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Periostin, a Cell Adhesion Molecule, Facilitates Invasion in the Tumor Microenvironment and Annotates a Novel Tumor-Invasive Signature in Esophageal Cancer

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Periostin, a Cell Adhesion Molecule, Facilitates Invasion in the Tumor Microenvironment and Annotates a Novel Tumor-Invasive Signature in Esophageal Cancer Microenvironment and Immunology Cancer Research Periostin, a Cell Adhesion Molecule, Facilitates Invasion in the Tumor Microenvironment and Annotates a Novel Tumor-Invasive Signature in Esophageal Cancer Carmen Z. Michaylira1,2,5, Gabrielle S. Wong1,2,5, Charles G. Miller1,2,5, Christie M. Gutierrez1,2,5, Hiroshi Nakagawa1,2,5, Rachel Hammond5,6, Andres J. Klein-Szanto7, Ju-Seog Lee9, Sang Bae Kim9, Meenhard Herlyn4, J. Alan Diehl5,8, Phyllis Gimotty5,6, and Anil K. Rustgi1,2,3,5 Abstract Human squamous cell cancers are the most common epithelially derived malignancies. One example is esophageal squamous cell carcinoma (ESCC), which is associated with a high mortality rate that is related to a propensity for invasion and metastasis. Here, we report that periostin, a highly expressed cell adhesion molecule, is a key component of a novel tumor-invasive signature obtained from an organotypic culture model of engineered ESCC. This tumor-invasive signature classifies with human ESCC microarrays, underscoring its utility in human cancer. Genetic modulation of periostin promotes tumor cell migration and invasion as re- vealed in gain-of-loss and loss-of-function experiments. Inhibition of epidermal growth factor receptor signa- ling and restoration of wild-type p53 function were each found to attenuate periostin, suggesting the interdependence of two common genetic alterations with periostin function. Collectively, our studies reveal periostin as an important mediator of ESCC tumor invasion and they indicate that organotypic (three- dimensional) culture can offer an important tool to discover novel biological effectors in cancer. Cancer Res; 70(13); 5281–92. ©2010 AACR. Introduction modeling EGFR overexpression and p53 missense mutation (R175H) in primary human esophageal epithelial cells The development of esophageal squamous cell carcinoma (EPC2), which have been immortalized by hTERT overex- (ESCC) involves a multistep, progressive process starting pression (designated as EPC2-hTERT-EGFR-p53R175H cells). with increased esophageal epithelial cell proliferation leading EPC2-hTERT-EGFR-p53R175H cells were grown in three- to basal cell hyperplasia, dysplasia, carcinoma in situ,and, dimensional organotypic culture, resulting in the invasion finally, advanced invasive carcinoma (1–3). Several genetic al- of these cells into the underlying extracellular matrix terations, such as amplification of the epidermal growth fac- (ECM) compared with EPC2-hTERT-EGFR or EPC2-hTERT- tor (EGF) receptor (EGFR), dysregulation of cyclin D1, and p53R175H cells, which did not invade (5). Combined expres- somatic mutations in the DNA binding domain of the tumor sion of these genes also resulted in anchorage-independent suppressor p53, are involved in initiation and progression of growth and in tumor formation in xenograft models, which ESCC (4). Although EGFR overexpression and p53 inactiva- was not observed in control cells overexpressing either EGFR tion are key genetic alterations associated with ESCC, how or mutant p53 alone (5). these genetic alterations contribute to ESCC progression re- Recent experimental results have provided mounting evi- mains to be elucidated. Previously, we had addressed this by dence that altered expression of cell adhesion molecules can contribute directly to tumor progression by modulating cell Authors' Affiliations: 1Division of Gastroenterology, Departments of signaling. Therefore, we sought to identify genes involved in 2Medicine, 3Genetics, and 4Cancer Biology, 5Abramson Cancer Center, cell adhesion that were differentially expressed in invading and 6Division of Biostatistics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania; 7Division of Basic Science, tumor cells and could shed new insights into processes af- Tumor Cell Biology, Fox Chase Cancer Center; and 8Wistar Institute, fecting tumor progression. Philadelphia, Pennsylvania; and 9Department of Systems Biology, M.D. Anderson Cancer Center, Houston, Texas Deriving a novel invasive tumor signature from a gene ex- pression profile analysis of invading EPC2-hTERT-EGFR- Note: Supplementary data for this article are available at Cancer R175H Research