Molecular Crosstalk between the Immunological Mechanism of the Tumor Microenvironment and Epithelial–Mesenchymal Transition in Oral Cancer

Oral cancer is a significant non-communicable disease affecting both emergent nations and developed countries. Squamous cell carcinoma of the head and neck represent the eight major familiar cancer types worldwide, accounting for more than 350,000 established cases every year. Oral cancer is one of the most exigent tumors to control and treat. The survival rate of oral cancer is poor due to local invasion along with recurrent lymph node metastasis. The tumor microenvironment contains a different population of cells, such as fibroblasts associated with cancer, immune-infiltrating cells, and other extracellular matrix non-components. Metastasis in a primary site is mainly due to multifaceted progression known as epithelial-to-mesenchymal transition (EMT). For the period of EMT, epithelial cells acquire mesenchymal cell functional and structural characteristics, which lead to cell migration enhancement and promotion of the dissemination of tumor cells. The present review links the tumor microenvironment and the role of EMT in inflammation, transcriptional factors, receptor involvement, microRNA, and other signaling events. It would, in turn, help to better understand the mechanism behind the tumor microenvironment and EMT during oral cancer.

[1]  Haidong Fan,et al.  TAB2 Promotes the Biological Functions of Head and Neck Squamous Cell Carcinoma Cells via EMT and PI3K Pathway , 2022, Disease markers.

[2]  J. W. Chadwick,et al.  TNFα Signaling Is Increased in Progressing Oral Potentially Malignant Disorders and Regulates Malignant Transformation in an Oral Carcinogenesis Model , 2021, Frontiers in Oncology.

[3]  R. Bologna-Molina,et al.  Expression of Interleukin-1ß and Interleukin-8 in Oral Potentially Malignant Disorders and Carcinomas , 2021, Frontiers in Oral Health.

[4]  I. Chattopadhyay,et al.  Exploring the Crosstalk between Inflammation and Epithelial-Mesenchymal Transition in Cancer , 2021, Mediators of inflammation.

[5]  A. Mackiewicz,et al.  Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance , 2021, Frontiers in Immunology.

[6]  B. Cheng,et al.  Epithelial‐to‐mesenchymal transition in oral squamous cell carcinoma: Challenges and opportunities , 2020, International journal of cancer.

[7]  R. de Bree,et al.  Staging and grading of oral squamous cell carcinoma: An update. , 2020, Oral oncology.

[8]  J. Selvaraj,et al.  Epithelial–mesenchymal transition in oral squamous cell carcinoma: An insight into molecular mechanisms and clinical implications , 2020, Journal of oral and maxillofacial pathology : JOMFP.

[9]  H. Kumamoto,et al.  Immunohistochemical assessment of Eph/ephrin expression in oral squamous cell carcinoma and precursor lesions , 2019, Odontology.

[10]  Pu Zhang,et al.  MTA1 promotes the invasion and migration of oral squamous carcinoma by inducing epithelial-mesenchymal transition via the hedgehog signaling pathway. , 2019, Experimental cell research.

[11]  Shanchun Guo,et al.  Targeting CXCL12/CXCR4 Axis in Tumor Immunotherapy. , 2019, Current medicinal chemistry.

[12]  Xiaobing Chen,et al.  CCL2 promotes cell migration by inducing epithelial-mesenchymal transition in oral squamous cell carcinoma. , 2019, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[13]  A. Abdollahi,et al.  Relative Expression of OCT4, SOX2 and NANOG in Oral Squamous Cell Carcinoma Versus Adjacent Non- Tumor Tissue , 2019, Asian Pacific journal of cancer prevention : APJCP.

[14]  K. Miyazawa,et al.  Addiction of mesenchymal phenotypes on the FGF/FGFR axis in oral squamous cell carcinoma cells , 2019, bioRxiv.

[15]  W. González-Arriagada,et al.  Prognostic value of immunoexpression of CCR4, CCR5, CCR7 and CXCR4 in squamous cell carcinoma of tongue and floor of the mouth , 2019, Medicina oral, patologia oral y cirugia bucal.

[16]  Xiao-Wei Zhao,et al.  The role of MAPK signaling pathway in formation of EMT in oral squamous carcinoma cells induced by TNF-α , 2019, Molecular Biology Reports.

[17]  M. Masařík,et al.  Effect of tumor microenvironment on pathogenesis of the head and neck squamous cell carcinoma: a systematic review , 2019, Molecular Cancer.

[18]  C. Blanpain,et al.  EMT Transition States during Tumor Progression and Metastasis. , 2019, Trends in cell biology.

[19]  A. Breeze,et al.  Structure, activation and dysregulation of fibroblast growth factor receptor kinases: perspectives for clinical targeting , 2018, Biochemical Society transactions.

