title: Cisplatin treatment induces a transient increase in tumorigenic potential associated with high interleukin-6 expression in head and neck squamous cell carcinoma.
abstract: Head and neck squamous cell carcinoma (HNSCC) is characterized by the 5-year survival rate of approximately 50%. Despite aggressive surgical, radiation, and chemotherapeutic interventions, 30% to 40% of patients die from the development of recurrent or disseminated disease that is resistant to chemotherapy. As a model of recurrence, we examined the effects of cisplatin on the ability of head and neck cancer cells to initiate tumors in a xenotransplant model. HNSCC cells were treated in vitro with cisplatin at a concentration that elicited >99% cytotoxicity and assessed for tumorigenic potential in nonobese diabetic/severe combined immunodeficient mice. HNSCC cells that survived cisplatin treatment formed tumors in nonobese diabetic/severe combined immunodeficient mice more efficiently than nontreated cells. Cisplatin-resistant cells were characterized using clonal analysis, in vivo imaging, and transcriptomic profiling. Preliminary functional assessment of a gene, interleukin-6 (IL-6), highly upregulated in cisplatin-treated cells was carried out using clonogenicity and tumorigenicity assays. We show that cisplatin-induced IL-6 expression can contribute to the increase in tumorigenic potential of head and neck cancer cells but does not contribute to cisplatin resistance. Finally, through clonal analysis, we show that cisplatin-induced IL-6 expression and cisplatin-induced tumorigenicity are stochastically derived. We report that cisplatin treatment of head and neck cancer cells results in a transient accumulation of cisplatin-resistant, small, and IL-6-positive cells that are highly tumorigenic. These data also suggest that therapies that reduce IL-6 action may reduce recurrence rates and/or increase disease-free survival times in head and neck cancer patients, and thus, IL-6 represents a promising new target in HNSCC treatment.
authors.affiliation: Diamantina Institute, The University of Queensland, Princess Alexandra Hospital, Ipswich Road, Brisbane, Queensland, Australia.
authors.forename: Kim J
authors.initials: KJ
authors.lastname: Poth
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Guminski
authors.forename: Gethin P
authors.initials: GP
authors.lastname: Thomas
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Leo
authors.forename: Ibtissam A
authors.initials: IA
authors.lastname: Jabbar
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Saunders
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D002999:Clone Cells; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D015398:Signal Transduction / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D015850:Interleukin-6; D002945:Cisplatin