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Molecular and Signaling Pathways During Oral Carcinogenesis

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Textbook of Oral Cancer

Part of the book series: Textbooks in Contemporary Dentistry ((TECD))

Abstract

Oral carcinogenesis is a consequence of multiple alterations in important pathways of a cell’s life. These altered pathways provide capabilities to tumorigenesis that include sustained proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprograming cellular energetics, and evading immune destruction. Several of the genes and proteins involved in these acquired capacities for oral carcinogenesis will be developed in this chapter. Many of them could be useful as diagnostic biomarkers and also as predictors of malignant transformation.

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References

  1. Khan Z, Bisen PS. Oncoapoptoticsignaling and deregulated target genes in cancers: special reference to oral cancer. Biochim Biophys Acta. 2013;1836(1):123–45.

    PubMed  Google Scholar 

  2. Hahn WC, Weinberg RA. Rules for making human tumors cells. N Engl J Med. 2002;347:1593–603.

    Article  PubMed  Google Scholar 

  3. Ha PK, Benoit NE, Yochem R, Sciubba J, Zahurak M, Sidransky D, Pevsner J, Westra WH, Califano J. A transcriptional progression model for head and neck cancer. Clin Cancer Res. 2003;9:3058–64.

    PubMed  Google Scholar 

  4. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.

    Article  PubMed  Google Scholar 

  5. Bernstein JM, Bernstein CR, West CM, Homer JJ. Molecular and celular processes underlying the hallmarks of head and neck cancer. Eur Arch Otorhinolaryngol. 2013;270(10):2585–93.

    Article  PubMed  Google Scholar 

  6. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  PubMed  Google Scholar 

  7. Chung CH, Parker JS, Karaca G, Wu J, Funkhouser WK, Moore D, Butterfoss D, Xiang D, Zanation A, Yin X, Shockley WW, Weissler MC, Dressler LG, Shores CG, Yarbrough WG, Perou CM. Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell. 2004;5(5):489–500.

    Article  PubMed  Google Scholar 

  8. Smeets SJ, Brakenhoff RH, Ylstra B, van Wieringen WN, van de Wiel MA, Leemans CR, Braakhuis BJ. Genetic classification of oral and oropharyngeal carcinomas identifies subgroups with a different prognosis. Cell Oncol. 2009;31(4):291–300.

    PubMed  PubMed Central  Google Scholar 

  9. Slebos RJ, Jehmlich N, Brown B, Yin Z, Chung CH, Yarbrough WG, Liebler DC. Proteomic analysis of oropharyngeal carcinomas reveals novel HPV-associated biological pathways. Int J Cancer. 2013;132(3):568–79.

    Article  PubMed  Google Scholar 

  10. Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82.

    Article  Google Scholar 

  11. Hermsen M, Guervós MA, Meijer G, Baak J, van Diest P, Marcos CA, Sampedro A. New chromosomal regions with high-level amplifications in squamous cell carcinomas of the larynx and pharynx, identified by comparative genomic hybridization. J Pathol. 2001;194(2):177–82.

    Article  PubMed  Google Scholar 

  12. Sinevici N, O'sullivan J. Oral cancer: deregulated molecular events and their use as biomarkers. Oral Oncol. 2016;61:12–8.

    Article  PubMed  Google Scholar 

  13. Lane DP. Cancer. P53, guardian of the genome. Nature. 1992;358:15–6.

    Article  PubMed  Google Scholar 

  14. Partridge M, Costea DE, Huang X. The changing face of p53 in head and neck cancer. Int J Oral Maxillofac Surg. 2007;36(12):1123–38.

    Article  PubMed  Google Scholar 

  15. Li VD, Li KH, Li JT. TP53 mutations as potential prognostic markers for specific cancers: analysis of data from The Cancer Genome Atlas and the International Agency for Research on Cancer TP53 database. J Cancer Res Clin Oncol. 2019;145(3):625–36.

    Article  PubMed  Google Scholar 

  16. Oliveira LR, Ribeiro-Silva A, Costa JP, Simões AL, Matteo MA, Zucoloto S. Prognostic factors and survival analysis in a sample of oral squamous cell carcinoma patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;106(5):685–95.

