Skip to main content

Targeting the Tumor Environment in Squamous Cell Carcinoma of the Head and Neck

Opinion statement

The survival rate for patients with advanced stages of squamous cell carcinoma of the head and neck (SCCHN) remains poor despite multimodal treatment options. Cetuximab, an anti-EGFR inhibitor, is the only FDA-approved targeted agent for this disease. Recent findings have implicated modifications of the microenvironment and, consequently, phenotypical modifications of the cancer cell, in treatment resistance mechanisms. For many years, cancer research has focused mainly on targetable sites on or inside the cancer cell. Nowadays, in preclinical and clinical studies, a greater emphasis is being placed on drugs that target the tumor microenvironment. Potential targets relate to tumor vascularization, immunology, extracellular matrix components, or cancer-associated fibroblasts. The combination of these new agents with standard treatment options is of particular interest to overcome resistance mechanisms and/or to increase treatment efficacy. Whereas antiangiogenic agents show poor clinical activity, immunotherapy seems to be a more promising tool with an objective response rate (ORR) of 20 % in patients with recurrent and/or metastatic squamous cell carcinoma (R/M SCC). Other targets, located inside the extracellular matrix or on cancer associated fibroblasts, are under preclinical investigation. These new agents all need to be tested in clinical trials alone, or in combination with standard treatment modalities, based on preclinical data. To increase our knowledge of the complex network between the cancer cell and its environment, preclinical studies should consider co-culture models, and clinical studies should incorporate a translational research objective.

This is a preview of subscription content, access via your institution.

Fig. 1

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Gillison ML, Restighini C. Anticipation of the impact of human papillomavirus on clinical decision making for the head and neck cancer patient. Hematol Oncol Clin North Am. 2015;29:1045–60.

    Article  PubMed  Google Scholar 

  2. Gregoire V, Lefebvre JL, Licitra L, Felip E, Group E-E-EGW. Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21 Suppl 5:v184–6.

    Article  PubMed  Google Scholar 

  3. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10.

    Article  PubMed  Google Scholar 

  4. Ferris RL. Immunology and immunotherapy of head and neck cancer. J Clin Oncol. 2015;33:3293–304.

    Article  PubMed  Google Scholar 

  5. Siveen KS, Kuttan G. Role of macrophages in tumour progression. Immunol Lett. 2009;123:97–102.

    CAS  Article  PubMed  Google Scholar 

  6. Leef G, Thomas SM. Molecular communication between tumor-associated fibroblasts and head and neck squamous cell carcinoma. Oral Oncol. 2013;49:381–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Malm IJ, Bruno TC, Fu J, Zeng Q, Taube JM, Westra W, et al. Expression profile and in vitro blockade of programmed death-1 in human papillomavirus-negative head and neck squamous cell carcinoma. Head Neck. 2015;37:1088–95. Translational study which supports the use of PD-1 blockade in HPV- SCCHN based on characterization of the expression profile of PD-1/PD-L1.

    Article  PubMed  Google Scholar 

  8. Seiwert T, Haddad RI, Gupta S, Mehra R, Tahara M, Berger R, et al. Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort. J Clin Oncol. 2015;33. First clinical trial reporting clinical benefits of immunotherapy in SCCHN.

  9. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14:847–56. Article which discussed the necessity and the difficulty to find valid biomarkers for immunotherapy.

    CAS  Article  PubMed  Google Scholar 

  10. Mendes F, Domingues C, Rodrigues-Santos P, Abrantes AM, Goncalves AC, Estrela J, et al. The role of immune system exhaustion on cancer cell escape and anti-tumor immune induction after irradiation. Biochim Biophys Acta. 1865;2016:168–75. This article gives several arguments to test immunotherapy in combination with radiotherapy.

    Google Scholar 

  11. Verbrugge I, Hagekyriakou J, Sharp LL, Galli M, West A, McLaughlin NM, et al. Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies. Cancer Res. 2012;72:3163–74.

