transforming-growth-factor-alpha and Squamous-Cell-Carcinoma-of-Head-and-Neck

Traditionally, squamous cell cancers of the head and neck (SCCHN) have been classified by their anatomic location and stage. This system has been unsatisfactory in that it leaves substantial heterogeneity in prognosis and inadequate definition of optimal therapy. The most promising novel marker for superior prognosis in SCCHN is human papillomavirus (HPV). Overexpression of the EGFR bears an adverse prognosis; no marker provides clear predictive power for benefit from EGFR inhibition. Low expression of the DNA repair enzymes and excision repair cross-complementing rodent repair deficiency (ERCC1) and x-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) may predict chemotherapy and chemoradiotherapy sensitivity. Tumors expressing cyclin D1 have a poor prognosis. Genomic characterization has subdivided SCCHN into four categories with clear biologic themes. Basal cancers express high levels of TGF-α and have other perturbations of the EGFR axis. Mesenchymal cancers show evidence for epithelial to mesenchymal transition. Atypical cancers lack both EGFR amplification and deletion of 9p; they also have a higher rate of HPV positivity than the other groups. Classical tumors demonstrate gene signatures similar to those previously associated with exposure to cigarette smoke; patients with this signature had a greater smoking history than patients in the other groups.

Topics: Animals; Carcinoma, Squamous Cell; Cricetinae; Cricetulus; Epithelial-Mesenchymal Transition; ErbB Receptors; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Prognosis; Smoking; Squamous Cell Carcinoma of Head and Neck; Transforming Growth Factor alpha

Predictive strategies for the treatment efficacy of cetuximab are currently not available for head and neck cancer. We investigated the correlation between the expression of epidermal growth factor receptor (EGFR) ligands and EGFR expression, and the growth inhibitory activity of cetuximab in a panel of head and neck squamous cell carcinoma (HNSCC) cell lines.. The growth inhibiting effect of cetuximab was measured for eight HNSCC cell lines and correlated with the autocrine production of five EGFR ligands as measured by ELISA, and the mRNA expression of two ligands, as measured by quantitative RT-PCR. EGFR expression was assessed by western blot analysis.. There was a good correlation between the expression of four of the EGFR ligands (TGF-α, amphiregulin, epiregulin and epigen) and the growth inhibiting effect of cetuximab. TGF-α had the highest predictive potential but had to be combined with epigen for full prediction. EGFR expression also correlated with cetuximab sensitivity but less clearly.. The results indicate that the expression of several EGFR ligands has to be used to predict sensitivity to cetuximab in HNSCC. This has to be further evaluated in clinical samples.

Topics: Amphiregulin; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Cetuximab; EGF Family of Proteins; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Epigen; Epiregulin; ErbB Receptors; Gene Expression Regulation, Neoplastic; Glycoproteins; Head and Neck Neoplasms; Humans; Intercellular Signaling Peptides and Proteins; Ligands; Predictive Value of Tests; Reverse Transcriptase Polymerase Chain Reaction; Squamous Cell Carcinoma of Head and Neck; Transforming Growth Factor alpha

Head and neck squamous cell carcinoma (HNSCC) is usually fatal, and innovative approaches targeting growth pathways are necessary to effectively treat this disease. Both the epidermal growth factor receptor (EGFR) and the hepatocyte growth factor (HGF)/c-Met pathways are overexpressed in HNSCC and initiate similar downstream signaling pathways. c-Met may act in consort with EGFR and/or be activated as a compensatory pathway in the presence of EGFR blockade.. Expression levels of EGFR and c-Met were determined by Western analysis in HNSCC cell lines and correlated with antitumor responses to inhibitors of these pathways.. Combining the c-Met inhibitor PF2341066 with the EGFR inhibitor gefitinib abrogated HNSCC cell proliferation, invasion, and wound healing significantly more than inhibition of each pathway alone in HNSCC cell lines. When both HGF and the EGFR ligand, TGF-α, were present in vitro, P-AKT and P-MAPK expression were maximally inhibited by targeting both EGFR and c-Met pathways, suggesting that c-Met or EGFR can compensate when phosphorylation of the other receptor is inhibited. We also showed that TGF-α can induce phosphorylation of c-Met over sixfold by 8 hours in the absence of HGF, supporting a ligand-independent mechanism. Combined targeting of c-Met and EGFR resulted in an enhanced inhibition of tumor volumes accompanied by a decreased number of proliferating cells and increased apoptosis compared with single agent treatment in vivo.. Together, these results suggest that dual blockade of c-Met and EGFR may be a promising clinical therapeutic strategy for treating HNSCC.

Topics: Animals; Antineoplastic Agents; Carcinoma; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; ErbB Receptors; Female; Gefitinib; Head and Neck Neoplasms; Hepatocyte Growth Factor; Humans; Mice; Mice, SCID; Mitogen-Activated Protein Kinases; Neoplasm Invasiveness; Neoplasms, Squamous Cell; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Quinazolines; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Transforming Growth Factor alpha; Wound Healing; Xenograft Model Antitumor Assays