    Article  PubMed  Google Scholar 

  17. Poeta ML, Manola J, Goldwasser MA, Forastiere A, Benoit N, Califano JA, Ridge JA, Goodwin J, Kenady D, Saunders J, Westra W, Sidransky D, Koch WM. Tp53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med. 2007;357:2552–61.

    Article  PubMed  PubMed Central  Google Scholar 

  18. van Houten VM, Tabor MP, van den Brekel MW, Kummer JA, Denkers F, Dijkstra J, Leemans R, van der Waal I, Snow GB, Brakenhoff RH. Mutated p53 as a molecular marker for the diagnosis of head and neck cancer. J Pathol. 2002;198:476–86.

    Article  PubMed  Google Scholar 

  19. Warnakulasuriya S. Lack of molecular markers to predict malignant potential of oral precancer. J Pathol. 2000;190(4):407–9.

    Article  PubMed  Google Scholar 

  20. Lu XJD, Liu KYP, Soares RC, Thomson T, Prisman E, Wu J, Poh CF. Potential clinical implications of HPV status and expressions of p53 and cyclin D1 among oropharyngeal cancer patients. J Oral Pathol Med. 2018;47(10):945–53.

    Article  PubMed  Google Scholar 

  21. Monteiro LS, Diniz-Freitas M, Warnakulasuriya S, Garcia-Caballero T, Forteza J, Fraga M. An immunohistochemical score to predict the outcome for oral squamous cell carcinoma. J Oral Pathol Med. 2018;47(4):375–81.

    Article  PubMed  Google Scholar 

  22. Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer. 2011;11(1):9–22.

    Article  PubMed  Google Scholar 

  23. Monteiro L, Ricardo S, Delgado M, Garcez F, do Amaral B, Lopes C. Phosphorylated EGFR at tyrosine 1173 correlates with poor prognosis in oral squamous cell carcinomas. Oral Dis. 2014;20(2):178–85.

    Article  PubMed  Google Scholar 

  24. O-charoenrat P, Rhys-Evans PH, Archer DJ, Eccles SA. C-erbB receptors in squamous cell carcinomas of the head and neck: clinical significance and correlation with matrix metalloproteinases and vascular endothelial growth factors. Oral Oncol. 2002;38:73–80.

    Article  PubMed  Google Scholar 

  25. Mao L, Hong WK, Papadimitrakopoulou VA. Focus on head and neck cancer. Cancer Cell. 2004;5(4):311–6.

    Article  PubMed  Google Scholar 

  26. Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med. 2001;345(26):1890–900.

    Article  PubMed  Google Scholar 

  27. Grandis JR, Melhem MF, Gooding WE, Day R, Holst VA, Wagener MM, Drenning SD, Tweardy DJ. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst. 1998;90(11):824–32.

    Article  Google Scholar 

  28. Monteiro LS, Diniz-Freitas M, Garcia-Caballero T, Warnakulasuriya S, Forteza J, Fraga M. Combined cytoplasmic and membranous EGFR and p53 overexpression is a poor prognostic marker in early stage oral squamous cell carcinoma. J Oral Pathol Med. 2012;41(7):559–67.

    PubMed  Google Scholar 

  29. Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res. 1993;53:3579–84.

    PubMed  Google Scholar 

  30. Loeffler-Ragg J, Witsch-Baumgartner M, Tzankov A, Hilbe W, Schwentner I, Sprinzl GM, Utermann G, Zwierzina H. Low incidence of mutations in EGFR kinase domain in Caucasian patients with head and neck squamous cell carcinoma. Eur J Cancer. 2006;42:109–11.

    Article  PubMed  Google Scholar 

  31. Temam S, Kawaguchi H, El-Naggar AK, Jelinek J, Tang H, Liu DD, Lang W, Issa JP, Lee JJ, Mao L. Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. J Clin Oncol. 2007;25:2164–70.

    Article  PubMed  Google Scholar 

  32. Sok JC, Coppelli FM, Thomas SM, Lango MN, Xi S, Hunt JL, Freilino ML, Graner MW, Wikstrand CJ, Bigner DD, Gooding WE, Furnari FB, Grandis JR. Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res. 2006;12:5064–73.

    Article  PubMed  Google Scholar 

  33. Sauer T, Guren MG, Noren T, Dueland S. Demonstration of EGFR gene copy loss in colorectal carcinomas by fluorescence in situ hybridization (FISH): a surrogate marker for sensitivity to specific anti-EGFR therapy? Histopathology. 2005;47:560–4.