    CAS  Article  PubMed  Google Scholar 

  12. Simone 2nd CB, Burri SH, Heinzerling JH. Novel radiotherapy approaches for lung cancer: combining radiation therapy with targeted and immunotherapies. Transl Lung Cancer Res. 2015;4:545–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Schoenfeld JD, Mahadevan A, Floyd SR, Dyer MA, Catalano PJ, Alexander BM, et al. Ipilmumab and cranial radiation in metastatic melanoma patients: a case series and review. J Immunother Cancer. 2015;3:50.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Jure-Kunkel M, Masters G, Girit E, Dito G, Lee F, Hunt JT, et al. Synergy between chemotherapeutic agents and CTLA-4 blockade in preclinical tumor models. Cancer Immunol Immunother. 2013;62:1533–45.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Machiels JP, Schmitz S. Epidermal growth factor receptor inhibition in squamous cell carcinoma of the head and neck. Hematol Oncol Clin North Am. 2015;29:1011–32. Review about the only FDA approved targeted agent in SCCHN.

    Article  PubMed  Google Scholar 

  16. Gerlowski LE, Jain RK. Microvascular permeability of normal and neoplastic tissues. Microvasc Res. 1986;31:288–305.

    CAS  Article  PubMed  Google Scholar 

  17. Palazon A, Aragones J, Morales-Kastresana A, de Landazuri MO, Melero I. Molecular pathways: hypoxia response in immune cells fighting or promoting cancer. Clin Cancer Res. 2012;18:1207–13.

    CAS  Article  PubMed  Google Scholar 

  18. Overgaard J. Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck—a systematic review and meta-analysis. Radiother Oncol. 2011;100:22–32.

    Article  PubMed  Google Scholar 

  19. Toustrup K, Sorensen BS, Alsner J, Overgaard J. Hypoxia gene expression signatures as prognostic and predictive markers in head and neck radiotherapy. Semin Radiat Oncol. 2012;22:119–27. Overview of the hypoxic issue in radiotherapy and presentation of a predictive hypoxia gene signature which is currently tested in a large EORTC clinical trial.

  20. Jain RK, Tong RT, Munn LL. Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. Cancer Res. 2007;67:2729–35.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001;7:987–9.

    CAS  Article  PubMed  Google Scholar 

  22. Matsumoto S, Saito K, Takakusagi Y, Matsuo M, Munasinghe JP, Morris HD, et al. In vivo imaging of tumor physiological, metabolic, and redox changes in response to the anti-angiogenic agent sunitinib: longitudinal assessment to identify transient vascular renormalization. Antioxid Redox Signal. 2014;21:1145–55.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Machiels JP, Henry S, Zanetta S, Kaminsky MC, Michoux N, Rommel D, et al. Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: GORTEC 2006-01. J Clin Oncol. 2010;28:21–8.

    CAS  Article  PubMed  Google Scholar 

  24. Fountzilas G, Fragkoulidi A, Kalogera-Fountzila A, Nikolaidou M, Bobos M, Calderaro J, et al. A phase II study of sunitinib in patients with recurrent and/or metastatic non-nasopharyngeal head and neck cancer. Cancer Chemother Pharmacol. 2010;65:649–60.

    CAS  Article  PubMed  Google Scholar 

  25. Choong NW, Kozloff M, Taber D, Hu HS, Wade 3rd J, Ivy P, et al. Phase II study of sunitinib malate in head and neck squamous cell carcinoma. Invest New Drugs. 2010;28:677–83.

  26. Williamson SK, Moon J, Huang CH, Guaglianone PP, LeBlanc M, Wolf GT, et al. Phase II evaluation of sorafenib in advanced and metastatic squamous cell carcinoma of the head and neck: Southwest Oncology Group Study S0420. J Clin Oncol. 2010;28:3330–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Harari PM, Khuntia D, Traynor AM. Phase I trial of bevacizumab combined with concurrent chemoradiation for squamous cell carcinoma of the head and neck: Preliminary outcome results. J Clin Oncol. 2011;29:abst 5518.

  28. Fury MG, Lee NY, Sherman E, Lisa D, Kelly K, Lipson B, et al. A phase 2 study of bevacizumab with cisplatin plus intensity-modulated radiation therapy for stage III/IVB head and neck squamous cell cancer. Cancer. 2012;118:5008–14.

  29. Argiris A, Kotsakis AP, Hoang T, Worden FP, Savvides P, Gibson MK, et al. Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck. Ann Oncol. 2013;24:220–5.

