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International Journal of Oral Science Sep 2023Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% of oral malignancies and impairs appearance,... (Review)
Review
Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% of oral malignancies and impairs appearance, pronunciation, swallowing, and flavor perception. In 2020, 377,713 OSCC cases were reported globally. According to the Global Cancer Observatory (GCO), the incidence of OSCC will rise by approximately 40% by 2040, accompanied by a growth in mortality. Persistent exposure to various risk factors, including tobacco, alcohol, betel quid (BQ), and human papillomavirus (HPV), will lead to the development of oral potentially malignant disorders (OPMDs), which are oral mucosal lesions with an increased risk of developing into OSCC. Complex and multifactorial, the oncogenesis process involves genetic alteration, epigenetic modification, and a dysregulated tumor microenvironment. Although various therapeutic interventions, such as chemotherapy, radiation, immunotherapy, and nanomedicine, have been proposed to prevent or treat OSCC and OPMDs, understanding the mechanism of malignancies will facilitate the identification of therapeutic and prognostic factors, thereby improving the efficacy of treatment for OSCC patients. This review summarizes the mechanisms involved in OSCC. Moreover, the current therapeutic interventions and prognostic methods for OSCC and OPMDs are discussed to facilitate comprehension and provide several prospective outlooks for the fields.
Topics: Humans; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Mouth Neoplasms; Head and Neck Neoplasms; Tumor Microenvironment
PubMed: 37736748
DOI: 10.1038/s41368-023-00249-w -
Nature Communications Aug 2023The spatial organization of the tumor microenvironment has a profound impact on biology and therapy response. Here, we perform an integrative single-cell and spatial...
The spatial organization of the tumor microenvironment has a profound impact on biology and therapy response. Here, we perform an integrative single-cell and spatial transcriptomic analysis on HPV-negative oral squamous cell carcinoma (OSCC) to comprehensively characterize malignant cells in tumor core (TC) and leading edge (LE) transcriptional architectures. We show that the TC and LE are characterized by unique transcriptional profiles, neighboring cellular compositions, and ligand-receptor interactions. We demonstrate that the gene expression profile associated with the LE is conserved across different cancers while the TC is tissue specific, highlighting common mechanisms underlying tumor progression and invasion. Additionally, we find our LE gene signature is associated with worse clinical outcomes while TC gene signature is associated with improved prognosis across multiple cancer types. Finally, using an in silico modeling approach, we describe spatially-regulated patterns of cell development in OSCC that are predictably associated with drug response. Our work provides pan-cancer insights into TC and LE biology and interactive spatial atlases ( http://www.pboselab.ca/spatial_OSCC/ ; http://www.pboselab.ca/dynamo_OSCC/ ) that can be foundational for developing novel targeted therapies.
Topics: Humans; Carcinoma, Squamous Cell; Transcriptome; Mouth Neoplasms; Gene Expression Profiling; Head and Neck Neoplasms; Tumor Microenvironment
PubMed: 37596273
DOI: 10.1038/s41467-023-40271-4 -
Journal of Advanced Research Feb 2024Metastasis is an important cause of high mortality and lethality of oral cancer. Fusobacterium nucleatum (Fn) can promote tumour metastasis. Outer membrane vesicles...
INTRODUCTION
Metastasis is an important cause of high mortality and lethality of oral cancer. Fusobacterium nucleatum (Fn) can promote tumour metastasis. Outer membrane vesicles (OMVs) are secreted by Fn. However, the effects of Fn-derived extracellular vesicles on oral cancer metastasis and the underlying mechanisms are unclear.
OBJECTIVES
We aimed to determine whether and how Fn OMVs mediate oral cancer metastasis.
METHODS
OMVs were isolated from brain heart infusion (BHI) broth supernatant of Fn by ultracentrifugation. Tumour-bearing mice were treated with Fn OMVs to evaluate the effect of OMVs on cancer metastasis. Transwell assays were performed to determine how Fn OMVs affect cancer cell migration and invasion. The differentially expressed genes in Fn OMV-treated/untreated cancer cells were identified by RNA-seq. Transmission electron microscopy, laser confocal microscopy, and lentiviral transduction were used to detect changes in autophagic flux in cancer cells stimulated with Fn OMVs. Western blotting assay was performed to determine changes in EMT-related marker protein levels in cancer cells. Fn OMVs' effects on migration after blocking autophagic flux by autophagy inhibitors were determined by in vitro and in vivo experiments.
