Modulation of head and neck cancer invasion and growth

Abstract

Head and neck squamous cell carcinoma (HNSCC) constitutes an anatomically heterogeneous group of neoplasms. Progression to aggressive disease involves local and/or regional invasion, recurrence of tumor after treatment and metastasis to regional lymph nodes. The first part of this thesis explores the contribution of chemotactic molecules and macrophages to HNSCC in vivo invasion. The second part involves a study of the possible mechanism and efficacy of an anticancer drug in preventing HNSCC growth.;We explore the mechanism through which a tumor cell detaches from the primary site and invades through host stroma using an in vivo invasion assay. This assay was previously used to report the existence of a paracrine loop between macrophages and breast carcinoma cells using EGF and CSF-1. This loop could be triggered by CXCL-12. Here, we determined that the EGF/CSF-1 loop is not required for HNSCC invasion. Rather, HNSCC tumors use CXCL12 to transactivate EGFR to induce invasion via release of EGFR-ligands.;We also explored the efficacy of using a small molecule histone deacetylase inhibitor (HDACi) called LBH589 in treating HNSCC. LBH589 is in phase II clinical trials for multiple hematological and solid tumors. As seen in other human tumors, LBH589 induced G2/M cell cycle arrest and cell death of human HNSCC cell lines. Gene expression analysis of LBH589-treated versus non-treated cell lines revealed down-regulation of genes required for DNA replication (MCM-3, MCM-4, MCM-5), chromosome segregation (NEK-6) and M-phase progression (PLK-1); these LBH589-induced changes in gene expression coupled with the down-regulation of MYC provides a plausible explanation for the early mitotic arrest and cell death observed as opposed to only exploring upregulated genes upon HDACi treatment. We also observed synergistic effects when LBH589 was combined with Taxol.;We were also the first to provide in vivo evidence of CXCL-12-mediated transactivation of EGFR. This finding suggests HNSCC patients could benefit from anti-EGFR therapies in combination with anti-CXCR4 therapies. Our data also suggest application of LBH589 in the treatment of HNSCC tumors.