  30. Argiris A, Li S, Savvides P, Forastière AA, Burtness B. Safety analysis of a phase III randomized trial of chemotherapy with or without bevacizumab (B) in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). J Clin Oncol. 2015;33.

  31. Blumenschein GR, Glisson BS, Lu C. Final results of a phase II study of sorafenib in combination with carboplatin and paclitaxel in patients with metastatic or recurrent squamous cell cancer of the head and neck (SCCHN). J Clin Oncol. 2012;30:abst 5592.

  32. Sano D, Matsumoto F, Valdecanas DR, Zhao M, Molkentine DP, Takahashi Y, et al. Vandetanib restores head and neck squamous cell carcinoma cells’ sensitivity to cisplatin and radiation in vivo and in vitro. Clin Cancer Res. 2011;17:1815–27.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Papadimitrakopoulou VA, Frank SJ, Cohen EW, Hirsch FR, Myers JN, Heymach JV, et al. Phase I study of vandetanib with radiation therapy with or without cisplatin in locally advanced head and neck squamous cell carcinoma. Head Neck. 2016;38:439–47.

  34. Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 2002;110:673–87.

    CAS  Article  PubMed  Google Scholar 

  35. Mantoni TS, Lunardi S, Al-Assar O, Masamune A, Brunner TB. Pancreatic stellate cells radioprotect pancreatic cancer cells through beta1-integrin signaling. Cancer Res. 2011;71:3453–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Samuel MS, Lopez JI, McGhee EJ, Croft DR, Strachan D, Timpson P, et al. Actomyosin-mediated cellular tension drives increased tissue stiffness and beta-catenin activation to induce epidermal hyperplasia and tumor growth. Cancer Cell. 2011;19:776–91.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Sun CC, Qu XJ, Gao ZH. Integrins: players in cancer progression and targets in cancer therapy. Anticancer Drugs. 2014;25:1107–21.

    CAS  Article  PubMed  Google Scholar 

  38. Seguin L, Desgrosellier JS, Weis SM, Cheresh DA. Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol. 2015;25:234–40.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Aoudjit F, Vuori K. Integrin signaling in cancer cell survival and chemoresistance. Chemother Res Pract. 2012;2012:283181.

    PubMed  PubMed Central  Google Scholar 

  40. Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K, et al. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol. 2007;9:1392–400.

    CAS  Article  PubMed  Google Scholar 

  41. Valiathan RR, Marco M, Leitinger B, Kleer CG, Fridman R. Discoidin domain receptor tyrosine kinases: new players in cancer progression. Cancer Metastasis Rev. 2012;31:295–321.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Hedberg ML, Goh G, Chiosea SI, Bauman JE, Freilino ML, Zeng Y, et al. Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma. J Clin Invest. 2016;126:169–80. First clinical trial testing the genetic landscape in metastatic and recurrent SCCHN, showing new interesting targets different from primary SCCHN.

    Article  PubMed  Google Scholar 

  43. Hammerman PS, Sos ML, Ramos AH, Xu C, Dutt A, Zhou W, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov. 2011;1:78–89.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Raju U, Riesterer O, Wang ZQ, Molkentine DP, Molkentine JM, Johnson FM, et al. Dasatinib, a multi-kinase inhibitor increased radiation sensitivity by interfering with nuclear localization of epidermal growth factor receptor and by blocking DNA repair pathways. Radiother Oncol. 2012;105:241–9.

    CAS  Article  PubMed  Google Scholar 

  45. Brooks HD, Glisson BS, Bekele BN, Johnson FM, Ginsberg LE, El-Naggar A, et al. Phase 2 study of dasatinib in the treatment of head and neck squamous cell carcinoma. Cancer. 2011;117:2112–9.

  46. Afratis N, Gialeli C, Nikitovic D, Tsegenidis T, Karousou E, Theocharis AD, et al. Glycosaminoglycans: key players in cancer cell biology and treatment. FEBS J. 2012;279:1177–97.

    CAS  Article  PubMed  Google Scholar 

  47. Theocharis AD, Skandalis SS, Tzanakakis GN, Karamanos NK. Proteoglycans in health and disease: novel roles for proteoglycans in malignancy and their pharmacological targeting. FEBS J. 2010;277:3904–23.