    Article  PubMed  Google Scholar 

  34. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–37.

    Article  PubMed  Google Scholar 

  35. Sacco AG, Worden FP. Molecularly targeted therapy for the treatment of head and neck cancer: a review of the ErbB family inhibitors. Onco Targets Ther. 2016;9:1927–43.

    PubMed  PubMed Central  Google Scholar 

  36. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567–78.

    Article  PubMed  Google Scholar 

  37. Venook AP. Epidermal growth factor receptor-targeted treatment for advanced colorectal carcinoma. Cancer. 2005;103:2435–46.

    Article  PubMed  Google Scholar 

  38. Gao P, Li C, Chang Z, Wang X, Xuan M. Carcinoma associated fibroblasts derived from oral squamous cell carcinoma promote lymphangiogenesis via c-Met/PI3K/AKT in vitro. Oncol Lett. 2018;15(1):331–7.

    PubMed  Google Scholar 

  39. Sun Z, Liu Q, Ye D, Ye K, Yang Z, Li D. Role of c-Met in the progression of human oral squamous cell carcinoma and its potential as a therapeutic target. Oncol Rep. 2018;39(1):209–16.

    PubMed  Google Scholar 

  40. Cheng CM, Shiah SG, Huang CC, Hsiao JR, Chang JY. Up-regulation of miR-455-5p by the TGF-β-SMAD signalling axis promotes the proliferation of oral squamous cancer cells by targeting UBE2B. J Pathol. 2016;240(1):38–49.

    Article  PubMed  Google Scholar 

  41. Sivadas VP, George NA, Kattoor J, Kannan S. Novel mutations and expression alterations in SMAD3/TGFBR2 genes in oral carcinoma correlate with poor prognosis. Genes Chromosomes Cancer. 2013;52(11):1042–52.

    Article  PubMed  Google Scholar 

  42. Hwang YS, Park KK, Chung WY. Stromal transforming growth factor-beta 1 is crucial for reinforcing the invasive potential of low invasive cancer. Arch Oral Biol. 2014;59(7):687–94.

    Article  PubMed  Google Scholar 

  43. Molinolo AA, Amornphimoltham P, Squarize CH, Castilho RM, Patel V, Gutkind JS. Dysregulated molecular networks in head and neck carcinogenesis. Oral Oncol. 2009;45(4–5):324–34.

    Article  PubMed  Google Scholar 

  44. Xu K, Liu P, Wei W. mTORsignaling in tumorigenesis. Biochim Biophys Acta. 2014;1846(2):638–54.

    PubMed  PubMed Central  Google Scholar 

  45. Marques AE, Elias ST, Porporatti AL, Castilho RM, Squarize CH, De Luca Canto G, Guerra EN. mTOR pathway protein immunoexpression as a prognostic factor for survival in head and neck cancer patients: a systematic review and meta-analysis. J Oral Pathol Med. 2016;45(5):319–28.

    Article  PubMed  Google Scholar 

  46. Monteiro LS, Delgado ML, Ricardo S, Garcez F, do Amaral B, Warnakulasuriya S, Lopes C. Phosphorylated mammalian target of rapamycin is associated with na adverse outcome in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115(5):638–45.

    Article  PubMed  Google Scholar 

  47. Simpson DR, Mell LK, Cohen EE. Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck. Oral Oncol. 2015;51(4):291–8.

    Article  PubMed  Google Scholar 

  48. Vitale-Cross L, Molinolo AA, Martin D, Younis RH, Maruyama T, Patel V, Chen W, Schneider A, Gutkind JS. Metformin prevents the development of oral squamous cell carcinomas from carcinogen-induced premalignant lesions. Cancer Prev Res (Phila). 2012;5(4):562–73.

    Article  Google Scholar 

  49. Murugan AK, Munirajan AK, Tsuchida N. Ras oncogenes in oral cancer: the past 20 years. Oral Oncol. 2012;48(5):383–92.

    Article  PubMed  Google Scholar 

  50. Saranath D, Chang SE, Bhoite LT, Panchal RG, Kerr IB, Mehta AR, Johnson NW, Deo MG. High frequency mutation in codons 12 and 61 of H-ras oncogene in chewingtobacco-related human oral carcinoma in India. Br J Cancer. 1991;63(4):573–8.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Saarilahti K, Kajanti M, Kouri M, Aaltonen LM, Franssila K, Joensuu H. Cyclin A and Ki-67 expression as predictors for locoregional recurrence and outcome in laryngeal cancer patients treated with surgery and postoperative radiotherapy. Int J Radiat Oncol Biol Phys. 2003;57(4):986–95.

