Novel Insights into Genetic Basis of High-Grade Oral Spindle-Cell Carcinoma

Squamous cell carcinoma (SCC) is the 6th most frequent cancer worldwide; comprising 50% of all malignancies. Spindle cell carcinoma is a rare high grade malignant tumor which occurs following unsuccessful radiation treatment of primary SCC. OBJECTIVES: To identify genes that regulate the transition to spindle cell carcinoma in a genetically-inbred mouse model utilizing global expression profiling and immunohistochemistry. METHODS: 9,10-dimethyl-1,2-benzanthracene-induced tumor tissues were microdissected from euthanized C57Bl6 mice for histopathological and immunohistochemical analyses. Transcriptional profiling was performed using Affymetrix GeneChip mouse genome 430 2.0 microarrays to examine 39,000 possible transcripts. RESULTS: 3 of 28 oral SCCs (11%) met the histopathologic criteria for spindle cell carcinoma. Immunohistochemical analysis showed reduced expression of growth factor receptors (epidermal growth factor receptor/EGFR, c-met and igand HGF) and cyclins A, -B, -D and -E compared to well and moderately differentiated SCCs. Microarray analysis revealed only 32 differentially expressed genes between well and moderately differentiated SCC, but 354 genes between well differentiated and spindle cell carcinoma. Significant reductions in expression of multiple epithelial keratin genes (up to -289 fold) and terminal differentiation markers (small proline-rich protein 1, -208.3 fold; loricrin, -96.3 fold; transglutaminase 3, -36.8 fold) were observed in spindle cell carcinomas. There were substantial downregulation of genes regulating intercellular adhesion (plakophilin, -28 fold; cadherin 1, - 17.3 fold; desmoglein, -16.5 fold; desmocollin, -14.6 fold). Expression of growth factors and receptors commonly upregulated in oral SCC was decreased in spindle cell carcinoma (transforming growth factor alpha, -11.4 fold; amphiregulin, -11.2 fold; ErbB3, -10.2 fold). Chemokines and their receptors which induce tumor metastasis were upregulated in spindle cell carcinomas (CCL12, 33.1 fold; CCL8, 12.8 fold; CCR5, 11.5 fold; CX3CR1, 11.3 fold; CXCL12, 11.2 fold). CONCLUSION: The genetic profile of oral spindle cell carcinomas revealed loss of stratified epithelial characteristics and suggests alternate tumor invasion and metastatic pathways.