Abstract C29: Periostin, a regulator of adhesion, is a novel effector of tumor invasion

Squamous cell cancers in aggregate comprise the most common forms of epithelial cancers, arising from the skin, head/neck, oral cavity, esophagus, lung and anogenital tract, and they share a number of environmental exposures and genomic alterations. A prototype of this cancer is esophageal squamous cell carcinoma (ESCC), which is associated with a high mortality rate worldwide. Local invasion and metastasis are important factors which influence patient survival. Amongst the frequent oncogene alterations are EGFR and cyclin D1 overexpression, and that in tumor suppressor genes are p53 mutation and p120-catenin loss or mislocalization. However, the functional interplay between these genetic alterations contributing to cancer progression remains unclear. Our previous studies have addressed this by presenting a tumor microenvironment model for tumor cell invasion using a 3D organotypic culture system and transformed human esophageal cells overexpressing EGFR and mutant p53 (Genes and Development 2007). From this, we have now utilized laser capture microdissection (LCM) and microarray analysis to identify novel targets of EGFR overexpression and mutant p53 by comparing gene expression of invading versus non-invading transformed cells. Results from these studies reveal a marked upregulation of periostin, a gene involved in cell adhesion, whose expression is restricted to invading tumor cells, as validated by qPCR, immunohistochemistry and Western blot. Furthermore, its expression was found to be upregulated in human esophageal cancer compared to normal esophagus. Using genetic approaches, gain-of-function of periostin fosters tumor cell invasion, whereas silencing of periostin markedly attenuates tumor cell invasion. Bioinformatic analyses reveal that periostin is upregulated in other human squamous cell cancers as well. Promoter studies assessing the transcriptional regulation of periostin upon EGFR overexpression and p53 mutation have been done. Our novel findings indicate periostin induction upon convergence of EGFR signaling and p53 mutation provides a cue for tumor cell invasion in the tumor microenvironment, and that it may be part of tumor invasion signature in squamous cell cancers in general. This work was supported by P01-CA098101, NIH/NRSA F32-DK075230 and T32 CA115299. Citation Information: Cancer Res 2009;69(23 Suppl):C29.