    Article  PubMed  Google Scholar 

  52. Hanken H, Gröbe A, Cachovan G, Smeets R, Simon R, Sauter G, Heiland M, Blessmann M. CCND1 amplification and cyclin D1 immunohistochemical expression in head and neck squamous cell carcinomas. Clin Oral Investig. 2014;18(1):269–76.

    Article  PubMed  Google Scholar 

  53. Huang SF, Cheng SD, Chuang WY, Chen IH, Liao CT, Wang HM, Hsieh LL. Cyclin D1 overexpression and poor clinical outcomes in Taiwanese oral cavity squamous cell carcinoma. World J Surg Oncol. 2012;10:40.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Noorlag R, van Kempen PM, Stegeman I, Koole R, van Es RJ, Willems SM. The diagnostic value of 11q13 amplification and protein expression in the detection of nodal metastasis from oral squamous cell carcinoma: a systematic review and meta-analysis. Virchows Arch. 2015;466(4):363–73.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Zhao Y, Yu D, Li H, Nie P, Zhu Y, Liu S, Zhu M, Fang B. Cyclin D1 overexpression is associated with poor clinicopathological outcome and survival in oral squamous cell carcinoma in Asian populations: insights from a meta-analysis. PLoS One. 2014;9(3):e93210.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Fraczek M, Wozniak Z, Ramsey D, Zatonski T, Krecicki T. Clinicopathologic significance and prognostic role of cyclin E and cyclin A expression in laryngeal epithelial lesions. Acta Otolaryngol. 2008;128(3):329–34.

    Article  PubMed  Google Scholar 

  57. Chen HM, Yen-Ping Kuo M, Lin KH, Lin CY, Chiang CP. Expression of cyclin A is related to progression of oral squamous cell carcinoma in Taiwan. Oral Oncol. 2003;39(5):476–82.

    Article  PubMed  Google Scholar 

  58. Tandon R, Cunningham LL, White DK, Herford AS, Cicciu M. Overexpression of cyclin A in oral dysplasia: an international comparison and literature review. Indian J Cancer. 2014;51(4):502–5.

    Article  PubMed  Google Scholar 

  59. Ko MT, Su CY, Huang SC, Chen CH, Hwang CF. Overexpression of cyclin E messenger ribonucleic acid in nasopharyngeal carcinoma correlates with poor prognosis. J Laryngol Otol. 2009;123(9):1021–6.

    Article  PubMed  Google Scholar 

  60. Hoffmann TK, Trellakis S, Okulicz K, Schuler P, Greve J, Arnolds J, Bergmann C, Bas M, Lang S, Lehnerdt G, Brandau S, Mattheis S, Scheckenbach K, Finn OJ, Whiteside TL, Sonkoly E. Cyclin B1 expression and p53 status in squamous cell carcinomas of the head and neck. Anticancer Res. 2011;31(10):3151–7.

    PubMed  PubMed Central  Google Scholar 

  61. Teixeira JH, Silva PM, Reis RM, Moura IM, Marques S, Fonseca J, Monteiro LS, Bousbaa H. An overview of the spindle assembly checkpoint status in oral cancer. Biomed Res Int. 2014;2014:145289.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Musacchio A, Salmon ED. The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol. 2007;8:379–93.

    Article  PubMed  Google Scholar 

  63. Kops GJ, Weaver BA, Cleveland DW. On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer. 2005;5:773–85.

    Article  PubMed  Google Scholar 

  64. Moura IM, Delgado ML, Silva PM, Lopes CA, do Amaral JB, Monteiro LS, Bousbaa H. High CDC20 expression is associated with poor prognosis in oral squamous cell carcinoma. J Oral Pathol Med. 2014;43(3):225–31.

    Article  PubMed  Google Scholar 

  65. Teixeira JH, Silva P, Faria J, Ferreira I, Duarte P, Delgado ML, Queirós O, Moreira R, Barbosa J, Lopes CA, do Amaral JB, Monteiro LS, Bousbaa H. Clinicopathologicsignificanceof BubR1 and Mad2 overexpression in oral cancer. Oral Dis. 2015;21(6):713–20.

