Oral Cancer Stem Cells Microenvironment

  • Prajna Paramita Naik
  • Prashanta Kumar Panda
  • Sujit K. BhutiaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1041)


Cancer stem cells (CSCs) play important role in tumor growth and metastasis coupled with increased recurrences and acquired therapeutic resistance in oral cancer. The tumor microenvironment imposes intense pressure in cancer evolution in response to adverse growth conditions, resource limitation and immune predation. Here, we discussed the dynamic interplay between cancer stem cells and tumor microenvironment in the formation of intratumoral heterogeneity to modulate tumor progression. The CSCs niche provide a special microhabitat for survival, maintenance of stemness and tumor re-propagation. Moreover, adaptive cellular behavior might be driven by tough tumor microenvironmental selective forces which highly regulate alterations in the gene expression leading to the reprogramming of signaling pathways generating stem-like characteristics, adaptive metabolic plasticity and energy fueling with autophagy to permit the CSCs to sustain in the ever changing microenvironments during tumor progression. On the other hand, CSCs also direct the tumor microenvironment modulation and remodeling in its favour. The cytokines, chemokines and growth factors released from CSCs regulates neoangiogensis, differentiation, degradation of matrix protein and immune suppression favoring tumor-promoting conditions and initiates multiple signaling cascades augmenting the tumor progression.


Oral cancer Tumor heterogeneity Cancer stem cell Tumor microenvironment 



Research support was partly provided by Department of Biotechnology [Grant Number: BT/PR7791/BRB/10/1187/2013]; Science and Engineering Research Board (SERB), Department of Science and Technology [Grant Number: SR/SO/BB-0101/2012]; Council of Scientific and Industrial Research (CSIR) [Grant Number: 37(1608)/13/EMR-II] Human Resource Development Group, Government of India; Science and Technology Department, Government of Odisha. PPN is obliged to DST SERB, New Delhi, India for providing fellowship.

Conflict of Interest

The authors declare no conflicts of interest.


  1. Akino T, Hida K, Hida Y, Tsuchiya K, Freedman D, Muraki C et al (2009) Cytogenetic abnormalities of tumor-associated endothelial cells in human malignant tumors. Am J Pathol 175:2657–2667PubMedPubMedCentralCrossRefGoogle Scholar
  2. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100:3983–3988PubMedPubMedCentralCrossRefGoogle Scholar
  3. Almendro V, Marusyk A, Polyak K (2013) Cellular heterogeneity and molecular evolution in cancer. Annu Rev Pathol 8:277–302PubMedCrossRefGoogle Scholar
  4. An Y, Kiang A, Lopez JP, Kuo SZ, Yu MA, Abhold EL et al (2012) Cigarette smoke promotes drug resistance and expansion of cancer stem cell-like side population. PLoS One 7:e47919PubMedPubMedCentralCrossRefGoogle Scholar
  5. Anderson AR, Weaver AM, Cummings PT, Quaranta V (2006) Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment. Cell 127:905–915PubMedCrossRefGoogle Scholar
  6. Bagordakis E, Sawazaki-Calone I, Macedo CCS, Carnielli CM, de Oliveira CE, Rodrigues PC et al (2016) Secretome profiling of oral squamous cell carcinoma-associated fibroblasts reveals organization and disassembly of extracellular matrix and collagen metabolic process signatures. Tumor Biol 37:9045–9057CrossRefGoogle Scholar
  7. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545PubMedCrossRefGoogle Scholar
  8. Barth PJ, Zu Schweinsberg TS, Ramaswamy A, Moll R (2004) CD34+ fibrocytes, α-smooth muscle antigen-positive myofibroblasts, and CD117 expression in the stroma of invasive squamous cell carcinomas of the oral cavity, pharynx, and larynx. Virchows Arch 444:231–234PubMedCrossRefGoogle Scholar
  9. Bhowmick NA, Neilson EG, Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432:332–337PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bhutia SK, Mukhopadhyay S, Sinha N, Das DN, Panda PK, Patra SK et al (2013) Autophagy: cancer’s friend or foe? Adv Cancer Res 118:61PubMedPubMedCentralCrossRefGoogle Scholar
