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 ∼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. Mol Cancer Ther; 9(8); 2430-9. ©2010 AACR.

Let-7 Expression Is a Significant Determinant of Response to Chemotherapy through the Regulation of IL-6/STAT3 Pathway in Esophageal Squamous Cell Carcinoma

“…This was based on Target scan and miRBase Targets database, which showed that IL-6 is potential target of let-7c, and also on previous finding of IL-6 as a putative let-7 target (18). In addition, a recent study has shown that IL-6 is released by genotoxic chemotherapy to protect cancer cell from cell death (19). First, we showed that cisplatin activated IL-6 mRNA in esophageal cancer cells (Fig.…”

Preclinical evaluation of dual PI3K-mTOR inhibitors and histone deacetylase inhibitors in head and neck squamous cell carcinoma

“…This would result in the expansion of drug-resistant clonal variants during the 4-week drug treatment. Therefore, we examined the effect of LBH589 or BEZ235 treatment on cell viability of clonal variants of the Detroit 562 HNSCC cell line (Cameron et al , 2010; Poth et al , 2010) (Figure 5F). The results indicate that some clones are sensitive to BEZ235 whereas other clones are insensitive (Figure 5F).…”

“…However, we observed a generalised, yet incomplete, antitumour response to PI3KI treatment, which would be consistent with a submaximal dose of PI3KI being achieved in vivo . With respect to the presence of clonal variants within tumours, we have recently shown that HNSCC cell lines contain clonal variants that differ in their transcriptomic signature, their tumourogenic potential and their sensitivity to cisplatin (Cameron et al , 2010; Poth et al , 2010). Significantly, we have also shown that these clonal variants exist in human SCCs in situ (Cameron et al , 2010).…”

“…SCC9, SCC25 and Cal27 tumour cell lines were grown and maintained as previously described (Erlich et al , 2008). Cell line validation has been previously reported (Poth et al , 2010). …”

EGFR Inhibition Induces Proinflammatory Cytokines via NOX4 in HNSCC

“…Cisplatin and radiation have long been the backbone and standard of care of HNSCC patients presenting with locally advanced disease. Cisplatin-based chemotherapy and radiation have already been shown to induce IL-6 secretion (41, 42) implying that EGFRI-induced IL-6 may not be unique to EGFR inhibitors. It is possible that the cell death caused by standard chemo-/radiotherapy in HNSCC may be activating pathways leading to IL-6 and other pro-inflammatory cytokines.…”