    Article  PubMed  Google Scholar 

  66. Shiah SG, Shieh YS, Chang JY. The role of WntSignaling in squamous cell carcinoma. J Dent Res. 2016;95(2):129–34.

    Article  PubMed  Google Scholar 

  67. Morris LG, Kaufman AM, Gong Y, Ramaswami D, Walsh LA, Turcan Ş, Eng S, Kannan K, Zou Y, Peng L, Banuchi VE, Paty P, Zeng Z, Vakiani E, Solit D, Singh B, Ganly I, Liau L, Cloughesy TC, Mischel PS, Mellinghoff IK, Chan TA. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat Genet. 2013;45(3):253–61.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Kayamori K, Katsube K, Sakamoto K, Ohyama Y, Hirai H, Yukimori A, Ohata Y, Akashi T, Saitoh M, Harada K, Harada H, Yamaguchi A. NOTCH3 is induced in cancer-associated fibroblasts and promotes angiogenesis in oral squamous cell carcinoma. PLoS One. 2016;11(4):e0154112.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Hijioka H, Setoguchi T, Miyawaki A, Gao H, Ishida T, Komiya S, Nakamura N. Upregulation of Notch pathway molecules in oral squamous cell carcinoma. Int J Oncol. 2010;36(4):817–22.

    PubMed  Google Scholar 

  70. Yap LF, Lee D, Khairuddin A, Pairan MF, Puspita B, Siar CH, Paterson IC. The opposing roles of NOTCH signalling in head and neck cancer: a mini review. Oral Dis. 2015;21(7):850–7.

    Article  PubMed  Google Scholar 

  71. Song X, Xia R, Li J, Long Z, Ren H, Chen W, Mao L. Common and complex Notch1 mutations in Chinese oral squamous cell carcinoma. Clin Cancer Res. 2014;20:701–10.

    Article  PubMed  Google Scholar 

  72. Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ, Fakhry C, Xie TX, Zhang J, Wang J, Zhang N, El-Naggar AK, Jasser SA, Weinstein JN, Treviño L, Drummond JA, Muzny DM, Wu Y, Wood LD, Hruban RH, Westra WH, Koch WM, Califano JA, Gibbs RA, Sidransky D, Vogelstein B, Velculescu VE, Papadopoulos N, Wheeler DA, Kinzler KW, Myers JN. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 2011;333(6046):1154–7.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Izumchenko E, Sun K, Jones S, Brait M, Agrawal N, Koch W, McCord CL, Riley DR, Angiuoli SV, Velculescu VE, Jiang WW, Sidransky D. Notch1 mutations are drivers of oral tumorigenesis. Cancer Prev Res (Phila). 2015;8:277–86.

    Article  Google Scholar 

  74. Yoshida R, Nagata M, Nakayama H, Niimori-Kita K, Hassan W, Tanaka T, Shinohara M, Ito T. The pathological significance of Notch1 in oral squamous cell carcinoma. Lab Investig. 2013;93(10):1068–81.

    Article  PubMed  Google Scholar 

  75. Zhang JP, Qin HY, Wang L, Liang L, Zhao XC, Cai WX, Wei YN, Wang CM, Han H. Overexpression of Notch ligand Dll1 in B16 melanoma cells leads to reduced tumor growth due to attenuated vascularization. Cancer Lett. 2011;309:220–7.

    Article  PubMed  Google Scholar 

  76. Monteiro LS, Amaral JB, Vizcaíno JR, Lopes CA, Torres FO. A clinical-pathological and survival study of oral squamous cell carcinomas from a population of the North of Portugal. Med Oral Patol Oral Cir Bucal. 2014;19(2):e120–6.

    Article  PubMed  Google Scholar 

  77. Diniz-Freitas M, García-Caballero T, Antúnez-López J, Gándara-Rey JM, García-García A. Reduced E-cadherin expression is an indicator of unfavourable prognosis in oral squamous cell carcinoma. Oral Oncol. 2006;42(2):190–200.

    Article  PubMed  Google Scholar 

  78. DE Vicente JC, Fernández-Valle Á, Vivanco-Allende B, Santamarta TR, Lequerica-Fernández P, Hernández-Vallejo G, Allonca-Campa E. The prognostic role of claudins −1 and −4 in oral squamous cell carcinoma. Anticancer Res. 2015;35(5):2949–59.