  11. Brandwein-Gensler M, Teixeira MS, Lewis CM, Lee B, Rolnitzky L, Hille JJ et al (2005) Oral squamous cell carcinoma: histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol 29:167–178PubMedCrossRefGoogle Scholar
  12. Brennan P, Mackenzie N, Quintero M (2005) Hypoxia-inducible factor 1α in oral cancer. J Oral Pathol Med 34:385–389PubMedCrossRefGoogle Scholar
  13. Brouty-Boyé D (2005) Developmental biology of fibroblasts and neoplastic disease. In: Developmental biology of neoplastic growth. Springer, Berlin, pp 55–77CrossRefGoogle Scholar
  14. Cabrera MC, Hollingsworth RE, Hurt EM (2015) Cancer stem cell plasticity and tumor hierarchy. World J Stem Cells 7:27–36PubMedPubMedCentralCrossRefGoogle Scholar
  15. Capparelli C, Whitaker-Menezes D, Guido C, Balliet R, Pestell TG, Howell A et al (2012) CTGF drives autophagy, glycolysis and senescence in cancer-associated fibroblasts via HIF1 activation, metabolically promoting tumor growth. Cell Cycle 11:2272–2284PubMedPubMedCentralCrossRefGoogle Scholar
  16. Castaño Z, Fillmore CM, Kim CF, McAllister SS (2012) The bed and the bugs: interactions between the tumor microenvironment and cancer stem cells. Semin Cancer Biol 22:462–470PubMedPubMedCentralCrossRefGoogle Scholar
  17. Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO et al (2011) Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci U S A 108:7950–7955PubMedPubMedCentralCrossRefGoogle Scholar
  18. Chaponnier C, Desmoulière A, Gabbiani G (2006) Tissue repair, contraction and the myofibroblast. Springer, USCrossRefGoogle Scholar
  19. Chen YJ, Chang JTC, Liao CT, Wang HM, Yen TC, Chiu CC et al (2008) Head and neck cancer in the betel quid chewing area: recent advances in molecular carcinogenesis. Cancer Sci 99:1507–1514PubMedCrossRefGoogle Scholar
  20. Chikamatsu K, Takahashi G, Sakakura K, Ferrone S, Masuyama K (2011) Immunoregulatory properties of CD44+ cancer stem-like cells in squamous cell carcinoma of the head and neck. Head Neck 33:208–215PubMedPubMedCentralCrossRefGoogle Scholar
  21. Chiu KC, Lee CH, Liu SY, Chou YT, Huang RY, Huang SM et al (2015) Polarization of tumor-associated macrophages and Gas6/Axl signaling in oral squamous cell carcinoma. Oral Oncol 51:683–689PubMedCrossRefGoogle Scholar
  22. Cho YA, Yoon HJ, Lee JI, Hong SP, Hong SD (2011) Relationship between the expressions of PD-L1 and tumor-infiltrating lymphocytes in oral squamous cell carcinoma. Oral Oncol 47:1148–1153PubMedCrossRefGoogle Scholar
  23. Costa NL, Valadares MC, Souza PPC, Mendonça EF, Oliveira JC, Silva TA et al (2013) Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma. Oral Oncol 49:216–223PubMedCrossRefGoogle Scholar
  24. Costea D, Tsinkalovsky O, Vintermyr O, Johannessen A, Mackenzie I (2006) Cancer stem cells–new and potentially important targets for the therapy of oral squamous cell carcinoma. Oral Dis 12:443–454PubMedCrossRefGoogle Scholar
  25. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867PubMedPubMedCentralCrossRefGoogle Scholar
  26. Curry JM, Sprandio J, Cognetti D, Luginbuhl A, Bar-ad V, Pribitkin E et al (2014) Tumor microenvironment in head and neck squamous cell carcinoma. Semin Oncol 41(2):217–234PubMedCrossRefGoogle Scholar
  27. Daly AJ, McIlreavey L, Irwin CR (2008) Regulation of HGF and SDF-1 expression by oral fibroblasts–implications for invasion of oral cancer. Oral Oncol 44:646–651PubMedCrossRefGoogle Scholar
  28. De Wever O, Demetter P, Mareel M, Bracke M (2008) Stromal myofibroblasts are drivers of invasive cancer growth. Int J Cancer 123:2229–2238PubMedCrossRefGoogle Scholar
  29. Dick D (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737PubMedCrossRefGoogle Scholar
  30. Dong C, Yuan T, Wu Y, Wang Y, Fan TW, Miriyala S et al (2013) Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell 23:316–331PubMedPubMedCentralCrossRefGoogle Scholar
  31. Duarte S, Loubat A, Momier D, Topi M, Faneca H, Pedroso de Lima MC et al (2012) Isolation of head and neck squamous carcinoma cancer stem-like cells in a syngeneic mouse model and analysis of hypoxia effect. Oncol Rep 28:1057–1062PubMedCrossRefGoogle Scholar
  32. Duffy SA, Taylor JM, Terrell JE, Islam M, Li Y, Fowler KE et al (2008) Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer 113:750–757PubMedCrossRefGoogle Scholar