[20]  D. Costea,et al.  Aberrant expression of vimentin predisposes oral premalignant lesion derived cells towards transformation. , 2018, Experimental and molecular pathology.

[21]  S. Rubtsova,et al.  Role of Epithelial-Mesenchymal Transition in Tumor Progression , 2018, Biochemistry (Moscow).

[22]  D. Antonini,et al.  Functional and Mechanistic Insights into the Pathogenesis of P63-Associated Disorders. , 2018, The journal of investigative dermatology. Symposium proceedings.

[23]  C. Soares,et al.  FGF‐2 and FGFR‐1 might be independent prognostic factors in oral tongue squamous cell carcinoma , 2018, Histopathology.

[24]  A. Burgess,et al.  Epidermal growth factor receptor: Structure‐function informing the design of anticancer therapeutics , 2018, Experimental cell research.

[25]  J. Murakami,et al.  Anti-EGFR antibody cetuximab is secreted by oral squamous cell carcinoma and alters EGF-driven mesenchymal transition. , 2018, Biochemical and biophysical research communications.

[26]  K. Miyazono,et al.  Intracellular and extracellular TGF-β signaling in cancer: some recent topics , 2018, Frontiers of Medicine.

[27]  Jianping Zhang,et al.  Notch signalling induces epithelial‑mesenchymal transition to promote metastasis in oral squamous cell carcinoma. , 2018, International journal of molecular medicine.

[28]  R. Weinberg,et al.  Epithelial-to-mesenchymal transition in cancer: complexity and opportunities , 2018, Frontiers of Medicine.

[29]  M. Jolehar,et al.  Prognostic New Marker (Bone Morphogenetic Protein 7) in Squamous Cell Carcinoma. , 2018, The journal of contemporary dental practice.

[30]  Z. Akram,et al.  S100 proteins in oral squamous cell carcinoma. , 2018, Clinica chimica acta; international journal of clinical chemistry.

[31]  Balakrishnan,et al.  Canonical Wnt pathway gene expression and their clinical correlation in oral squamous cell carcinoma , 2018, Indian journal of dental research : official publication of Indian Society for Dental Research.

[32]  R. Kandpal,et al.  Differential Expression Patterns of Eph Receptors and Ephrin Ligands in Human Cancers , 2018, BioMed research international.

[33]  John Kuriyan,et al.  Deep mutational analysis reveals functional trade-offs in the sequences of EGFR autophosphorylation sites , 2018, Proceedings of the National Academy of Sciences.

[34]  D. Moslemi,et al.  Immunohistochemical expression of TWIST in oral squamous cell carcinoma and its correlation with clinicopathologic factors , 2018, Journal of cancer research and therapeutics.

[35]  M. Dong,et al.  Calreticulin promotes EGF-induced EMT in pancreatic cancer cells via Integrin/EGFR-ERK/MAPK signaling pathway , 2017, Cell Death and Disease.

[36]  K. Anvari,et al.  Expression of p63 and CD44 in oral squamous cell carcinoma and correlation with clinicopathological parameters. , 2017, Archives of oral biology.

[37]  R. Sader,et al.  Tumor-associated Macrophages, Angiogenesis, and Tumor Cell Migration in Oral Squamous Cell Carcinoma , 2017, Annals of African medicine.

[38]  B. Manjunatha,et al.  Immunohistochemical evaluation of p63 and cyclin D1 in oral squamous cell carcinoma and leukoplakia , 2017, Journal of the Korean Association of Oral and Maxillofacial Surgeons.

[39]  A. Shavandi,et al.  Keratin: dissolution, extraction and biomedical application. , 2017, Biomaterials science.

[40]  G. Sauter,et al.  High‐level &bgr;III‐tubulin overexpression occurs in most head and neck cancers but is unrelated to clinical outcome , 2017, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[41]  G. Berx,et al.  EMT transcription factors in cancer development re-evaluated: Beyond EMT and MET. , 2017, Biochimica et biophysica acta. Reviews on cancer.

[42]  T. Salo,et al.  Histamine H4 receptor signalling in tongue cancer and its potential role in oral carcinogenesis - a short report , 2017, Cellular Oncology.

[43]  Dongxi Xiang,et al.  Wnt Signaling in Oral Cancer Initiating Cells , 2017 .

[44]  Zhengmao Li,et al.  TNF-α inhibits the migration of oral squamous cancer cells mediated by miR-765-EMP3-p66Shc axis. , 2017, Cellular signalling.

[45]  Brendan J. McConkey,et al.  The GRHL2/ZEB Feedback Loop—A Key Axis in the Regulation of EMT in Breast Cancer , 2017, Journal of cellular biochemistry.

