into the cancerous microenvironment, escaping the immune evasion and rapid clearance from the systemic circulation, minimizing the immunogenicity, and enabling the cell-cell communication via cell membrane markers of biomimetic nanomedicines. Moreover, the preeminence of cell-membrane cloaked nanomedicines in improving the bio-imaging and theranostic applications, alone or in combination with phototherapy or radiotherapy, have also been pondered.
    Matched MeSH terms: Tumor Microenvironment
  16. Fulltext Cephalomannine inhibits hypoxia-induced cellular function via the suppression of APEX1/HIF-1α interaction in lung cancer
    Ullah A, Leong SW, Wang J, Wu Q, Ghauri MA, Sarwar A, et al.
    Cell Death Dis, 2021 05 14;12(5):490.
    PMID: 33990544 DOI: 10.1038/s41419-021-03771-z
    Lung cancer (LC) is one of the leading causes of cancer-related death. As one of the key features of tumor microenvironment, hypoxia conditions are associated with poor prognosis in LC patients. Upregulation of hypoxic-induced factor-1α (HIF-1α) leads to the activation of various factors that contribute to the increased drug resistance, proliferation, and migration of tumor cells. Apurinic/apyrimidinic endonuclease-1 (APEX1) is a multi-functional protein that regulates several transcription factors, including HIF-1α, that contribute to tumor growth, oxidative stress responses, and DNA damage. In this study, we explored the mechanisms underlying cell responses to hypoxia and modulation of APEX1, which regulate HIF-1α and downstream pathways. We found that hypoxia-induced APEX1/HIF-1α pathways regulate several key cellular functions, including reactive oxygen species (ROS) production, carbonic anhydrase 9 (CA9)-mediated intracellular pH, migration, and angiogenesis. Cephalomannine (CPM), a natural compound, exerted inhibitory effects in hypoxic LC cells via the inhibition of APEX1/HIF-1α interaction in vitro and in vivo. CPM can significantly inhibit cell viability, ROS production, intracellular pH, and migration in hypoxic LC cells as well as angiogenesis of HUVECs under hypoxia through the inhibition of APEX1/HIF-1α interaction. Taken together, CPM could be considered as a promising compound for LC treatment.
    Matched MeSH terms: Tumor Microenvironment
  17. Fulltext Clinicopathologic and Molecular Characteristics of Epstein-Barr Virus-Associated Smooth Muscle Tumor Compared With Those of Leiomyoma and Leiomyosarcoma
    Wah NW, Mok Y, Omar N, Chang KTE, Tay TKY, Hue SS, et al.
    Mod Pathol, 2023 Jun;36(6):100127.
    PMID: 36965331 DOI: 10.1016/j.modpat.2023.100127
    Epstein-Barr virus (EBV)-associated smooth muscle tumors (EBV-SMTs) are rare smooth muscle neoplasms exclusively associated with immunosuppression, such as in patients with HIV/AIDS, posttransplant, and congenital immunodeficiency. However, the genomic landscape of EBV-SMTs is poorly understood. Leiomyosarcomas harbor genomic instability and multiple recurrent DNA copy number alterations, whereas leiomyomas lack such changes. Thus, this study aimed to fill this knowledge gap by characterizing copy number alterations in EBV-SMTs and correlating this information with clinicopathologic characteristics. Our study investigated and compared the pathologic characteristics and copy number profiles of 9 EBV-SMTs (from 7 post-transplant and AIDS patients), 6 leiomyomas, and 7 leiomyosarcomas, using chromosomal microarray platforms. Our results showed a lower copy number alteration burden in EBV-SMTs and leiomyoma than in leiomyosarcoma. This contrast in the molecular profile between EBV-SMTs and leiomyosarcoma is concordant with the different clinical behaviors and pathologic characteristics exhibited by these tumors. Despite having an overall copy number alteration profile closer to leiomyoma, recurrent copy number gain of oncogenes, such as RUNX1, CCND2, and ETS2, was found in EBV-SMTs. Epigenetic alterations may play an important role in tumorigenesis as recurrent copy number gains were found in histone deacetylases. A gene enrichment analysis also demonstrated enrichment of genes involved in the host response to viral infection, suggesting that the tumor immune microenvironment may play an important role in EBV-SMT tumorigenesis.
    Matched MeSH terms: Tumor Microenvironment
  18. Fulltext Comprehensive analysis of co-expressed genes with TDP-43: prognostic and therapeutic potential in lung adenocarcinoma
    Zhang H, Lin J, Yahaya BH
    J Cancer Res Clin Oncol, 2024 Jan 28;150(2):44.
    PMID: 38281298 DOI: 10.1007/s00432-023-05554-9
    BACKGROUND: Transactivating DNA-binding protein 43 (TDP-43) is intimately associated with tumorigenesis and progression by regulating mRNA splicing, transport, stability, and non-coding RNA molecules. The exact role of TDP-43 in lung adenocarcinoma (LUAD) has not yet been fully elucidated, despite extensive research on its function in various cancer types. An imperative aspect of comprehending the underlying biological characteristics associated with TDP-43 involves investigating the genes that are co-expressed with this protein. This study assesses the prognostic significance of these co-expressed genes in LUAD and subsequently explores potential therapeutic strategies based on these findings.