  33. Dumitru CA, Gholaman H, Trellakis S, Bruderek K, Dominas N, Gu X et al (2011) Tumor-derived macrophage migration inhibitory factor modulates the biology of head and neck cancer cells via neutrophil activation. Int J Cancer 129:859–869PubMedCrossRefGoogle Scholar
  34. Egeblad M, Nakasone ES, Werb Z (2010) Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18:884–901PubMedPubMedCentralCrossRefGoogle Scholar
  35. El-Rouby DH (2010) Association of macrophages with angiogenesis in oral verrucous and squamous cell carcinomas. J Oral Pathol Med 39:559–564PubMedCrossRefGoogle Scholar
  36. Fan S, Tang QL, Lin YJ, Wl C, Li JS, Huang ZQ et al (2011) A review of clinical and histological parameters associated with contralateral neck metastases in oral squamous cell carcinoma. Int J Oral Sci 3:180–191PubMedPubMedCentralCrossRefGoogle Scholar
  37. Ferlay J, Bray F, Forman D, Mathers C, Parkin D (2010) Cancer incidence and mortality worldwide: IARC CancerBase No. 10. International Agency for Research on Cancer, Lyon, France [cited 2012 04/04/2012]Google Scholar
  38. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mather C (2015) Globocan 2012 version 1.0: cancer incidence and mortality worldwide—IARC CancerBase No. 11. International Agency for Research on Cancer, Lyon, FranceGoogle Scholar
  39. Ferris RL, Whiteside TL, Ferrone S (2006) Immune escape associated with functional defects in antigen-processing machinery in head and neck cancer. Clin Cancer Res 12:3890–3895PubMedCrossRefGoogle Scholar
  40. Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS (2007) Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res 67:3560–3564PubMedCrossRefGoogle Scholar
  41. Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29:15–18PubMedCrossRefGoogle Scholar
  42. Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12:298–306PubMedCrossRefGoogle Scholar
  43. Friedl P, Alexander S (2011) Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147:992–1009PubMedCrossRefGoogle Scholar
  44. Fuchs E, Tumbar T, Guasch G (2004) Socializing with the neighbors: stem cells and their niche. Cell 116:769–778PubMedCrossRefGoogle Scholar
  45. Fullár A, Kovalszky I, Bitsche M, Romani A, Schartinger VH, Sprinzl GM et al (2012) Tumor cell and carcinoma-associated fibroblast interaction regulates matrix metalloproteinases and their inhibitors in oral squamous cell carcinoma. Exp Cell Res 318:1517–1527PubMedPubMedCentralCrossRefGoogle Scholar
  46. Galdiero MR, Garlanda C, Jaillon S, Marone G, Mantovani A (2013) Tumor associated macrophages and neutrophils in tumor progression. J Cell Physiol 228:1404–1412PubMedCrossRefGoogle Scholar
  47. Gilbertson RJ, Rich JN (2007) Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer 7:733–736PubMedCrossRefGoogle Scholar
  48. Gonçalves AS, Costa NL, Arantes DAC, Cássia Gonçalves Alencar R, Silva TA, Batista AC (2013) Immune response in cervical lymph nodes from patients with primary oral squamous cell carcinoma. J Oral Pathol Med 42:535–540PubMedCrossRefGoogle Scholar
  49. Grandis JR, Falkner DM, Melhem MF, Gooding WE, Drenning SD, Morel PA (2000) Human leukocyte antigen class I allelic and haplotype loss in squamous cell carcinoma of the head and neck: clinical and immunogenetic consequences. Clin Cancer Res 6:2794–2802PubMedGoogle Scholar
  50. Hanahan D, Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21:309–322PubMedCrossRefGoogle Scholar
  51. Harada T, Shinohara M, Nakamura S, Oka M (1994) An immunohistochemical study of the extracellular matrix in oral squamous cell carcinoma and its association with invasive and metastatic potential. Virchows Arch 424:257–266PubMedCrossRefGoogle Scholar
  52. He KF, Zhang L, Huang CF, Ma SR, Wang YF, Wang WM et al (2014) CD163+ tumor-associated macrophages correlated with poor prognosis and cancer stem cells in oral squamous cell carcinoma. Biomed Res Int 2014:838632PubMedPubMedCentralGoogle Scholar
  53. Heddleston J, Li Z, Lathia J, Bao S, Hjelmeland A, Rich J (2010) Hypoxia inducible factors in cancer stem cells. Br J Cancer 102:789–795PubMedPubMedCentralCrossRefGoogle Scholar
  54. Hida K, Hida Y, Amin DN, Flint AF, Panigrahy D, Morton CC et al (2004) Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res 64:8249–8255PubMedCrossRefGoogle Scholar