    Google Scholar 

  79. Lourenço SV, Coutinho-Camillo CM, Buim ME, Pereira CM, Carvalho AL, Kowalski LP, Soares FA. Oral squamous cell carcinoma: status of tight junction claudins in the different histopathological patterns and relationship with clinical parameters. A tissue-microarray-based study of 136 cases. J Clin Pathol. 2010;63(7):609–14.

    Article  PubMed  Google Scholar 

  80. Monteiro LS, Delgado ML, Ricardo S, Garcez F, do Amaral B, Pacheco JJ, Lopes C, Bousbaa H. EMMPRIN expression in oral squamous cell carcinomas: correlation with tumor proliferation and patient survival. Biomed Res Int. 2014;2014:905680.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Monteiro LS, Delgado ML, Ricardo S, do Amaral B, Salazar F, Pacheco JJ, Lopes CA, Bousbaa H, Warnakulasuryia S. Prognostic significance of CD44v6, p63, podoplanin and MMP-9 in oral squamous cell carcinomas. Oral Dis. 2016;22(4):303–12.

    Article  PubMed  Google Scholar 

  82. Folkman J. Tumor angiogenesis. Therapeutic implications. N Engl J Med. 1971;285:1182–6.

    Article  PubMed  Google Scholar 

  83. Zang J, Li C, Zhao LN, Shi M, Zhou YC, Wang JH, Li X. Prognostic value of vascular endothelial growth factor in patients with head and neck cancer: a meta-analysis. Head Neck. 2013;35(10):1507–14.

    PubMed  Google Scholar 

  84. Neuchrist C, Erovic BM, Handisurya A, Steiner GE, Rockwell P, Gedlicka C, Burian M. Vascular endothelial growth factor receptor 2 (VEGFR2) expression in squamous cell carcinomas of the head and neck. Laryngoscope. 2001;111(10):1834–41.

    Article  PubMed  Google Scholar 

  85. Vassilakopoulou M, Psyrri A, Argiris A. Targeting angiogenesis in head and neck cancer. Oral Oncol. 2015;51(5):409–15.

    Article  PubMed  Google Scholar 

  86. Hiratsuka S, Nakamura K, Iwai S, Murakami M, Itoh T, Kijima H, Shipley JM, Senior RM, Shibuya M. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell. 2002;2(4):289–300.

    Article  PubMed  Google Scholar 

  87. Hsu HW, Wall NR, Hsueh CT, Kim S, Ferris RL, Chen CS, Mirshahidi S. Combination antiangiogenic therapy and radiation in head and neck cancers. Oral Oncol. 2014;50(1):19–26.

    Article  PubMed  Google Scholar 

  88. Preuss SF, Anagiotos A, Seuthe IM, Drebber U, Wedemeyer I, Kreppel M, Semrau R, Eslick GD, Klussmann JP, Huebbers CU. Expression of podoplanin and prognosis in oropharyngeal cancer. Eur Arch Otorhinolaryngol. 2015;272(7):1749–54.

    Article  PubMed  Google Scholar 

  89. Kahn HJ, Marks A. A new monoclonal antibody, D2-40, for detection of lymphatic invasion in primary tumors. Lab Investig. 2002;82(9):1255–7.

    Article  PubMed  Google Scholar 

  90. Ochoa-Alvarez JA, Krishnan H, Pastorino JG, Nevel E, Kephart D, Lee JJ, Retzbach EP, Shen Y, Fatahzadeh M, Baredes S, Kalyoussef E, Honma M, Adelson ME, Kaneko MK, Kato Y, Young MA, Deluca-Rapone L, Shienbaum AJ, Yin K, Jensen LD, Goldberg GS. Antibody and lectin target podoplanin to inhibit oral squamous carcinoma cell migration and viability by distinct mechanisms. Oncotarget. 2015;6(11):9045–60.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Li YY, Zhou CX, Gao Y. Podoplanin promotes the invasion of oral squamous cell carcinoma in coordination with MT1-MMP and Rho GTPases. Am J Cancer Res. 2015;5(2):514–29.

