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Präklinische Modelle für Kopf-Hals-Tumoren

Aufklärung zellulärer und molekularer Resistenzmechanismen im Gewebekontext

Preclinical models in head and neck tumors

Evaluation of cellular and molecular resistance mechanisms in the tumor microenvironment

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Zusammenfassung

Da Plattenepithelkarzinome im Kopf-Hals-Bereich („head and neck squamous cell carcinoma“, HNSCC) durch ausgeprägte inter- und intratumorigene Heterogenität charakterisiert sind, variieren sie im Ansprechen auf etablierte Therapieschemata oft erheblich. Darüber hinaus drängt derzeit eine Vielzahl zielgerichteter Therapeutika auf den Markt, die eine effizientere und weniger toxische Behandlung von HNSCC-Patienten ermöglichen sollen. Es besteht daher dringender Bedarf an geeigneten Modellsystemen, um sowohl das individuelle Ansprechen auf die avisierten Therapieregime mit Bestrahlung, Zytostatika und zielgerichteten Therapeutika vorab zu prüfen als auch um die Effektivität neuer Medikamente zu testen. Dabei sollte der pathophysiologische Gewebekontext der Tumorzellen erhalten bleiben, denn direkte und parakrine Interaktionen zwischen Tumorzellen und stromalen Zellen können das Therapieansprechen beeinflussen. In der Vergangenheit wurden komplexere Modellsysteme für die individualisierte Sensitivitätstestung auf Therapeutika etabliert. Sie gelten als viel versprechende Werkzeuge auf dem Weg zur personalisierten Krebstherapie. Der Übersichtsartikel stellt verschiedene Techniken vor, wie 3‑D-organotypische Modelle, patientenabgeleitete Xenograftmodelle (PDX), organotypische multizelluläre Sphäroide und Ex-vivo-Gewebekulturen, die Tumor- wie Stromazellen gleichermaßen repräsentieren, und diskutiert Vor- und Nachteile in Bezug auf die Translation in die klinische Praxis.

Abstract

Because head and neck squamous cell carcinomas (HNSCC) are characterized by a distinct intertumorigenic and intratumorigenic heterogeneity, they often show substantial differences in the response to established therapy strategies. At present, a multitude of biologics and new pharmacological compounds for targeted therapies are available that allow more efficient and less toxic treatment. There is increasing pressure to establish predictive assays not only for ex ante analysis of the individual patient response to combined chemoradiotherapy and targeted therapies but also for investigation of the efficacy of new drugs. In this respect it is essential to maintain the pathophysiological tissue composition as it is known that paracrine tumor-stroma cell interactions may influence tumor reactivity to treatment. More complex models for individualized sensitivity testing have recently been described and the results are promising to pave the way for personalized cancer therapy. This review article focuses on different systems for maintaining the tumor microenvironment and hence the individual cellular composition, such as 3D organotypic models, organotypic multicellular spheroids, patient-derived xenografts and ex vivo tissue cultures and discusses the advantages and disadvantages in terms of translation into clinical application.

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Literatur

  1. Al-Sarraf M (2002) Treatment of locally advanced head and neck cancer: Historical and critical review. Cancer Control 9:387–399

    PubMed  Google Scholar 

  2. Adelstein DJ, Li Y, Adams GL et al (2003) An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21(1):92–98

    Article  PubMed  Google Scholar 

  3. Forastiere AA, Zhang Q, Weber R et al (2013) Long-term results of RTOG 91–11: A comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 31:845–852

    Article  CAS  PubMed  Google Scholar 

  4. Sacco AG, Cohen EE (2015) Current treatment options for recurrent or metastatic head and neck squamous cell carcinoma. J Clin Oncol 33(29):3305–3313

    Article  CAS  PubMed  Google Scholar 

  5. Bußmann L, Busch CJ, Knecht R (2015) Treatment of head and neck squamous cell carcinoma recurrences and distant metastases: Highlights of the ASCO Meeting 2015. HNO 63(9):620–624

    Article  PubMed  Google Scholar 

  6. Vermorken JB, Mesia R, Rivera F et al (2008) Platinum-based chemotherapy plus cetuximab in head and neckcancer. N Engl J Med 359(11):1116–1127

    Article  CAS  PubMed  Google Scholar 

  7. Bonner JA, Harari PM, Giralt J et al (2010) Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5‑year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 11:21–28

    Article  CAS  PubMed  Google Scholar 

  8. Peddi P, Shi R, Nair B et al (2015) Cisplatin, cetuximab, and radiation in locally advanced head and neck squamous cell cancer: A retrospective review. Clin Med Insights Oncol 9:1–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Magrini SM, Buglione M, Corvò R et al (2016) Cetuximab and radiotherapy versus cisplatin and radiotherapy for locally advanced head and neck cancer: A randomized phase II trial. J Clin Oncol 34(5):427–435