  55. Hjelmeland AB, Wu Q, Heddleston J, Choudhary G, MacSwords J, Lathia JD et al (2011) Acidic stress promotes a glioma stem cell phenotype. Cell Death Differ 18:829–840PubMedCrossRefGoogle Scholar
  56. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG (2013) Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13:714–726PubMedCrossRefGoogle Scholar
  57. Hovinga KE, Shimizu F, Wang R, Panagiotakos G, Van Der Heijden M, Moayedpardazi H et al (2010) Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem Cells 28:1019–1029PubMedPubMedCentralCrossRefGoogle Scholar
  58. Hu Y, He MY, Zhu LF, Yang CC, Zhou ML, Wang Q et al (2016) Tumor-associated macrophages correlate with the clinicopathological features and poor outcomes via inducing epithelial to mesenchymal transition in oral squamous cell carcinoma. J Exp Clin Cancer Res 35:12PubMedPubMedCentralCrossRefGoogle Scholar
  59. Huang Z, Wang L, Wang Y, Zhuo Y, Li H, Chen J et al (2013) Overexpression of CD147 contributes to the chemoresistance of head and neck squamous cell carcinoma cells. J Oral Pathol Med 42:541–546PubMedCrossRefGoogle Scholar
  60. Huang Z, Tan N, Guo W, Wang L, Li H, Zhang T et al (2014) Overexpression of EMMPRIN isoform 2 is associated with head and neck cancer metastasis. PLoS One 9:e91596PubMedPubMedCentralCrossRefGoogle Scholar
  61. Huntly BJ, Gilliland DG (2005) Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer 5:311–321PubMedCrossRefGoogle Scholar
  62. Ishikawa T, Nakashiro K, Klosek SK, Goda H, Hara S, Uchida D et al (2009) Hypoxia enhances CXCR4 expression by activating HIF-1 in oral squamous cell carcinoma. Oncol Rep 21:707–712PubMedGoogle Scholar
  63. Jiang J, Tang YL, Liang XH (2011) EMT: a new vision of hypoxia promoting cancer progression. Cancer Biol Ther 11:714–723PubMedCrossRefGoogle Scholar
  64. Johansson N, Airola K, Grenman R, Kariniemi A-L, Saarialho-Kere U, Kähäri V (1997) Expression of collagenase-3 (matrix metalloproteinase-13) in squamous cell carcinomas of the head and neck. Am J Pathol 151:499PubMedPubMedCentralGoogle Scholar
  65. Jonuleit H, Schmitt E, Schuler G, Knop J, Enk AH (2000) Induction of interleukin 10–producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med 192:1213–1222PubMedPubMedCentralCrossRefGoogle Scholar
  66. Judd NP, Winkler AE, Murillo-Sauca O, Brotman JJ, Law JH, Lewis JS et al (2012) ERK1/2 regulation of CD44 modulates oral cancer aggressiveness. Cancer Res 72:365–374PubMedCrossRefGoogle Scholar
  67. Kamarajan P, Shin JM, Qian X, Matte B, Zhu JY, Kapila YL (2013) ADAM17-mediated CD44 cleavage promotes orasphere formation or stemness and tumorigenesis in HNSCC. Cancer Med 2:793–802PubMedPubMedCentralCrossRefGoogle Scholar
  68. Karin M, Greten FR (2005) NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5:749–759PubMedCrossRefGoogle Scholar
  69. Kawashiri S, Tanaka A, Noguchi N, Hase T, Nakaya H, Ohara T et al (2009) Significance of stromal desmoplasia and myofibroblast appearance at the invasive front in squamous cell carcinoma of the oral cavity. Head Neck 31:1346–1353PubMedCrossRefGoogle Scholar
  70. Keith B, Simon MC (2007) Hypoxia-inducible factors, stem cells, and cancer. Cell 129:465–472PubMedPubMedCentralCrossRefGoogle Scholar
  71. Kellermann MG, Sobral LM, da Silva SD, Zecchin KG, Graner E, Lopes MA et al (2008) Mutual paracrine effects of oral squamous cell carcinoma cells and normal oral fibroblasts: induction of fibroblast to myofibroblast transdifferentiation and modulation of tumor cell proliferation. Oral Oncol 44:509–517PubMedCrossRefGoogle Scholar
  72. Kim CFB, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S et al (2005) Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121:823–835PubMedCrossRefGoogle Scholar
  73. Krishnamurthy S, Dong Z, Vodopyanov D, Imai A, Helman JI, Prince ME et al (2010) Endothelial cell-initiated signaling promotes the survival and self-renewal of cancer stem cells. Cancer Res 70:9969–9978PubMedPubMedCentralCrossRefGoogle Scholar
  74. Lee E, Yang J, Ku M, Kim N, Park Y, Park C et al (2015) Metabolic stress induces a Wnt-dependent cancer stem cell-like state transition. Cell Death Dis 6:e1805PubMedPubMedCentralCrossRefGoogle Scholar