[46]  K. Cherubini,et al.  Role of tumour-associated macrophages in oral squamous cells carcinoma progression: an update on current knowledge , 2017, Diagnostic Pathology.

[47]  Takaaki Ito,et al.  Notch1 in oral squamous cell carcinoma. , 2017, Histology and histopathology.

[48]  D. Birnbaum,et al.  De-repression of the RAC activator ELMO1 in cancer stem cells drives progression of TGFβ-deficient squamous cell carcinoma from transition zones , 2017, eLife.

[49]  Qiang Zhang,et al.  Clinicopathological significance of ZEB-1 and E-cadherin proteins in patients with oral cavity squamous cell carcinoma , 2017 .

[50]  T. Shibata,et al.  Transforming growth factor-β1 suppresses bone morphogenetic protein-2-induced mesenchymal-epithelial transition in HSC-4 human oral squamous cell carcinoma cells via Smad1/5/9 pathway suppression , 2016, Oncology reports.

[51]  K. Sakamoto Notch signaling in oral squamous neoplasia , 2016, Pathology international.

[52]  T. Dineshkumar,et al.  Salivary and Serum Interleukin-6 Levels in Oral Premalignant Disorders and Squamous Cell Carcinoma: Diagnostic Value and Clinicopathologic Correlations , 2016, Asian Pacific journal of cancer prevention : APJCP.

[53]  J. Ernst,et al.  Expression of CK19 is an independent predictor of negative outcome for patients with squamous cell carcinoma of the tongue , 2016, Oncotarget.

[54]  S. Guelcher,et al.  Hedgehog and TGFβ signaling converge on Gli2 to control bony invasion and bone destruction in oral squamous cell carcinoma , 2016, Oncotarget.

[55]  M. Nie,et al.  [Expression of cytokeratin 19 in the development and progression of oral squamous cell carcinoma]. , 2016, Shanghai kou qiang yi xue = Shanghai journal of stomatology.

[56]  Longlong Wang,et al.  Targeted silencing of CXCR4 inhibits epithelial-mesenchymal transition in oral squamous cell carcinoma. , 2016, Oncology letters.

[57]  A. Bhatt,et al.  Role of interleukin-6 in cancer progression and therapeutic resistance , 2016, Tumor Biology.

[58]  Jie Cheng,et al.  p70S6K promotes IL-6-induced epithelial-mesenchymal transition and metastasis of head and neck squamous cell carcinoma , 2016, Oncotarget.

[59]  B. Seliger,et al.  Clinical relevance of the tumor microenvironment and immune escape of oral squamous cell carcinoma , 2016, Journal of Translational Medicine.

[60]  Ming Tan,et al.  GRHL2-miR-200-ZEB1 maintains the epithelial status of ovarian cancer through transcriptional regulation and histone modification , 2016, Scientific Reports.

[61]  R. Muschel,et al.  Targeting the CCL2-CCR2 signaling axis in cancer metastasis , 2016, Oncotarget.

[62]  Stephen T. C. Wong,et al.  EMT is not required for lung metastasis but contributes to chemoresistance , 2015, Nature.

[63]  Hao Sun,et al.  [Expression of Twist and relation with epithelial-mesenchymal transition in oral squamous cell carcinoma]. , 2015, Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology.

[64]  C. Obayashi,et al.  Multivariate analyses of Ki-67, cytokeratin 13 and cytokeratin 17 in diagnosis and prognosis of oral precancerous lesions. , 2015, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[65]  Yan Liu,et al.  Over-expression of TWIST, an epithelial-mesenchymal transition inducer, predicts poor survival in patients with oral carcinoma. , 2015, International journal of clinical and experimental medicine.

[66]  Qing Xu,et al.  Expression of E-cadherin and vimentin in oral squamous cell carcinoma. , 2015, International journal of clinical and experimental pathology.

[67]  T. Okamoto,et al.  Overexpression of integrin αv facilitates proliferation and invasion of oral squamous cell carcinoma cells via MEK/ERK signaling pathway that is activated by interaction of integrin αvβ8 with type Ⅰ collagen. , 2014, International journal of oncology.

[68]  D. Medici,et al.  Signaling mechanisms of the epithelial-mesenchymal transition , 2014, Science Signaling.

[69]  Yunong Wu,et al.  Neuropilin-1 Promotes Epithelial-to-Mesenchymal Transition by Stimulating Nuclear Factor-Kappa B and Is Associated with Poor Prognosis in Human Oral Squamous Cell Carcinoma , 2014, PloS one.

[70]  N. Dey,et al.  Clinical significance of aberrant vimentin expression in oral premalignant lesions and carcinomas. , 2014, Oral diseases.