    PubMed  PubMed Central  Google Scholar 

  92. Inoue H, Miyazaki Y, Kikuchi K, Yoshida N, Ide F, Ohmori Y, Tomomura A, Sakashita H, Kusama K. Podoplanin promotes cell migration via the EGF-Src-Cas pathway in oral squamous cell carcinoma cell lines. J Oral Sci. 2012;54(3):241–50.

    Article  PubMed  Google Scholar 

  93. Huber GF, Fritzsche FR, Züllig L, Storz M, Graf N, Haerle SK, Jochum W, Stoeckli SJ, Moch H. Podoplanin expression correlates with sentinel lymph node metastasis in early squamous cell carcinomas of the oral cavity and oropharynx. Int J Cancer. 2011;129(6):1404–9.

    Article  PubMed  Google Scholar 

  94. Cueni LN, Hegyi I, Shin JW, Albinger-Hegyi A, Gruber S, Kunstfeld R, Moch H, Detmar M. Tumorlymphangiogenesis and metastasis to lymph nodes induced by cancer cell expression of podoplanin. Am J Pathol. 2010;177(2):1004–16.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Swain N, Kumar SV, Routray S, Pathak J, Patel S. Podoplanin-a novel marker in oral carcinogenesis. Tumour Biol. 2014;35(9):8407–13.

    Article  PubMed  Google Scholar 

  96. Yuan P, Temam S, El-Naggar A, Zhou X, Liu DD, Lee JJ, Mao L. Overexpression of podoplanin in oral cancer and its association with poor clinical outcome. Cancer. 2006;107(3):563–9.

    Article  PubMed  Google Scholar 

  97. Vormittag L, Thurnher D, Geleff S, Pammer J, Heiduschka G, Brunner M, Grasl MC, Erovic BM. Co-expression of Bmi-1 and podoplanin predicts overall survival in patients with squamous cell carcinoma of the head and neck treated with radio(chemo)therapy. Int J Radiat Oncol Biol Phys. 2009;73(3):913–8.

    Article  PubMed  Google Scholar 

  98. Kreppel M, Drebber U, Wedemeyer I, Eich HT, Backhaus T, Zöller JE, Scheer M. Podoplanin expression predicts prognosis in patients with oral squamous cell carcinoma treated with neoadjuvantradiochemotherapy. Oral Oncol. 2011;47(9):873–8.

    Article  PubMed  Google Scholar 

  99. Retzbach EP, Sheehan SA, Nevel EM, Batra A, Phi T, Nguyen ATP, Kato Y, Baredes S, Fatahzadeh M, Shienbaum AJ, Goldberg GS. Podoplanin emerges as a functionally relevant oral cancer biomarker and therapeutic target. Oral Oncol. 2018;78:126–36.

    Article  PubMed  Google Scholar 

  100. Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9:239–52.

    Article  PubMed  Google Scholar 

  101. Yu M, Chen S, Hong W, Gu Y, Huang B, Lin Y, Zhou Y, Jin H, Deng Y, Tu L, Hou B, Jian Z. Prognostic role of glycolysis for cancer outcome: evidence from 86 studies. J Cancer Res Clin Oncol. 2019;145(4):967–99.

    Article  PubMed  Google Scholar 

  102. Vander Heiden M, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Romero-Garcia S, Moreno-Altamirano M, Prado-Garcia H, Sánchez-García F. Lactate contribution to the tumor microenvironment: mechanisms, effects on immune cells and therapeutic relevance. Front Immunol. 2016;7:52.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Festino L, Botti G, Lorigan P, Masucci GV, Hipp JD, Horak CE, Ascierto PA. Cancer treatment with anti-PD-1/PD-L1 agents: is PD-L1 expression a biomarker for patient selection? Drugs. 2016;76(9):925–45.

    Article  PubMed  Google Scholar 

  105. Pai SI, Zandberg DP, Strome SE. The role of antagonists of the PD-1:PD-L1/PD-L2 axis in head and neck cancer treatment. Oral Oncol. 2016;61:152–8.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Zandberg DP, Strome SE. The role of the PD-L1:PD-1 pathway in squamous cell carcinoma of the head and neck. Oral Oncol. 2014;50(7):627–32.

    Article  PubMed  Google Scholar 

  107. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677–86.

    Article  PubMed  Google Scholar 

  108. Mori K, Hiroi M, Shimada J, Ohmori Y. Infiltration of m2 tumor-associated macrophages in oral squamous cell carcinoma correlates with tumor malignancy. Cancers (Basel). 2011;3(4):3726–39.