    Article  CAS  PubMed  Google Scholar 

  10. Gliese A, Busch CJ, Knecht R (2015) The most important study results concerning nonsurgical primary treatment of locally advanced head and neck cancer: Highlights of the ASCO Meeting 2015. HNO 63(9):606–611

    Article  CAS  PubMed  Google Scholar 

  11. Bourhis J, Sun SX, Sire C et al (2016) Cetuximab-radiotherapy versus cetuximab radiotherapy plus concurrent chemotherapy inpatients with N0–N2 a squamous cell carcinoma of the head and neck (SCCHN): Results of the GORTEC 2007–01 phase III randomized trial. J Clin Oncol 34(Suppl):abstr6003

    Google Scholar 

  12. Gliese A, Busch CJ, Knecht R (2016) Study results of primary therapy for head and neck tumors: Highlights of the 2016 ASCO Annual Meeting. HNO 64(10):717–722

    Article  CAS  PubMed  Google Scholar 

  13. Perri F, Pacelli R, Della Vittoria Scarpati G et al (2015) Radioresistance in head and neck squamous cell carcinoma: Biological bases and therapeutic implications. Head Neck 37(5):763–770

    Article  PubMed  Google Scholar 

  14. Psyrri A, Seiwert TY, Jimeno A (2013) Molecular pathways in head and neck cancer: EGFR, PI3K, and more. Am Soc Clin Oncol Educ Book 2013:246–255

    Article  Google Scholar 

  15. Rothenberg SM, Ellisen LW (2012) The molecular pathogenesis of head and neck squamous cell carcinoma. J Clin Invest 122(6):1951–1957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Iglesias-Bartolome R, Martin D, Gutkind JS (2013) Exploiting the head and neck cancer oncogenome: widespread PI3K-mTOR pathway alterations and novel molecular targets. Cancer Discov 3(7):722–725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chang L, Graham P, Hao J et al (2016) Cancer stem cells and signaling pathways in radioresistance. Oncotarget 7(10):11002–11017

    PubMed  Google Scholar 

  18. Begg AC, Stewart FA, Vens C (2011) Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer 11(4):239–253

    Article  CAS  PubMed  Google Scholar 

  19. Tenzer A, Zingg D, Riesterer O et al (2002) Signal transduction inhibitors as radiosensitizers. Curr Med Chem Anticancer Agents 2:727–742

    Article  CAS  PubMed  Google Scholar 

  20. Ethier SP (2002) Signal transduction pathways: the molecular basis for targeted therapies. Semin Radiat Oncol 12:3–10

    Article  PubMed  Google Scholar 

  21. McCubrey JA et al (2007) Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 773:1263–1284

    Article  Google Scholar 

  22. Golding SE, Morgan RN, Adams BR et al (2009) Pro-survival AKT and ERK signaling from EGFR and mutant EGFRvIII enhances DNA double-strand break repair in human glioma cells. Cancer Biol Ther 8(8):730–738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chung EJ, Brown AP, Asano H et al (2009) In vitro and in vivo radiosensitization with AZD6244 (ARRY-142886), an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 kinase. Clin Cancer Res 15(9):3050–3057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Leiker AJ, DeGraff W, Choudhuri R et al (2015) Radiation enhancement of head and neck squamous cell carcinoma by the dual PI3K/mTOR inhibitor PF-05212384. Clin Cancer Res 21(12):2792–2801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zumsteg Z, Morse N, Krigsfeld G et al (2016) Taselisib (GDC-0032), a potent β‑sparing small molecule inhibitor of PI3K, radiosensitizes head and neck squamous carcinomas containing activating PIK3CA alterations. Clin Cancer Res 22(8):2009–2019

    Article  CAS  PubMed  Google Scholar 

  26. Affolter A, Fruth K, Brochhausen C et al (2011) Activation of MAP kinase ERK in head and neck squamous cell carcinomas after irradiation: part of a rescue mechanism? Head Neck 33(10):1448–1457

    Article  PubMed  Google Scholar 

  27. Freudlsperger C, Horn D, Weißfuß S et al (2015) Phosphorylation of AKT(Ser473) serves as an independent prognostic marker for radiosensitivity in advanced Head and neck squamous cell carcinoma. Int J Cancer 136(12):2775–2785

    Article  CAS  PubMed  Google Scholar 

  28. Kim SY, Lee CH, Midura BV et al (2007) Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases. Clin Exp Metastasis 25:201–211

    Article  PubMed  PubMed Central  Google Scholar 

  29. Guleng B, Tateishi K, Ohta M et al (2005) Blockade of the stromal cell-derived factor-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor-independent manner. Cancer Res 65:5864–5871

