Elodie Hanns1, Sylvie Job2, Pierre Coliat1, Christine Wasylyk3, Ludivine Ramolu1, Erwan Pencreach4, Meggy Suarez-Carmona5, Michael Herfs5, Sonia Ledrappier1, Christine Macabre1, Joseph Abecassis1, Bohdan Wasylyk3, Alain C Jung6. 1. Laboratoire de Biologie Tumorale, Centre Régional de Lutte Contre le Cancer Paul Strauss, EA3430 de l'Université de Strasbourg, F. 67065 Strasbourg, France; EA3430 de l'Université de Strasbourg, Bâtiment U113, F. 67000 Strasbourg, France. 2. Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, F. 75014 Paris, France. 3. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, F. 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, F. 67404 Illkirch, France; Université de Strasbourg, F. 67404 Illkirch, France. 4. EA3430 de l'Université de Strasbourg, Bâtiment U113, F. 67000 Strasbourg, France; Laboratoire de Biochimie et Biologie Moléculaire, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, F. 67000 Strasbourg, France. 5. Laboratoire de Pathologie Expérimentale, GIGA-Cancer, Université de Liège, B. 4000 Liège, Belgium. 6. Laboratoire de Biologie Tumorale, Centre Régional de Lutte Contre le Cancer Paul Strauss, EA3430 de l'Université de Strasbourg, F. 67065 Strasbourg, France; EA3430 de l'Université de Strasbourg, Bâtiment U113, F. 67000 Strasbourg, France. Electronic address: AJung@strasbourg.unicancer.fr.
Abstract
OBJECTIVES: Human Papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OSCC) patients have improved prognosis compared to other head and neck (HNSCC) cancers. Since poor prognosis is associated with tumour hypoxia, we studied whether the hypoxic response is different in HPV-related cells and tumours. MATERIAL AND METHODS: HPV-positive and -negative cells were incubated in hypoxia and analyzed by qRTPCR, western blotting and cell proliferation assays. Tumours formed by xenografting these cells in nude mice were studied by IHC. HNSCC patient samples were analyzed by unsupervised clustering of hypoxia-related gene expression, quantitative real-time PCR (qRTPCR) and immunohistochemical (IHC) detection of neo-blood vessels. RESULTS AND CONCLUSION: HPV-positive and -negative cells responded differently to hypoxia, in terms of gene expression (HIF-1α, PHD-3, GLUT-1 and VEGF-A) and cell survival. Tumour xenografts formed by HPV-positive cells had fewer hypoxic areas than those formed by HPV-negative cells. HPV related tumours were less hypoxic, expressed lower levels of hypoxia-responsive genes, and had a higher density of neo-blood vessels. HPV-related OSCC display lower tumour hypoxia, which could be linked to the distinct intrinsic abilities of HPV-positive tumour cells to adapt to hypoxia and to their better prognosis.
OBJECTIVES:Human Papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OSCC) patients have improved prognosis compared to other head and neck (HNSCC) cancers. Since poor prognosis is associated with tumour hypoxia, we studied whether the hypoxic response is different in HPV-related cells and tumours. MATERIAL AND METHODS:HPV-positive and -negative cells were incubated in hypoxia and analyzed by qRTPCR, western blotting and cell proliferation assays. Tumours formed by xenografting these cells in nude mice were studied by IHC. HNSCC patient samples were analyzed by unsupervised clustering of hypoxia-related gene expression, quantitative real-time PCR (qRTPCR) and immunohistochemical (IHC) detection of neo-blood vessels. RESULTS AND CONCLUSION:HPV-positive and -negative cells responded differently to hypoxia, in terms of gene expression (HIF-1α, PHD-3, GLUT-1 and VEGF-A) and cell survival. Tumour xenografts formed by HPV-positive cells had fewer hypoxic areas than those formed by HPV-negative cells. HPV related tumours were less hypoxic, expressed lower levels of hypoxia-responsive genes, and had a higher density of neo-blood vessels. HPV-related OSCC display lower tumour hypoxia, which could be linked to the distinct intrinsic abilities of HPV-positive tumour cells to adapt to hypoxia and to their better prognosis.
Authors: Hongzheng Zhang; Sungjin Kim; Zhengjia Chen; Sreenivas Nannapaneni; Amy Y Chen; Charles E Moore; Gabriel Sica; Marina Mosunjac; Minh Ly T Nguyen; Gypsyamber D'Souza; Thomas E Carey; Lisa A Peterson; Jonathan B McHugh; Martin Graham; Christine M Komarck; Gregory T Wolf; Heather M Walline; Emily Bellile; James Riddell; Sara I Pai; David Sidransky; William H Westra; William N William; J Jack Lee; Adel K El-Naggar; Robert L Ferris; Raja Seethala; Jennifer R Grandis; Zhuo Georgia Chen; Nabil F Saba; Dong M Shin Journal: Head Neck Date: 2017-09-25 Impact factor: 3.147