  75. Lee Y, Shin JH, Longmire M, Wang H, Kohrt HE, Chang HY et al (2016) CD44+ Cells in Head and Neck Squamous Cell Carcinoma Suppress T-Cell–Mediated Immunity by Selective Constitutive and Inducible Expression of PD-L1. Clin Cancer Res 22:3571–3581PubMedPubMedCentralCrossRefGoogle Scholar
  76. Leef G, Thomas SM (2013) Molecular communication between tumor-associated fibroblasts and head and neck squamous cell carcinoma. Oral Oncol 49:381–386PubMedPubMedCentralCrossRefGoogle Scholar
  77. Leemans CR, Tiwari R, Nauta JJ, Waal IVD, Snow GB (1994) Recurrence at the primary site in head and neck cancer and the significance of neck lymph node metastases as a prognostic factor. Cancer 73:187–190PubMedCrossRefGoogle Scholar
  78. Lessard J, Sauvageau G (2003) Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423:255–260PubMedCrossRefGoogle Scholar
  79. Lewis M, Lygoe K, Nystrom M, Anderson W, Speight P, Marshall J et al (2004) Tumour-derived TGF-β1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells. Br J Cancer 90:822–832PubMedPubMedCentralCrossRefGoogle Scholar
  80. Li C, Shintani S, Terakado N, Nakashiro K, Hamakawa H (2002) Infiltration of tumor-associated macrophages in human oral squamous cell carcinoma. Oncol Rep 9:1219–1223PubMedGoogle Scholar
  81. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V et al (2007) Identification of pancreatic cancer stem cells. Cancer Res 67:1030–1037PubMedCrossRefGoogle Scholar
  82. Li DW, Dong P, Wang F, Chen XW, Xu CZ, Zhou L (2013) Hypoxia induced multidrug resistance of laryngeal cancer cells via hypoxia-inducible factor-1α. Asian Pac J Cancer Prev 14(8):4853PubMedCrossRefGoogle Scholar
  83. Licitra L, Perrone F, Bossi P, Suardi S, Mariani L, Artusi R et al (2006) High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 24:5630–5636PubMedCrossRefGoogle Scholar
  84. Lim KP, Cirillo N, Hassona Y, Wei W, Thurlow JK, Cheong SC et al (2011) Fibroblast gene expression profile reflects the stage of tumour progression in oral squamous cell carcinoma. J Pathol 223:459–469PubMedCrossRefGoogle Scholar
  85. Lin Q, Yun Z (2010) Impact of the hypoxic tumor microenvironment on the regulation of cancer stem cell characteristics. Cancer Biol Ther 9:949–956PubMedPubMedCentralCrossRefGoogle Scholar
  86. Lin CY, Tsai PH, Kandaswami CC, Lee PP, Huang CJ, Hwang JJ et al (2011) Matrix metalloproteinase-9 cooperates with transcription factor Snail to induce epithelial–mesenchymal transition. Cancer Sci 102:815–827PubMedCrossRefGoogle Scholar
  87. Liu SY, Chang LC, Pan LF, Hung YJ, Lee CH, Shieh YS (2008) Clinicopathologic significance of tumor cell-lined vessel and microenvironment in oral squamous cell carcinoma. Oral Oncol 44:277–285PubMedCrossRefGoogle Scholar
  88. Lúcio PSC, Ribeiro DC, Aguiar MC, Alves PM, Nonaka CFW, Godoy GP (2016) Tumor-associated macrophages (TAMs): clinical-pathological parameters in squamous cell carcinomas of the lower lip. Braz Oral Res 30:e95PubMedCrossRefGoogle Scholar
  89. Lyons A, Jones J (2007) Cell adhesion molecules, the extracellular matrix and oral squamous carcinoma. Int J Oral Maxillofac Surg 36:671–679PubMedCrossRefGoogle Scholar
  90. Marcus B, Arenberg D, Lee J, Kleer C, Chepeha DB, Schmalbach CE et al (2004) Prognostic factors in oral cavity and oropharyngeal squamous cell carcinoma. Cancer 101:2779–2787PubMedCrossRefGoogle Scholar
  91. Marjanovic ND, Weinberg RA, Chaffer CL (2013) Cell plasticity and heterogeneity in cancer. Clin Chem 59:168–179PubMedCrossRefGoogle Scholar
  92. Markwell SM, Weed SA (2015) Tumor and stromal-based contributions to head and neck squamous cell carcinoma invasion. Cancers (Basel) 7:382–406CrossRefGoogle Scholar
  93. Marron M, Boffetta P, Zhang ZF, Zaridze D, Wünsch-Filho V, Winn DM et al (2010) Cessation of alcohol drinking, tobacco smoking and the reversal of head and neck cancer risk. Int J Epidemiol 39:182–196PubMedCrossRefGoogle Scholar
  94. Marsh D, Suchak K, Moutasim KA, Vallath S, Hopper C, Jerjes W et al (2011) Stromal features are predictive of disease mortality in oral cancer patients. J Pathol 223:470–481PubMedCrossRefGoogle Scholar
  95. Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 6:12703CrossRefGoogle Scholar