    CAS  Article  PubMed  Google Scholar 

  48. Vynios DH, Theocharis DA, Papageorgakopoulou N, Papadas TA, Mastronikolis NS, Goumas PD, et al. Biochemical changes of extracellular proteoglycans in squamous cell laryngeal carcinoma. Connect Tissue Res. 2008;49:239–43.

    CAS  Article  PubMed  Google Scholar 

  49. Stylianou M, Skandalis SS, Papadas TA, Mastronikolis NS, Theocharis DA, Papageorgakopoulou N, et al. Stage-related decorin and versican expression in human laryngeal cancer. Anticancer Res. 2008;28:245–51.

    CAS  PubMed  Google Scholar 

  50. Pukkila M, Kosunen A, Ropponen K, Virtaniemi J, Kellokoski J, Kumpulainen E, et al. High stromal versican expression predicts unfavourable outcome in oral squamous cell carcinoma. J Clin Pathol. 2007;60:267–72.

    Article  PubMed  Google Scholar 

  51. Arichi N, Mitsui Y, Hiraki M, Nakamura S, Hiraoka T, Sumura M, et al. Versican is a potential therapeutic target in docetaxel-resistant prostate cancer. Oncoscience. 2015;2:193–204.

  52. Wang Z, Li Z, Wang Y, Cao D, Wang X, Jiang M, et al. Versican silencing improves the antitumor efficacy of endostatin by alleviating its induced inflammatory and immunosuppressive changes in the tumor microenvironment. Oncol Rep. 2015;33:2981–91. Preclinical research on versican, underlining the important role which plays this proteoglycan in the tumor environment and supporting association between antiangiogenic therapies and versican inhibitors.

    PubMed  Google Scholar 

  53. Merline R, Moreth K, Beckmann J, Nastase MV, Zeng-Brouwers J, Tralhao JG, et al. Signaling by the matrix proteoglycan decorin controls inflammation and cancer through PDCD4 and MicroRNA-21. Sci Signal. 2011;4:ra75.

    Article  PubMed  Google Scholar 

  54. Bi XL, Yang W. Biological functions of decorin in cancer. Chin J Cancer. 2013;32:266–9.

  55. Sofeu Feugaing DD, Gotte M, Viola M. More than matrix: the multifaceted role of decorin in cancer. Eur J Cell Biol. 2013;92:1–11.

    CAS  Article  PubMed  Google Scholar 

  56. Dil N, Banerjee AG. Knockdown of aberrantly expressed nuclear localized decorin attenuates tumour angiogenesis related mediators in oral cancer progression model in vitro. Head Neck Oncol. 2012;4:11.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Kasamatsu A, Uzawa K, Minakawa Y, Ishige S, Kasama H, Endo-Sakamoto Y, et al. Decorin in human oral cancer: a promising predictive biomarker of S-1 neoadjuvant chemosensitivity. Biochem Biophys Res Commun. 2015;457:71–6. Preclinical study which determines decorin as a key regulator of chemoresistance in oral SCC.

    CAS  Article  PubMed  Google Scholar 

  58. Xian X, Gopal S, Couchman JR. Syndecans as receptors and organizers of the extracellular matrix. Cell Tissue Res. 2010;339:31–46.

    CAS  Article  PubMed  Google Scholar 

  59. Vihinen P, Ala-aho R, Kahari VM. Matrix metalloproteinases as therapeutic targets in cancer. Curr Cancer Drug Targets. 2005;5:203–20.

    CAS  Article  PubMed  Google Scholar 

  60. Burduk PK, Bodnar M, Sawicki P, Szylberg L, Wisniewska E, Kazmierczak W, et al. Expression of metalloproteinases 2 and 9 and tissue inhibitors 1 and 2 as predictors of lymph node metastases in oropharyngeal squamous cell carcinoma. Head Neck. 2015;37:418–22. Clinical study suggesting the major role of environment changes in tumor progression of SCCHN.

    Article  PubMed  Google Scholar 

  61. Ma J, Wang J, Fan W, Pu X, Zhang D, Fan C, et al. Upregulated TIMP-1 correlates with poor prognosis of laryngeal squamous cell carcinoma. Int J Clin Exp Pathol. 2014;7:246–54.