[71]  Shaohui Huang,et al.  Pituitary tumor-transforming gene 1 (PTTG1) is overexpressed in oral squamous cell carcinoma (OSCC) and promotes migration, invasion and epithelial–mesenchymal transition (EMT) in SCC15 cells , 2014, Tumor Biology.

[72]  Amy Y. Chen,et al.  Acetylated Tubulin (AT) as a Prognostic Marker in Squamous Cell Carcinoma of the Head and Neck , 2014, Head and Neck Pathology.

[73]  Hau-Ren Chen,et al.  Monocyte Chemotactic Protein 1 (MCP-1) Modulates Pro-Survival Signaling to Promote Progression of Head and Neck Squamous Cell Carcinoma , 2014, PloS one.

[74]  N. Brockton,et al.  Head and neck cancer: from anatomy to biology , 2013, International journal of cancer.

[75]  B. Zhou,et al.  The Role of Snail in EMT and Tumorigenesis. , 2013, Current cancer drug targets.

[76]  E. Nkenke,et al.  The relevance of EGFR overexpression for the prediction of the malignant transformation of oral leukoplakia. , 2013, Oncology reports.

[77]  M. Grimm,et al.  Prognostic value of histamine H1 receptor expression in oral squamous cell carcinoma , 2013, Clinical Oral Investigations.

[78]  H. Taubert,et al.  Correlation of expression of hypoxia-related proteins with prognosis in oral squamous cell carcinoma patients , 2012, Oral and Maxillofacial Surgery.

[79]  B. Shalmon,et al.  Mutational analysis of PTEN/PIK3CA/AKT pathway in oral squamous cell carcinoma. , 2011, Oral oncology.

[80]  Hongmei Zhou,et al.  Downregulation of TGF-beta receptor types II and III in oral squamous cell carcinoma and oral carcinoma-associated fibroblasts , 2011, BMC Cancer.

[81]  S. Mocellin,et al.  The dual role of tumor necrosis factor (TNF) in cancer biology. , 2010, Current Medicinal Chemistry.

[82]  P. Lequerica-Fernández,et al.  Expression of MMP-7 and MT1-MMP in oral squamous cell carcinoma as predictive indicator for tumor invasion and prognosis. , 2007, Journal of Oral Pathology & Medicine.

[83]  C. Sotiriou,et al.  Molecular markers of head and neck squamous cell carcinoma: Promising signs in need of prospective evaluation , 2006, Head & neck.

[84]  J. Kim,et al.  Prognostic value of activated Akt expression in oral squamous cell carcinoma , 2005, Journal of Clinical Pathology.

[85]  E. Porfiri,et al.  Beta-catenin gene analysis in oral squamous cell carcinoma. , 2005, International journal of immunopathology and pharmacology.

[86]  D. Odde,et al.  Modeling Cell Migration Mechanics. , 2018, Advances in experimental medicine and biology.

[87]  Gang Chen,et al.  Sonic Hedgehog Signalling Activation Contributes to ALCAM Over-Expression and Poor Clinical Outcome in Patients with Oral Squamous Cell Carcinoma. , 2018, The Chinese journal of dental research : the official journal of the Scientific Section of the Chinese Stomatological Association.

[88]  Xiao‐Jing Wang,et al.  Paradoxical roles of TGF-&bgr; signaling in suppressing and promoting squamous cell carcinoma , 2018, Acta biochimica et biophysica Sinica.

[89]  N. Cirillo,et al.  Cancer-associated fibroblasts regulate keratinocyte cell–cell adhesion via TGF-&bgr;-dependent pathways in genotype-specific oral cancer , 2017, Carcinogenesis.

[90]  Bi-Jun Huang,et al.  IL-8 suppresses E-cadherin expression in nasopharyngeal carcinoma cells by enhancing E-cadherin promoter DNA methylation. , 2016, International journal of oncology.

[91]  Juri Kwak,et al.  Hepatitis B virus X protein induces epithelial-mesenchymal transition by repressing E-cadherin expression via upregulation of E12/E47. , 2016, The Journal of general virology.

[92]  J. Yook,et al.  Snail-induced EMT promotes cancer stem cell-like properties in head and neck cancer cells. , 2016, Oncology reports.

[93]  Yoichi Tanaka,et al.  Cytokeratin 13, Cytokeratin 17, Ki-67 and p53 Expression in Upper Layers of Epithelial Dysplasia Surrounding Tongue Squamous Cell Carcinoma. , 2015, The Bulletin of Tokyo Dental College.

[94]  Seiji Nakamura,et al.  Possible involvement of ΔNp63 downregulation in the invasion and metastasis of oral squamous cell carcinoma via induction of a mesenchymal phenotype , 2013, Clinical & Experimental Metastasis.