  96. Marusyk A, Almendro V, Polyak K (2012) Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer 12:323–334PubMedCrossRefGoogle Scholar
  97. McGranahan N, Swanton C (2017) Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168:613–628PubMedCrossRefGoogle Scholar
  98. Meacham CE, Morrison SJ (2013) Tumour heterogeneity and cancer cell plasticity. Nature 501:328–337PubMedPubMedCentralCrossRefGoogle Scholar
  99. Morrison SJ, Spradling AC (2008) Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132:598–611PubMedPubMedCentralCrossRefGoogle Scholar
  100. Mueller MM, Fusenig NE (2002) Tumor-stroma interactions directing phenotype and progression of epithelial skin tumor cells. Differentiation 70:486–497PubMedCrossRefGoogle Scholar
  101. Naik PP, Das DN, Panda PK, Mukhopadhyay S, Sinha N, Praharaj PP et al (2016) Implications of cancer stem cells in developing therapeutic resistance in oral cancer. Oral Oncol 62:122–135PubMedCrossRefGoogle Scholar
  102. Neiva KG, Zhang Z, Miyazawa M, Warner KA, Karl E, Nör JE (2009) Cross talk initiated by endothelial cells enhances migration and inhibits anoikis of squamous cell carcinoma cells through STAT3/Akt/ERK signaling. Neoplasia 11:583IN12–593IN14CrossRefGoogle Scholar
  103. Nör C, Zhang Z, Warner KA, Bernardi L, Visioli F, Helman JI et al (2014) Cisplatin induces Bmi-1 and enhances the stem cell fraction in head and neck cancer. Neoplasia 16:137–146PubMedPubMedCentralCrossRefGoogle Scholar
  104. Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194:23–28PubMedCrossRefGoogle Scholar
  105. Ogino T, Shigyo H, Ishii H, Katayama A, Miyokawa N, Harabuchi Y et al (2006) HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a poor prognostic marker. Cancer Res 66:9281–9289PubMedCrossRefGoogle Scholar
  106. Okubo M, Kioi M, Nakashima H, Sugiura K, Mitsudo K, Aoki I et al (2016) M2-polarized macrophages contribute to neovasculogenesis, leading to relapse of oral cancer following radiation. Sci Rep 6:27548PubMedPubMedCentralCrossRefGoogle Scholar
  107. Paget S (1889) The distribution of secondary growths in cancer of the breast. Lancet 133:571–573CrossRefGoogle Scholar
  108. Pavlides S, Tsirigos A, Migneco G, Whitaker-Menezes D, Chiavarina B, Flomenberg N et al (2010) The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism. Cell Cycle 9:3485–3505PubMedPubMedCentralCrossRefGoogle Scholar
  109. Pisco A, Huang S (2015) Non-genetic cancer cell plasticity and therapy-induced stemness in tumour relapse:‘what does not kill me strengthens me’. Br J Cancer 112:1725–1732PubMedPubMedCentralCrossRefGoogle Scholar
  110. Powell DW, Adegboyega PA, Di Mari JF, Mifflin RC (2005) Epithelial cells and their neighbors I. Role of intestinal myofibroblasts in development, repair, and cancer. Am J Physiol Gastrointest Liver Physiol 289:G2–G7PubMedCrossRefGoogle Scholar
  111. Prince M, Sivanandan R, Kaczorowski A, Wolf G, Kaplan M, Dalerba P et al (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A 104:973–978PubMedPubMedCentralCrossRefGoogle Scholar
  112. Punt S, Dronkers EA, Welters MJ, Goedemans R, Koljenović S, Bloemena E et al (2016) A beneficial tumor microenvironment in oropharyngeal squamous cell carcinoma is characterized by a high T cell and low IL-17+ cell frequency. Cancer Immunol Immunother 65:393–403PubMedPubMedCentralCrossRefGoogle Scholar
  113. Qing G, Simon MC (2009) Hypoxia inducible factor-2α: a critical mediator of aggressive tumor phenotypes. Curr Opin Genet Dev 19:60–66PubMedPubMedCentralCrossRefGoogle Scholar
  114. Quan H, Fang L, Pan H, Deng Z, Gao S, Liu O et al (2016) An adaptive immune response driven by mature, antigen-experienced T and B cells within the microenvironment of oral squamous cell carcinoma. Int J Cancer 138(12):2952–2962PubMedCrossRefGoogle Scholar
  115. Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ (2008) Efficient tumour formation by single human melanoma cells. Nature 456:593–598PubMedPubMedCentralCrossRefGoogle Scholar
  116. Raggi C, Mousa H, Correnti M, Sica A, Invernizzi P (2016) Cancer stem cells and tumor-associated macrophages: a roadmap for multitargeting strategies. Oncogene 35:671–682PubMedCrossRefGoogle Scholar