RESULTS
Fn OMVs were structurally similar to vesicles. In the in vivo experiment, Fn OMVs promoted lung metastasis in tumour-bearing mice, while chloroquine (CHQ, an autophagy inhibitor) treatment reduced the number of pulmonary metastases resulting from the intratumoral Fn OMV injection. Fn OMVs promoted the migration and invasion of cancer cells in vivo, leading to altered expression levels of EMT-related proteins (E-cadherin downregulation; Vimentin/N-cadherin upregulation). RNA-seq showed that Fn OMVs activate intracellular autophagy pathways. Blocking autophagic flux with CHQ reduced in vitro and in vivo migration of cancer cells induced by Fn OMVs as well as reversed changes in EMT-related protein expression.
CONCLUSION
Fn OMVs not only induced cancer metastasis but also activated autophagic flux. Blocking autophagic flux weakened Fn OMV-stimulated cancer metastasis.
Topics: Animals; Mice; Fusobacterium nucleatum; Mouth Neoplasms; Autophagy
PubMed: 37059221
DOI: 10.1016/j.jare.2023.04.002 -
Chinese Journal of Integrative Medicine Aug 2023Diosgenin, a steroidal sapogenin, obtained from Trigonella foenum-graecum, Dioscorea, and Rhizoma polgonati, has shown high potential and interest in the treatment of... (Review)
Review
Diosgenin, a steroidal sapogenin, obtained from Trigonella foenum-graecum, Dioscorea, and Rhizoma polgonati, has shown high potential and interest in the treatment of various cancers such as oral squamous cell carcinoma, laryngeal cancer, esophageal cancer, liver cancer, gastric cancer, lung cancer, cervical cancer, prostate cancer, glioma, and leukemia. This article aims to provide an overview of the in vivo, in vitro, and clinical studies reporting the diosgenin's anticancer effects. Preclinical studies have shown promising effects of diosgenin on inhibiting tumor cell proliferation and growth, promoting apoptosis, inducing differentiation and autophagy, inhibiting tumor cell metastasis and invasion, blocking cell cycle, regulating immunity and improving gut microbiome. Clinical investigations have revealed clinical dosage and safety property of diosgenin. Furthermore, in order to improve the biological activity and bioavailability of diosgenin, this review focuses on the development of diosgenin nano drug carriers, combined drugs and the diosgenin derivatives. However, further designed trials are needed to unravel the diosgenin's deficiencies in clinical application.
Topics: Male; Humans; Carcinoma, Squamous Cell; Diosgenin; Mouth Neoplasms; Apoptosis; Prostatic Neoplasms
PubMed: 36940072
DOI: 10.1007/s11655-023-3693-1 -
Biomedicine & Pharmacotherapy =... Sep 2023Oral cancer is a neoplastic disorder of the oral cavities, including the lips, tongue, buccal mucosa, and lower and upper gums. Oral cancer assessment entails a... (Review)
Review
Oral cancer is a neoplastic disorder of the oral cavities, including the lips, tongue, buccal mucosa, and lower and upper gums. Oral cancer assessment entails a multistep process that requires deep knowledge of the molecular networks involved in its progression and development. Preventive measures including public awareness of risk factors and improving public behaviors are necessary, and screening techniques should be encouraged to enable early detection of malignant lesions. Herpes simplex virus (HSV), human papillomavirus (HPV), Epstein-Barr virus (EBV), and Kaposi sarcoma-associated herpesvirus (KSHV) are associated with other premalignant and carcinogenic conditions leading to oral cancer. Oncogenic viruses induce chromosomal rearrangements; activate signal transduction pathways via growth factor receptors, cytoplasmic protein kinases, and DNA binding transcription factors; modulate cell cycle proteins, and inhibit apoptotic pathways. In this review, we present an up-to-date overview on the use of nanomaterials for regulating viral proteins and oral cancer as well as the role of phytocompounds on oral cancer. The targets linking oncoviral proteins and oral carcinogenesis were also discussed.