    Article  Google Scholar 

  109. Castellsagué X, Alemany L, Quer M, Halec G, Quirós B, Tous S, Clavero O, Alòs L, Biegner T, Szafarowski T, Alejo M, Holzinger D, Cadena E, Claros E, Hall G, Laco J, Poljak M, Benevolo M, Kasamatsu E, Mehanna H, Ndiaye C, Guimerà N, Lloveras B, León X, Ruiz-Cabezas JC, Alvarado-Cabrero I, Kang CS, Oh JK, Garcia-Rojo M, Iljazovic E, Ajayi OF, Duarte F, Nessa A, Tinoco L, Duran-Padilla MA, Pirog EC, Viarheichyk H, Morales H, Costes V, Félix A, Germar MJ, Mena M, Ruacan A, Jain A, Mehrotra R, Goodman MT, Lombardi LE, Ferrera A, Malami S, Albanesi EI, Dabed P, Molina C, López-Revilla R, Mandys V, González ME, Velasco J, Bravo IG, Quint W, Pawlita M, Muñoz N, de Sanjosé S, Xavier Bosch F, ICO International HPV in Head and Neck Cancer Study Group. HPV involvement in head and neck cancers: comprehensive assessment of biomarkers in 3680 patients. J Natl Cancer Inst. 2016;108(6):djv403.

    Article  PubMed  Google Scholar 

  110. Zhang Y, Koneva LA, Virani S, Arthur AE, Virani A, Hall PB, Warden CD, Carey TE, Chepeha DB, Prince ME, McHugh JB, Wolf GT, Rozek LS, Sartor MA. Subtypes of HPV-positive head and neck cancers are associated with HPV characteristics, copy number alterations, PIK3CA mutation, and pathway signatures. Clin Cancer Res. 2016;22(18):4735–45.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Rivera C, Oliveira AK, Costa RAP, De Rossi T, PaesLeme AF. Prognostic biomarkers in oral squamous cell carcinoma: a systematic review. Oral Oncol. 2017;72:38–47.

    Article  PubMed  Google Scholar 

  112. Almangush A, Heikkinen I, Mäkitie AA, Coletta RD, Läärä E, Leivo I, Salo T. Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis. Br J Cancer. 2017;117(6):856–66.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Lakshminarayana S, Augustine D, Rao RS, Patil S, Awan KH, Venkatesiah SS, Haragannavar VC, Nambiar S, Prasad K. Molecular pathways of oral cancer that predict prognosis and survival: a systematic review. J Carcinog. 2018;17:7.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Peterle GT, Maia LL, Trivilin LO, de Oliveira MM, Dos Santos JG, Mendes SO, Stur E, Agostini LP, Rocha LA, Moysés RA, Cury PM, Nunes FD, Louro ID, Dos Santos M, da Silva AMÁ. PAI-1, CAIX, and VEGFA expressions as prognosis markers in oral squamous cell carcinoma. J Oral Pathol Med. 2018;47(6):566–74.

    Article  PubMed  Google Scholar 

  115. Götz C, Bissinger O, Nobis C, Wolff KD, Drecoll E, Kolk A. ALDH1 as a prognostic marker for lymph node metastasis in OSCC. Biomed Rep. 2018;9(4):284–90.

    PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Medicine and Oral Surgery Department, Cancer Research Group – IINFACTS, Instituto Universitário de Ciências da Saúde (IUCS) – CESPU, Gandra, Portugal

    Luis Monteiro

  2. Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, UK

    Saman Warnakulasuriya

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  1. Luis Monteiro
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  1. Faculty of Dentistry, Oral & Craniofacial Sciences,, King’s College London, London, UK

    Saman Warnakulasuriya

  2. Department of Orofacial Sciences, Schools of Dentistry and Medicine, University of California San Francisco, San Francisco, CA, USA

    John S. Greenspan

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Monteiro, L., Warnakulasuriya, S. (2020). Molecular and Signaling Pathways During Oral Carcinogenesis. In: Warnakulasuriya, S., Greenspan, J. (eds) Textbook of Oral Cancer. Textbooks in Contemporary Dentistry. Springer, Cham. https://doi.org/10.1007/978-3-030-32316-5_14

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