  117. Ramanathan S, Jagannathan N (2014) Tumor associated macrophage: a review on the phenotypes, traits and functions. Iran J Cancer Prev 7:1–8PubMedPubMedCentralGoogle Scholar
  118. Ramos DM, Chen BL, Boylen K, Stern M, Kramer RH, Sheppard D et al (1997) Stromal fibroblasts influence oral squamous-cell carcinoma cell interactions with tenascin-C. Int J Cancer 72:369–376PubMedCrossRefGoogle Scholar
  119. Rampias T, Boutati E, Pectasides E, Sasaki C, Kountourakis P, Weinberger P et al (2010) Activation of Wnt signaling pathway by human papillomavirus E6 and E7 oncogenes in HPV16-positive oropharyngeal squamous carcinoma cells. Mol Cancer Res 8:433–443PubMedCrossRefGoogle Scholar
  120. Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434:843–850PubMedCrossRefGoogle Scholar
  121. Roy A, Bera S (2016) CAF cellular glycolysis: linking cancer cells with the microenvironment. Tumor Biol 37:8503–8514CrossRefGoogle Scholar
  122. Senovilla L, Vacchelli E, Galon J, Adjemian S, Eggermont A, Fridman WH et al (2012) Trial watch: Prognostic and predictive value of the immune infiltrate in cancer. Oncoimmunology 1:1323–1343PubMedPubMedCentralCrossRefGoogle Scholar
  123. Shackleton M, Quintana E, Fearon ER, Morrison SJ (2009) Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138:822–829PubMedCrossRefGoogle Scholar
  124. Shieh YS, Hung YJ, Hsieh CB, Chen JS, Chou KC, Liu SY (2009) Tumor-associated macrophage correlated with angiogenesis and progression of mucoepidermoid carcinoma of salivary glands. Ann Surg Oncol 16:751–760PubMedCrossRefGoogle Scholar
  125. Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42:717–727PubMedCrossRefGoogle Scholar
  126. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828PubMedGoogle Scholar
  127. Sinha N, Mukhopadhyay S, Das DN, Panda PK, Bhutia SK (2013) Relevance of cancer initiating/stem cells in carcinogenesis and therapy resistance in oral cancer. Oral Oncol 49:854–862PubMedCrossRefGoogle Scholar
  128. Sobral LM, Bufalino A, Lopes MA, Graner E, Salo T, Coletta RD (2011) Myofibroblasts in the stroma of oral cancer promote tumorigenesis via secretion of activin A. Oral Oncol 47:840–846PubMedCrossRefGoogle Scholar
  129. Sottoriva A, Spiteri I, Piccirillo SG, Touloumis A, Collins VP, Marioni JC et al (2013) Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci U S A 110:4009–4014PubMedPubMedCentralCrossRefGoogle Scholar
  130. Sparmann A, Bar-Sagi D (2004) Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6:447–458PubMedCrossRefGoogle Scholar
  131. Takahashi H, Sakakura K, Kawabata-Iwakawa R, Rokudai S, Toyoda M, Nishiyama M et al (2015) Immunosuppressive activity of cancer-associated fibroblasts in head and neck squamous cell carcinoma. Cancer Immunol Immunother 64(11):1–11CrossRefGoogle Scholar
  132. Takiar R, Nadayil D, Nandakumar A (2010) Projections of number of cancer cases in India (2010-2020) by cancer groups. Asian Pac J Cancer Prev 11:1045–1049PubMedGoogle Scholar
  133. Tlsty TD, Coussens LM (2006) Tumor stroma and regulation of cancer development. Annu Rev Pathol 1:119–150PubMedCrossRefGoogle Scholar
  134. Tourkova IL, Shurin GV, Chatta GS, Perez L, Finke J, Whiteside TL et al (2005) Restoration by IL-15 of MHC class I antigen-processing machinery in human dendritic cells inhibited by tumor-derived gangliosides. J Immunol 175:3045–3052PubMedCrossRefGoogle Scholar
  135. Uchida D, Kuribayashi N, Kinouchi M, Ohe G, Tamatani T, Nagai H et al (2013) Expression and function of CXCR4 in human salivary gland cancers. Clin Exp Metastasis 30:133–142PubMedCrossRefGoogle Scholar
  136. Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239PubMedCrossRefGoogle Scholar
  137. Vered M, Dayan D, Yahalom R, Dobriyan A, Barshack I, Bello IO et al (2010) Cancer-associated fibroblasts and epithelial-mesenchymal transition in metastatic oral tongue squamous cell carcinoma. Int J Cancer 127:1356–1362PubMedCrossRefGoogle Scholar
  138. Vigneswaran N, Wu J, Song A, Annapragada A, Zacharias W (2011) Hypoxia-induced autophagic response is associated with aggressive phenotype and elevated incidence of metastasis in orthotopic immunocompetent murine models of head and neck squamous cell carcinomas (HNSCC). Exp Mol Pathol 90:215–225PubMedPubMedCentralCrossRefGoogle Scholar