    Article  CAS  PubMed  Google Scholar 

  30. Fischer H, Taylor N, Allerstorfer S et al (2008) Fibroblast growth factor receptor-mediated signals contribute to the malignant phenotype of non-small cell lung cancer cells: therapeutic implications and synergism with epidermal growth factor receptor inhibition. Mol Cancer Ther 7:3408–3419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Affolter A, Schmidtmann I, Mann WJ et al (2013) Cancer-associated fibroblasts do not respond to combined irradiation and kinase inhibitor treatment. Oncol Rep 29(2):785–790

    CAS  PubMed  Google Scholar 

  32. Wichmann G, Dietz A (2016) Preclinical models to establish innovative therapy strategies : Ex-vivo assessment of head and neck tumor chemo- and immune responses. HNO 64(7):460–469

    Article  CAS  PubMed  Google Scholar 

  33. Dohmen AJ, Swartz JE, Van Den Brekel MW et al (2015) Feasibility of primary tumor culture models and preclinical prediction assays for head and neck cancer: A narrative review. Cancers (Basel) 7(3):1716–1742

    Article  Google Scholar 

  34. Li H, Wawrose JS, Gooding WE et al (2014) Genomic analysis of head and neck squamous cell carcinoma cell lines and human tumors: a rational approach to preclinical model selection. Mol Cancer Res 12(4):571–582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li H, Wheeler S, Park Y et al (2016) Proteomic characterization of head and neck cancer patient-derived xenografts. Mol Cancer Res 14(3):278–286

    Article  CAS  PubMed  Google Scholar 

  36. Morton JJ, Bird G, Keysar SB (2016) XactMice: humanizing mouse bone marrow enables microenvironment reconstitution in a patient-derived xenograft model of head and neck cancer. Oncogene 35(3):290–300

    Article  CAS  PubMed  Google Scholar 

  37. Kenter MJ, Cohen AF (2006) Establishing risk of human experimentation with drugs: lessons from TGN1412. Lancet 368:1387–1391

    Article  CAS  PubMed  Google Scholar 

  38. Weiswald LB, Bellet D, Dangles-Marie V (2015) Spherical cancer models in tumor biology. Neoplasia 17(1):1–15

    Article  PubMed  PubMed Central  Google Scholar 

  39. Chen C, Wei Y, Hummel M et al (2011) Evidence for epithelial-mesenchymal transition in cancer stem cells of head and neck squamous cell carcinoma. PLOS ONE 6(1):e16466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hoffmann TK, Schirlau K, Sonkoly E et al (2009) A novel mechanism for anti-EGFR antibody action involves chemokine-mediated leukocyte infiltration. Int J Cancer 124(11):2589–2596

    Article  CAS  PubMed  Google Scholar 

  41. Bjerkvig R, Tonnesen A, Laerum OD et al (1990) Multicellular tumor spheroids from human gliomas maintained in organ culture. J Neurosurg 72:463–475

    Article  CAS  PubMed  Google Scholar 

  42. Heimdal J, Aarstad HJ, Olofsson J (2000) Monocytes secrete interleukin-6 when co-cultured in vitro with benign or malignant autologous fragment spheroids from squamous cell carcinoma patients. Scand J Immunol 51:271–278

    Article  CAS  PubMed  Google Scholar 

  43. Kross KW, Heimdal JH, Olsnes C et al (2008) Co-culture of head and neck squamous cell carcinoma spheroids with autologous monocytes predicts prognosis. Scand J Immunol 67(4):392–399

    Article  CAS  PubMed  Google Scholar 

  44. Choi SY, Lin D, Gout PW et al (2014) Lessons from patient-derived xenografts for better in vitro modeling of human cancer. Adv Drug Deliv Rev 79–80:222–237

    Article  PubMed  Google Scholar 

  45. Daniel VC, Marchionni L, Hierman JS et al (2009) A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro. Cancer Res 69:3364–3373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Garber K (2009) From human to mouse and back: „tumorgraft“ models surge in popularity. J Natl Cancer Inst 101:6–844

    Article  PubMed  Google Scholar 

  47. Tentler JJ, Tan AC, Weekes CD et al (2012) Patient-derived tumour xenografts as models for oncology drug development. Nat Rev Clin Oncol 9:338–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Klinghammer K, Raguse JD, Plath T et al (2015) A comprehensively characterized large panel of head and neck cancer patient-derived xenografts identifies the mTOR inhibitor everolimus as potential new treatment option. Int J Cancer 136(12):2940–2948

    Article  CAS  PubMed  Google Scholar 

  49. Peng S, Creighton CJ, Zhang Y et al (2013) Tumor grafts derived from patients with head and neck squamous carcinoma authentically maintain the molecular and histologic characteristics of human cancers. J Transl Med 11:198

