Radiation-Induced Dedifferentiation of Head and Neck Cancer Cells into Cancer Stem Cells Depends on HPV status

Publication date: Available online 14 January 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Erina Vlashi, Allen M. Chen, Sabrina Boyrie, Garrett Yu, Andrea Nguyen, Philip A. Brower, Clayton B. Hess, Frank Pajonk
PurposeHuman papilloma virus (HPV), HPV-16, is one of the most important prognostic factors for patients with head and neck squamous cell carcinomas (HNSCCs). HPV-positive HNSCCs have a favorable response to radiation therapy (RT) and superior overall survival (OS) compared to HPV-negative HNSCCs. However, an explanation for the mechanisms responsible for the inherent radiosensitivity of HPV-positive HNSCC remains elusive.Methods and MaterialsRecords of a cohort of 162 HNSCC patients were reviewed and their outcomes were correlated with their HPV status. Using a panel of HPV-positive and HPV-negative HNSCC cell lines expressing a reporter for cancer stem cells (CSCs) we characterized HPV-positive and HPV-negative lines via flow cytometry, sphereforming capacity assays in vitro, and limiting dilution assays in vivo. Non-CSCs were treated with different doses of radiation and the dedifferentiation of non-CSCs into CSCs was investigated via flow cytometry and qRT-PCR for re-expression of reprogramming factors.ResultsPatients with HPV-positive tumors have superior OS and local-regional control. HPV-positive HNSCC cell lines have lower numbers of CSCs, which inversely correlates with radiosensitivity. HPV-negative HNSCC cell lines lack hierarchy due to enhanced spontaneous dedifferentiation. Non-CSCs from HPV-negative lines show enhanced radiation-induced dedifferentiation compared to HPV-positive lines, and RT induced re-expression of Yamanaka reprogramming factors.ConclusionsSupporting the favorable prognosis of HPV-positive HNSCCs, we show that HPV-positive HNSCCs have (1) a lower frequency of CSCs, (2) RT can dedifferentiate HNSCC cells into CSCs, and (3) radiation-induced dedifferentiation depends on the HPV status of the tumor.

Teaser

Our studies provide another layer of scientific evidence that offers an alternative explanation for the improved long-term outcome of HPV-positive HNSCC patients: lower frequency of intrinsic CSCs, and an impaired ability to dedifferentiate into HNSCC stem cells after radiation therapy. Thus, preventing spontaneous and radiation-induced dedifferentiation events from occurring could potentially result in significantly improved loco-regional control for these patients.


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