    PubMed  Google Scholar 

  62. Nanda DP, Dutta K, Ganguly KK, Hajra S, Mandal SS, Biswas J, et al. MMP-9 as a potential biomarker for carcinoma of oral cavity: a study in eastern India. Neoplasma. 2014;61:747–57.

    CAS  Article  PubMed  Google Scholar 

  63. Boeckx C, Blockx L, de Beeck KO, Limame R, Camp GV, Peeters M, et al. Establishment and characterization of cetuximab resistant head and neck squamous cell carcinoma cell lines: focus on the contribution of the AP-1 transcription factor. Am J Cancer Res. 2015;5:1921–38. Preclinical study investigating cetuximab resistance in SCCHN cell lines by gene expression profiling. Beside several upregulated genes related to tumor environment, EMT was also observed in Cetuximab resistant cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Johansson AC, Ansell A, Jerhammar F, Lindh MB, Grenman R, Munck-Wikland E, et al. Cancer-associated fibroblasts induce matrix metalloproteinase-mediated cetuximab resistance in head and neck squamous cell carcinoma cells. Mol Cancer Res. 2012;10:1158–68. Preclinical study identifying CAFs and MMPs as potential sources of cetuximab resistance.

    CAS  Article  PubMed  Google Scholar 

  65. Vandenbroucke RE, Libert C. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat Rev Drug Discov. 2014;13:904–27.

    CAS  Article  PubMed  Google Scholar 

  66. Eustace BK, Jay DG. Extracellular roles for the molecular chaperone, hsp90. Cell Cycle. 2004;3:1098–100.

    CAS  Article  PubMed  Google Scholar 

  67. Stellas D, El Hamidieh A, Patsavoudi E. Monoclonal antibody 4C5 prevents activation of MMP2 and MMP9 by disrupting their interaction with extracellular HSP90 and inhibits formation of metastatic breast cancer cell deposits. BMC Cell Biol. 2010;11:51.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Hunter MC, O’Hagan KL, Kenyon A, Dhanani KC, Prinsloo E, Edkins AL. Hsp90 binds directly to fibronectin (FN) and inhibition reduces the extracellular fibronectin matrix in breast cancer cells. PLoS One. 2014;9:e86842.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Spiegelberg D, Dascalu A, Mortensen AC, Abramenkovs A, Kuku G, Nestor M, et al. The novel HSP90 inhibitor AT13387 potentiates radiation effects in squamous cell carcinoma and adenocarcinoma cells. Oncotarget. 2015;6:35652–66. Preclinical study showing the benefit and potential mechanisms of HSP90 inhibition in squamous cell carcinoma to overcome radioresistance.

    PubMed  PubMed Central  Google Scholar 

  70. Patel K, Wen J, Magliocca K, Muller S, Liu Y, Chen ZG, et al. Heat shock protein 90 (HSP90) is overexpressed in p16-negative oropharyngeal squamous cell carcinoma, and its inhibition in vitro potentiates the effects of chemoradiation. Cancer Chemother Pharmacol. 2014;74:1015–22.

  71. De Boeck A, Narine K, De Neve W, Mareel M, Bracke M, De Wever O. Resident and bone marrow-derived mesenchymal stem cells in head and neck squamous cell carcinoma. Oral Oncol. 2010;46:336–42.

    Article  PubMed  Google Scholar 

  72. Erez N, Truitt M, Olson P, Arron ST, Hanahan D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell. 2010;17:135–47.

    CAS  Article  PubMed  Google Scholar 

  73. Kojima Y, Acar A, Eaton EN, Mellody KT, Scheel C, Ben-Porath I, et?al. Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci U S A. 2010;107:20009–14.

  74. Ishikawa T, Nakashiro K, Klosek SK, Goda H, Hara S, Uchida D, et?al. Hypoxia enhances CXCR4 expression by activating HIF-1 in oral squamous cell carcinoma. Oncol Rep. 2009;21:707–12.

  75. Orimo A, Weinberg RA. Heterogeneity of stromal fibroblasts in tumors. Cancer Biol Ther. 2007;6:618–9.

    CAS  Article  PubMed  Google Scholar 

  76. Sugimoto H, Mundel TM, Kieran MW, Kalluri R. Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol Ther. 2006;5:1640–6.