    Article  PubMed  PubMed Central  Google Scholar 

  50. Cassidy JW, Caldas C, Bruna A (2015) Maintaining tumor heterogeneity in patient-derived tumor xenografts. Cancer Res 75(15):2963–2968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schoop VM, Mirancea N, Fusenig NE (1999) Epidermal organization and differentiation of HaCaT keratinocytes in organotypic coculture with human dermal fibroblasts. J Invest Dermatol 112:343–353

    Article  CAS  PubMed  Google Scholar 

  52. Szabowski A, Maas-Szabowski N, Andrecht S et al (2000) c‑Jun and JunB antagonistically control cytokine-regulated mesenchymal-epidermal interaction in skin. Cell 103:745–755

    Article  CAS  PubMed  Google Scholar 

  53. Linde N, Gutschalk CM, Hoffmann C et al (2012) Integrating macrophages into organotypic co-cultures: a 3D in vitro model to study tumor-associated macrophages. PLOS ONE 7(7):e40058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Colley HE, Hearnden V, Jones AV et al (2011) Development of tissue-engineered models of oral dysplasia and early invasive oral squamous cell carcinoma. Br J Cancer 105(10):1582–1592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Scanlon CS, Van Tubergen EA, Chen LC et al (2013) Characterization of squamous cell carcinoma in an organotypic culture via subsurface non-linear optical molecular imaging. Exp Biol Med (Maywood) 238(11):1233–1241

    Article  CAS  Google Scholar 

  56. Donnadieu J, Lachaier E, Peria M et al (2016) Short-term culture of tumour slices reveals the heterogeneous sensitivity of human head and neck squamous cell carcinoma to targeted therapies. BMC Cancer 16(1):273

    Article  PubMed  PubMed Central  Google Scholar 

  57. Peria M, Donnadieu J, Racz C et al (2016) Evaluation of individual sensitivity of head and neck squamous cell carcinoma to cetuximab by short-term culture of tumor slices. Head Neck 38(Suppl 1):E911–915

    Article  PubMed  Google Scholar 

  58. Gerlach MM, Merz F, Wichmann G et al (2014) Slice cultures from head and neck squamous cell carcinoma: a novel test system for drug susceptibility and mechanisms of resistance. Br J Cancer 110(2):479–488

    Article  CAS  PubMed  Google Scholar 

  59. Affolter A, Muller MF, Sommer K et al (2016) Targeting irradiation-induced MAPK activation in vitro and in an ex vivo model for human head and neck cancer. Head Neck 38(Suppl 1):E2049–61

    Article  PubMed  Google Scholar 

  60. Hickman JA, Graeser R, de Hoogt R, IMI PREDECT Consortium et al (2014) Three-dimensional models of cancer for pharmacology and cancer cell biology: capturing tumor complexity in vitro/ex vivo. Biotechnol J 9(9):1115–1128

    Article  CAS  PubMed  Google Scholar 

  61. Laban S, Doescher J, Schuler PJ et al (2015) Immunotherapy of head and neck tumors: Highlights of the ASCO Meeting 2015. HNO 63(9):612–619

    Article  CAS  PubMed  Google Scholar 

  62. Seiwert TY, Burtness B, Mehra R et al (2016) Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 17(7):956

    Article  CAS  PubMed  Google Scholar 

  63. Busch CJ, Laban S, Knecht R, Hoffmann TK (2016) Immunotherapeutic studies of head and neck tumors: Highlights of the 2016 ASCO Annual Meeting. HNO 64(10):708–716

    Article  PubMed  Google Scholar 

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Danksagung

Die Autoren danken der Medizinischen Fakultät Heidelberg für die Förderung durch das Olympia-Morata-Programm (AA), der Deutschen Krebshilfe für die Bereitstellung des Mildred-Scheel-Promotionsstipendiums sowie Frau Dr. Jennifer Grünow für Durchsicht des Manuskriptes und konstruktive Diskussion.

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  1. Hals-Nasen-Ohren-Klinik des Universitätsklinikums Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Deutschland

    A. Affolter & J. Hess

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  1. A. Affolter
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  2. J. Hess
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Correspondence to A. Affolter.

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Interessenkonflikt

A. Affolter und J. Heß geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

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W. Baumgartner, Wien

P. K. Plinkert, Heidelberg

M. Ptok, Hannover

C. Sittel, Stuttgart

N. Stasche, Kaiserslautern

B. Wollenberg, Lübeck

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Affolter, A., Hess, J. Präklinische Modelle für Kopf-Hals-Tumoren. HNO 64, 860–869 (2016). https://doi.org/10.1007/s00106-016-0276-x

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