Topics: Humans; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Retroviridae; Mouth Neoplasms; Risk Factors
PubMed: 37364477
DOI: 10.1016/j.biopha.2023.115035 -
Seminars in Cancer Biology Jul 2023The family of mammalian E2F transcription factors (E2Fs) comprise of 8 members (E2F1-E2F8) classified as activators (E2F1-E2F3) and repressors (E2F4-E2F8) primarily... (Review)
Review
The family of mammalian E2F transcription factors (E2Fs) comprise of 8 members (E2F1-E2F8) classified as activators (E2F1-E2F3) and repressors (E2F4-E2F8) primarily regulating the expression of several genes related to cell proliferation, apoptosis and differentiation, mainly in a cell cycle-dependent manner. E2F activity is frequently controlled via the retinoblastoma protein (pRb), cyclins, p53 and the ubiquitin-proteasome pathway. Additionally, genetic or epigenetic changes result in the deregulation of E2F family genes expression altering S phase entry and apoptosis, an important hallmark for the onset and development of cancer. Although studies reveal E2Fs to be involved in several human malignancies, the mechanisms underlying the role of E2Fs in oral cancer lies nascent and needs further investigations. This review focuses on the role of E2Fs in oral cancer and the etiological factors regulating E2Fs activity, which in turn transcriptionally control the expression of their target genes, thus contributing to cell proliferation, metastasis, and drug/therapy resistance. Further, we will discuss therapeutic strategies for E2Fs, which may prevent oral tumor growth, metastasis, and drug resistance.
Topics: Animals; Humans; E2F Transcription Factors; Transcription Factors; Cell Cycle; Cell Cycle Proteins; Mouth Neoplasms; Mammals
PubMed: 36924812
DOI: 10.1016/j.semcancer.2023.03.004 -
International Journal of Molecular... Jan 2024Cannabinoids have incited scientific interest in different conditions, including malignancy, due to increased exposure to cannabis. Furthermore, cannabinoids are... (Review)
Review
Cannabinoids have incited scientific interest in different conditions, including malignancy, due to increased exposure to cannabis. Furthermore, cannabinoids are increasingly used to alleviate cancer-related symptoms. This review paper aims to clarify the recent findings on the relationship between cannabinoids and oral cancer, focusing on the molecular mechanisms that could link cannabinoids with oral cancer pathogenesis. In addition, we provide an overview of the current and future perspectives on the management of oral cancer patients using cannabinoid compounds. Epidemiological data on cannabis use and oral cancer development are conflicting. However, in vitro studies assessing the effects of cannabinoids on oral cancer cells have unveiled promising anti-cancer features, including apoptosis and inhibition of cell proliferation. Downregulation of various signaling pathways with anti-cancer effects has been identified in experimental models of oral cancer cells exposed to cannabinoids. Furthermore, in some countries, several synthetic or phytocannabinoids have been approved as medical adjuvants for the management of cancer patients undergoing chemoradiotherapy. Cannabinoids may improve overall well-being by relieving anxiety, depression, pain, and nausea. In conclusion, the link between cannabinoid compounds and oral cancer is complex, and further research is necessary to elucidate the potential risks or their protective impact on oral cancer.
Topics: Humans; Cannabinoids; Mouth Neoplasms; Hallucinogens; Cannabis; Cannabinoid Receptor Agonists
PubMed: 38256042
DOI: 10.3390/ijms25020969 -
International Journal of Oral Science Sep 2023Oral potentially malignant disorders (OPMDs) are precursors of oral squamous cell carcinoma (OSCC). Deregulated cellular energy metabolism is a critical hallmark of...
Oral potentially malignant disorders (OPMDs) are precursors of oral squamous cell carcinoma (OSCC). Deregulated cellular energy metabolism is a critical hallmark of cancer cells. Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α) plays vital role in mitochondrial energy metabolism. However, the molecular mechanism of PGC1α on OPMDs progression is less unclear. Therefore, we investigated the effects of knockdown PGC1α on human dysplastic oral keratinocytes (DOKs) comprehensively, including cell proliferation, cell cycle, apoptosis, xenograft tumor, mitochondrial DNA (mtDNA), mitochondrial electron transport chain complexes (ETC), reactive oxygen species (ROS), oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and glucose uptake. We found that knockdown PGC1α significantly inhibited the proliferation of DOKs in vitro and tumor growth in vivo, induced S-phase arrest, and suppressed PI3K/Akt signaling pathway without affecting cell apoptosis. Mechanistically, downregulated of PGC1α decreased mtDNA, ETC, and OCR, while enhancing ROS, glucose uptake, ECAR, and glycolysis by regulating lactate dehydrogenase A (LDHA). Moreover, SR18292 (an inhibitor of PGC1α) induced oxidative phosphorylation dysfunction of DOKs and declined DOK xenograft tumor progression. Thus, our work suggests that PGC1α plays a crucial role in cell proliferation by reprograming energy metabolism and interfering with energy metabolism, acting as a potential therapeutic target for OPMDs.