    CAS  Article  PubMed  Google Scholar 

  77. De Wever O, Nguyen QD, Van Hoorde L, Bracke M, Bruyneel E, Gespach C, et?al. Tenascin-C and SF/HGF produced by myofibroblasts in?vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. FASEB J. 2004;18:1016–8.

  78. Kikuchi Y, Kashima TG, Nishiyama T, Shimazu K, Morishita Y, Shimazaki M, et?al. Periostin is expressed in pericryptal fibroblasts and cancer-associated fibroblasts in the colon. J Histochem Cytochem. 2008;56:753–64.

  79. Pietras K, Sjoblom T, Rubin K, Heldin CH, Ostman A. PDGF receptors as cancer drug targets. Cancer Cell. 2003;3:439–43.

    CAS  Article  PubMed  Google Scholar 

  80. Li M, Li M, Yin T, Shi H, Wen Y, Zhang B, et al. Targeting of cancer associated fibroblasts enhances the efficacy of cancer chemotherapy by regulating the tumor microenvironment. Mol Med Rep. 2016.

  81. Wheeler SE, Shi H, Lin F, Dasari S, Bednash J, Thorne S, et al. Enhancement of head and neck squamous cell carcinoma proliferation, invasion, and metastasis by tumor-associated fibroblasts in preclinical models. Head Neck. 2014;36:385–92. Preclinical study showing the major role of CAFs in tumor growth and metastasis in SCCHN. CAFs were isolated from patients with SCCHN.

  82. Qin X, Yan M, Zhang J, Wang X, Shen Z, Lv Z, et?al. TGFbeta3-mediated induction of periostin facilitates head and neck cancer growth and is associated with metastasis. Sci Rep. 2016;6:20587.

  83. Zhu M, Saxton RE, Ramos L, Chang DD, Karlan BY, Gasson JC, et al. Neutralizing monoclonal antibody to periostin inhibits ovarian tumor growth and metastasis. Mol Cancer Ther. 2011;10:1500–8.

  84. Kyutoku M, Taniyama Y, Katsuragi N, Shimizu H, Kunugiza Y, Iekushi K, et al. Role of periostin in cancer progression and metastasis: inhibition of breast cancer progression and metastasis by anti-periostin antibody in a murine model. Int J Mol Med. 2011;28:181–6.

  85. Teichgraber V, Monasterio C, Chaitanya K, Boger R, Gordon K, Dieterle T, et al. Specific inhibition of fibroblast activation protein (FAP)-alpha prevents tumor progression in vitro. Adv Med Sci. 2015;60:264–72. The study shows that inhibition of FAP, a well known marker for CAFs, suppresses pro-tumorigenic activities in epithelial tumor cells.

    Article  PubMed  Google Scholar 

  86. Albrengues J, Bertero T, Grasset E, Bonan S, Maiel M, Bourget I, et al. Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts. Nat Commun. 2015;6:10204.

  87. Kumar D, Kandl C, Hamilton CD, Shnayder Y, Tsue TT, Kakarala K, et al. Mitigation of tumor-associated fibroblast-facilitated head and neck cancer progression with anti-hepatocyte growth factor antibody ficlatuzumab. JAMA Otolaryngol Head Neck Surg. 2015;141:1133–9. Preclinical investigation of CAF secreted HGF. Inhibition with ficlatuzumab shows stromal influences on SCCHN progression.

    Article  PubMed  Google Scholar 

  88. Steinbichler TB, Metzler V, Pritz C, Riechelmann H, Dudas J. Tumor-associated fibroblast-conditioned medium induces CDDP resistance in HNSCC cells. Oncotarget. 2015. This study underlines the interest of co-cultures in preclinical investigations. Medium coming from co-cultures was able to induce EMT in SCCHN cells and increases chemoresistance.

  89. Zhou B, Chen WL, Wang YY, Lin ZY, Zhang DM, Fan S, et al. A role for cancer-associated fibroblasts in inducing the epithelial-to-mesenchymal transition in human tongue squamous cell carcinoma. J Oral Pathol Med. 2014;43:585–92.