    METHODS: Transcriptomic and clinical data pertaining to LUAD were retrieved from open-access databases to establish an association between mRNA expression profiles and the presence of TDP-43. A risk-prognosis model was developed to compare patient survival rates across various groups, and its accuracy was also assessed. Additionally, differences in tumor stemness, mutational profiles, tumor microenvironment (TME) characteristics, immune checkpoints, and immune cell infiltration were analyzed in the different groups. Moreover, the study entailed predicting the potential response to immunotherapy as well as the sensitivity to commonly employed chemotherapeutic agents and targeted drugs for each distinct group.

    RESULTS: The TDP-43 Co-expressed Gene Risk Score (TCGRS) model was constructed utilizing four genes: Kinesin Family Member 20A (KIF20A), WD Repeat Domain 4 (WDR4), Proline Rich 11 (PRR11), and Glia Maturation Factor Gamma (GMFG). The value of this model in predicting LUAD patient survival is effectively illustrated by both the Kaplan-Meier (K-M) survival curve and the area under the receiver operating characteristic curve (AUC-ROC). The Gene Set Enrichment Analysis (GSEA) revealed that the high TCGRS group was primarily enriched in biological pathways and functions linked to DNA replication and cell cycle; the low TCGRS group showed primary enrichment in immune-related pathways and functions. The high and low TCGRS groups showed differences in tumor stemness, mutational burden, TME, immune infiltration level, and immune checkpoints. The predictions analysis of immunotherapy indicates that the Tumor Immune Dysfunction and Exclusion (TIDE) score (p 

    Matched MeSH terms: Tumor Microenvironment
  19. Fulltext Comprehensive functional profiling of long non-coding RNAs through a novel pan-cancer integration approach and modular analysis of their protein-coding gene association networks
    Walters K, Sarsenov R, Too WS, Hare RK, Paterson IC, Lambert DW, et al.
    BMC Genomics, 2019 Jun 03;20(1):454.
    PMID: 31159744 DOI: 10.1186/s12864-019-5850-7
    BACKGROUND: Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of cellular processes in diseases such as cancer, although the functions of most remain poorly understood. To address this, here we apply a novel strategy to integrate gene expression profiles across 32 cancer types, and cluster human lncRNAs based on their pan-cancer protein-coding gene associations. By doing so, we derive 16 lncRNA modules whose unique properties allow simultaneous inference of function, disease specificity and regulation for over 800 lncRNAs.

    RESULTS: Remarkably, modules could be grouped into just four functional themes: transcription regulation, immunological, extracellular, and neurological, with module generation frequently driven by lncRNA tissue specificity. Notably, three modules associated with the extracellular matrix represented potential networks of lncRNAs regulating key events in tumour progression. These included a tumour-specific signature of 33 lncRNAs that may play a role in inducing epithelial-mesenchymal transition through modulation of TGFβ signalling, and two stromal-specific modules comprising 26 lncRNAs linked to a tumour suppressive microenvironment and 12 lncRNAs related to cancer-associated fibroblasts. One member of the 12-lncRNA signature was experimentally supported by siRNA knockdown, which resulted in attenuated differentiation of quiescent fibroblasts to a cancer-associated phenotype.

    CONCLUSIONS: Overall, the study provides a unique pan-cancer perspective on the lncRNA functional landscape, acting as a global source of novel hypotheses on lncRNA contribution to tumour progression.

    Matched MeSH terms: Tumor Microenvironment
  20. Fulltext Conditioned media of pancreatic cancer cells and pancreatic stellate cells induce myeloid-derived suppressor cells differentiation and lymphocytes suppression
    Chong YP, Peter EP, Lee FJM, Chan CM, Chai S, Ling LPC, et al.
    Sci Rep, 2022 Jul 19;12(1):12315.
    PMID: 35853996 DOI: 10.1038/s41598-022-16671-9
    As pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs) are the two major cell types that comprise the immunosuppressive tumor microenvironment of pancreatic cancer, we aimed to investigate the role of conditioned medium derived from PCCs and PSCs co-culture on the viability of lymphocytes. The conditioned medium (CM) collected from PCCs and/or PSCs was used to treat peripheral blood mononuclear cells (PBMCs) to determine CM ability in reducing lymphocytes population. A proteomic analysis has been done on the CM to investigate the differentially expressed protein (DEP) expressed by two PCC lines established from different stages of tumor. Subsequently, we investigated if the reduction of lymphocytes was directly caused by CM or indirectly via CM-induced MDSCs. This was achieved by isolating lymphocyte subtypes and treating them with CM and CM-induced MDSCs. Both PCCs and PSCs were important in suppressing lymphocytes, and the PCCs derived from a metastatic tumor appeared to have a stronger suppressive effect than the PCCs derived from a primary tumor. According to the proteomic profiles of CM, 416 secreted proteins were detected, and 13 DEPs were identified between PANC10.05 and SW1990. However, CM was found unable to reduce lymphocytes viability through a direct pathway. In contrast, CM that contains proteins secreted by PCC and/or PSC appear immunogenic as they increase the viability of lymphocytes subtypes. Lymphocyte subtype treated with CM-induced MDSCs showed reduced viability in T helper 1 (Th1), T helper 2 (Th2), and T regulatory (Treg) cells, but not in CD8+ T cells, and B cells. As a conclusion, the interplay between PCCs and PSCs is important as their co-culture displays a different trend in lymphocytes suppression, hence, their co-culture should be included in future studies to better mimic the tumor microenvironment.
    Matched MeSH terms: Tumor Microenvironment
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