  139. Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8:755–768PubMedCrossRefGoogle Scholar
  140. Wang M, Li X, Lu X, Qu Y, Xu O, Sun Q (2011) Cancer stem cells promotes resistance of laryngeal squamous cancer to irradiation mediated by hypoxia. Lin chuang er bi yan hou tou jing wai ke za zhi. J Clin Otorhinolaryngol Head Neck Surg 25:823–826Google Scholar
  141. Wang SJ, Earle C, Wong G, Bourguignon LY (2013) Role of hyaluronan synthase 2 to promote CD44-dependent oral cavity squamous cell carcinoma progression. Head Neck 35:511–520PubMedCrossRefGoogle Scholar
  142. Wang TY, Peng CY, Lee SS, Chou MY, Yu CC, Chang YC (2016) Acquisition cancer stemness, mesenchymal transdifferentiation, and chemoresistance properties by chronic exposure of oral epithelial cells to arecoline. Oncotarget 7:84072–84081PubMedPubMedCentralGoogle Scholar
  143. Westermarck J, Li S, Jaakkola P, Kallunki T, Grénman R, Kähäri VM (2000) Activation of fibroblast collagenase-1 expression by tumor cells of squamous cell carcinomas is mediated by p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase-2. Cancer Res 60:7156–7162PubMedGoogle Scholar
  144. Whiteside TL (2006a) The role of immune cells in the tumor microenvironment. In: The link between inflammation and cancer. Springer, Boston, pp 103–124CrossRefGoogle Scholar
  145. Whiteside TL (2006b) Immune suppression in cancer: effects on immune cells, mechanisms and future therapeutic intervention. Semin Cancer Biol 16:3–15PubMedCrossRefGoogle Scholar
  146. Winquist RJ, Boucher DM, Wood M, Furey BF (2009) Targeting cancer stem cells for more effective therapies: Taking out cancer’s locomotive engine. Biochem Pharmacol 78:326–334PubMedCrossRefGoogle Scholar
  147. Wu CP, Du HD, Gong HL, Li DW, Tao L, Tian J et al (2014) Hypoxia promotes stem-like properties of laryngeal cancer cell lines by increasing the CD133+ stem cell fraction. Int J Oncol 44:1652–1660PubMedCrossRefGoogle Scholar
  148. Xie T, Li L (2007) Stem cells and their niche: an inseparable relationship. Development 134:2001–2006PubMedCrossRefGoogle Scholar
  149. Yang CC, Zhu LF, Xu XH, Ning TY, Ye JH, Liu LK (2013) Membrane Type 1 Matrix Metalloproteinase induces an epithelial to mesenchymal transition and cancer stem cell-like properties in SCC9 cells. BMC Cancer 13:171PubMedPubMedCentralCrossRefGoogle Scholar
  150. Ye X, Zhang J, Lu R, Zhou G (2016) Signal regulatory protein alpha associated with the progression of oral leukoplakia and oral squamous cell carcinoma regulates phenotype switch of macrophages. Oncotarget 7:81305–81321PubMedPubMedCentralGoogle Scholar
  151. Young MRI (2006) Protective mechanisms of head and neck squamous cell carcinomas from immune assault. Head Neck 28:462–470PubMedCrossRefGoogle Scholar
  152. Yun CO (2008) Overcoming the extracellular matrix barrier to improve intratumoral spread and therapeutic potential of oncolytic virotherapy. Curr Opin Mol Ther 10:356–361PubMedGoogle Scholar
  153. Zamarron BF, Chen W (2011) Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci 7:651–658PubMedPubMedCentralCrossRefGoogle Scholar
  154. Zeng Q, Li S, Chepeha DB, Giordano TJ, Li J, Zhang H et al (2005) Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell 8:13–23PubMedCrossRefGoogle Scholar
  155. Zhang Z, Sant’Ana Filho M, Nör JE (2012) The biology of head and neck cancer stem cells. Oral Oncol 48:1–9PubMedCrossRefGoogle Scholar
  156. Zhang H, Wu H, Zheng J, Yu P, Xu L, Jiang P et al (2013) Transforming growth factor β1 signal is crucial for dedifferentiation of cancer cells to cancer stem cells in osteosarcoma. Stem Cells 31:433–446PubMedCrossRefGoogle Scholar
  157. Zhou BB, Zhang H, Damelin M, Geles KG, Grindley JC, Dirks PB (2009) Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov 8:806–823PubMedCrossRefGoogle Scholar
  158. Ziober AF, Falls EM, Ziober BL (2006) The extracellular matrix in oral squamous cell carcinoma: friend or foe? Head Neck 28:740–749PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Prajna Paramita Naik
    • 1
  • Prashanta Kumar Panda
    • 1
  • Sujit K. Bhutia
    • 1
    Email author
  1. 1.Department of Life ScienceNational Institute of TechnologyRourkelaIndia

Personalised recommendations