  90. Schmitz S, Bindea G, Albu RI, Mlecnik B, Machiels JP. Cetuximab promotes epithelial to mesenchymal transition and cancer associated fibroblasts in patients with head and neck cancer. Oncotarget. 2015;6:34288–99. First clinical study demonstrating EMT and CAF in patients treated by cetuximab in a window of opportunity study.

    PubMed  PubMed Central  Google Scholar 

  91. Oliveira-Neto HH, Silva ET, Leles CR, Mendonca EF, Alencar Rde C, Silva TA, et al. Involvement of CXCL12 and CXCR4 in lymph node metastases and development of oral squamous cell carcinomas. Tumour Biol. 2008;29:262–71.

  92. Albert S, Riveiro ME, Halimi C, Hourseau M, Couvelard A, Serova M, et?al. Focus on the role of the CXCL12/CXCR4 chemokine axis in head and neck squamous cell carcinoma. Head Neck. 2013;35:1819–28.

  93. Albert S, Hourseau M, Halimi C, Serova M, Descatoire V, Barry B, et al. Prognostic value of the chemokine receptor CXCR4 and epithelial-to-mesenchymal transition in patients with squamous cell carcinoma of the mobile tongue. Oral Oncol. 2012;48:1263–71. Clinical translational study suggesting that CXCR4 is a marker of tumor aggressiveness in patients with oral SCCHN. Vimentin is also considered as an independent prognostic factor of poor survival.

  94. Yu T, Wu Y, Huang Y, Yan C, Liu Y, Wang Z, et al. RNAi targeting CXCR4 inhibits tumor growth through inducing cell cycle arrest and apoptosis. Mol Ther. 2012;20:398–407.

    CAS  Article  PubMed  Google Scholar 

  95. Koontongkaew S, Amornphimoltham P, Monthanpisut P, Saensuk T, Leelakriangsak M. Fibroblasts and extracellular matrix differently modulate MMP activation by primary and metastatic head and neck cancer cells. Med Oncol. 2012;29:690–703.

    CAS  Article  PubMed  Google Scholar 

  96. Onoue T, Uchida D, Begum NM, Tomizuka Y, Yoshida H, Sato M. Epithelial-mesenchymal transition induced by the stromal cell-derived factor-1/CXCR4 system in oral squamous cell carcinoma cells. Int J Oncol. 2006;29:1133–8.

    CAS  PubMed  Google Scholar 

  97. Yoon Y, Liang Z, Zhang X, Choe M, Zhu A, Cho HT, et al. CXC chemokine receptor-4 antagonist blocks both growth of primary tumor and metastasis of head and neck cancer in xenograft mouse models. Cancer Res. 2007;67:7518–24.

    CAS  Article  PubMed  Google Scholar 

  98. Liang Z, Brooks J, Willard M, Liang K, Yoon Y, Kang S, et?al. CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway. Biochem Biophys Res Commun. 2007;359:716–22.

  99. Tan CT, Chu CY, Lu YC, Chang CC, Lin BR, Wu HH, et al. CXCL12/CXCR4 promotes laryngeal and hypopharyngeal squamous cell carcinoma metastasis through MMP-13-dependent invasion via the ERK1/2/AP-1 pathway. Carcinogenesis. 2008;29:1519–27.

    CAS  Article  PubMed  Google Scholar 

  100. Azad BB, Chatterjee S, Lesniak WG, Lisok A, Pullambhatla M, Bhujwalla ZM, et al. A fully human CXCR4 antibody demonstrates diagnostic utility and therapeutic efficacy in solid tumor xenografts. Oncotarget. 2016.

Download references

Acknowledgments

The authors wish to thank Aileen Eiszele for writing assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sandra Schmitz MD, PhD.

Ethics declarations

Conflict of interest

Sandra Schmitz and Jean-Pascal Machiels declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human and animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Head and Neck Cancer

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schmitz, S., Machiels, JP. Targeting the Tumor Environment in Squamous Cell Carcinoma of the Head and Neck. Curr. Treat. Options in Oncol. 17, 37 (2016). https://doi.org/10.1007/s11864-016-0412-6

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-016-0412-6

Keywords

  • Squamous cell carcinoma
  • Head and neck cancer
  • Angiogenesis
  • Immunology
  • New treatment options
  • Extracellular matrix
  • Cancer associated fibroblasts
  • Preclinical data
  • Clinical data