Topics: Humans; Carcinoma, Squamous Cell; Cell Proliferation; DNA, Mitochondrial; Energy Metabolism; Glucose; Mouth Neoplasms; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphatidylinositol 3-Kinases; Reactive Oxygen Species
PubMed: 37661238
DOI: 10.1038/s41368-023-00242-3 -
Journal For Immunotherapy of Cancer Aug 2023, the most mutated gene in solid cancers, has a profound impact on most hallmarks of cancer. Somatic mutations occur in high frequencies in head and neck cancers,...
BACKGROUND
, the most mutated gene in solid cancers, has a profound impact on most hallmarks of cancer. Somatic mutations occur in high frequencies in head and neck cancers, including oral squamous cell carcinoma (OSCC). Our study aims to understand the role of gain-of-function mutation in modulating the tumor immune microenvironment (TIME) in OSCC.
METHODS
Short hairpin RNA knockdown of mutant in syngeneic oral tumors demonstrated changes in tumor growth between immunocompetent and immunodeficient mice. HTG EdgeSeq targeted messenger RNA sequencing was used to analyze cytokine and immune cell markers in tumors with inactivated mutant . Flow cytometry and multiplex immunofluorescence (mIF) confirmed the role of mutant in the TIME. The gene expression of patients with OSCC was analyzed by CIBERSORT and mIF was used to validate the immune landscape at the protein level.
RESULTS
Mutant contributes to a cytokine transcriptome network that inhibits the infiltration of cytotoxic CD8 T cells and promotes intratumoral recruitment of regulatory T cells and M2 macrophages. Moreover, also regulates the spatial distribution of immunocyte populations, and their distribution between central and peripheral intratumoral locations. Interestingly, -mutated tumors are infiltrated with CD8 and CD4 T cells expressing programmed cell death protein 1, and these tumors responded to immune checkpoint inhibitor and stimulator of interferon gene 1 agonist therapy. CIBERSORT analysis of human OSCC samples revealed associations between immune cell populations and the mutation, which paralleled the findings from our syngeneic mouse tumor model.
CONCLUSIONS
These findings demonstrate that syngeneic tumors bearing the gain-of-function mutation modulate the TIME to evade tumor immunity, leading to tumor progression and decreased survival.
Topics: Animals; Humans; Mice; Carcinoma, Squamous Cell; CD8-Positive T-Lymphocytes; Cytokines; Disease Models, Animal; Gain of Function Mutation; Head and Neck Neoplasms; Mouth Neoplasms; Mutation; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment; Tumor Suppressor Protein p53
PubMed: 37604640
DOI: 10.1136/jitc-2023-006666 -
Clinical Cancer Research : An Official... Jul 2023Perineural invasion (PNI) in oral cavity squamous cell carcinoma (OSCC) is associated with poor survival. Because of the risk of recurrence, patients with PNI receive...
PURPOSE
Perineural invasion (PNI) in oral cavity squamous cell carcinoma (OSCC) is associated with poor survival. Because of the risk of recurrence, patients with PNI receive additional therapies after surgical resection. Mechanistic studies have shown that nerves in the tumor microenvironment promote aggressive tumor growth. Therefore, in this study, we evaluated whether nerve density (ND) influences tumor growth and patient survival. Moreover, we assessed the reliability of artificial intelligence (AI) in evaluating ND.
EXPERIMENTAL DESIGN
To investigate whether increased ND in OSCC influences patient outcome, we performed survival analyses. Tissue sections of OSCC from 142 patients were stained with hematoxylin and eosin and IHC stains to detect nerves and tumor. ND within the tumor bulk and in the adjacent 2 mm was quantified; normalized ND (NND; bulk ND/adjacent ND) was calculated. The impact of ND on tumor growth was evaluated in chick chorioallantoic-dorsal root ganglia (CAM-DRG) and murine surgical denervation models. Cancer cells were grafted and tumor size quantified. Automated nerve detection, applying the Halo AI platform, was compared with manual assessment.
RESULTS
Disease-specific survival decreased with higher intratumoral ND and NND in tongue SCC. Moreover, NND was associated with worst pattern-of-invasion and PNI. Increasing the number of DRG, in the CAM-DRG model, increased tumor size. Reduction of ND by denervation in a murine model decreased tumor growth. Automated and manual detection of nerves showed high concordance, with an F1 score of 0.977.
CONCLUSIONS
High ND enhances tumor growth, and NND is an important prognostic factor that could influence treatment selection for aggressive OSCC. See related commentary by Hondermarck and Jiang, p. 2342.
Topics: Humans; Animals; Mice; Artificial Intelligence; Reproducibility of Results; Neoplasm Invasiveness; Mouth Neoplasms; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms; Tumor Microenvironment
PubMed: 37039710
DOI: 10.1158/1078-0432.CCR-22-3496