Online (http://cancerres.aacrjournals.org/). p53 cells in three-dimensional culture and human ESCC C.Z. Michaylira and G.S. Wong contributed equally to this work. tumor microarrays, we have identified periostin to be the Corresponding Author: Anil K. Rustgi, 600 CRB University of Pennsylvania, most significantly upregulated gene triggering tumor cell in- 415 Curie Boulevard, Philadelphia, PA 19104. Phone: 215-898-0154; Fax: vasion. Periostin (POSTN) is a secreted 90-kDa protein that 215-573-5412; E-mail: [email protected]. was identified originally as a bone adhesion molecule respon- doi: 10.1158/0008-5472.CAN-10-0704 sible for differentially recruiting and attaching osteoblasts to ©2010 American Association for Cancer Research. the periosteum (6). Periostin is a member of the fasciclin www.aacrjournals.org 5281 Michaylira et al. family and has a NH2-terminal signal peptide sequence, a embedded for laser capture microdissection (LCM) studies cysteine-rich domain, four internal homologous repeats, by embedding in OCT medium followed by freezing in liquid and a hydrophilic COOH-terminal domain (6). These four in- nitrogen and then stored at −80°C. ternal repeat domains share structural homology with Fasci- clin 1, an insect neuronal adhesion protein (6, 7), and big-h3, LCM and RNA isolation atransforminggrowthfactor-β1(TGFβ1)–inducible gene Frozen organotypic cultures were sectioned to 8 μm onto (7, 8). The high degree of structural and sequence similarity membrane-mounted metal frame slides (MMI) using a with these cell adhesion molecules suggests that periostin Microm HM 505E cryostat (Richard Allen Scientific). Sections has a role in cell adhesion and migration. Indeed, not only were immediately fixed, stained, and dehydrated before laser is its expression induced in human ESCC and mouse tumor microdissection. Microdissection was performed with a xenografts, but more importantly, genetic modulation of Nikon Eclipse TE 2000-5 microscope with a UV laser periostin also affects tumor invasion in a direct fashion. (MMI). Microdissected cells were collected, and 50 μL of ex- The novel identification of periostin as an essential mediator traction buffer (Arcturus) were added and incubated for of tumor invasion in the microenvironment has implications 30 minutes at 42°C, followed by centrifugation at 800 × g for upon tumor detection and therapy. 2 minutes. RNA was extracted using the Arcturus PicoPure RNA isolation kit following the manufacturer's instructions. The integrity and concentration of the RNA was assessed Materials and Methods using the Agilent Bioanalyzer 2100 (Agilent Technologies). Cell culture RNA amplification and microarray studies Primary esophageal cells (EPC2) were established from The RNA obtained from the LCM studies was amplified surgical specimens of normal esophagus as previously des- using the Affymetrix GeneChip Expression 3′-Amplification cribed (9) and immortalized by overexpression of the cataly- Two-Cycle cDNA Synthesis kit (Affymetrix) followed by the tic subunit of telomerase (hTERT; EPC2-hTERT cells; ref. 10). Affymetrix GeneChip Hybridization Wash and Stain kit (Affy- All cells were maintained in keratinocyte-SFM medium (Invi- metrix). The resulting cRNA (200 ng) was used as template trogen) supplemented with 40 mg/mL BPE, 1.0 ng/mL EGF, for random-primed cDNA synthesis and a second round of 100 U/mL penicillin, and 100 mg/mL streptomycin (full ker- in vitro transcription, which incorporated biotinylated CTP atinocyte-SFM medium). Cells were grown at 37°C in 5% CO2. and UTP. The cRNA products were fragmented to 200 bp or less, heated at 99°C for 5 minutes, and hybridized for Retroviral vectors and cell line generation 16 hours at 45°C to Affymetrix U133Plus 2.0 oligonucleotide The PFB-neo or pBABE-zeo retroviral vectors were used to microarrays (Affymetrix). Microarrays were subsequently overexpress human EGFR in EPC2-hTERT cells. Additionally, washed at low (6×saline-sodium phosphate-EDTA) and high p53R175H was subcloned into the pBABE-puro or the pBABE- (100 mmol/L MES, 0.1 mol/L NaCl) stringency, and stained zeo retroviral vectors. Periostin cDNA was used (Open Bio- with streptavidin-phycoerythrin. The fluorescence signal systems) and subcloned into the pFBneo retroviral vector. was amplified by the addition of biotinylated anti-streptavidin Two periostin short hairpin RNAs (shRNA#1 5′-CCCATGGA- and an additional aliquot of streptavidin-phycoerythrin stain. GAGCCAATTAT-3′and shRNA#2 5′-CTCTGACATCATGA- A confocal scanner was used to acquire the fluorescent signal CAACAAAT-3′)wereused(OpenBiosystems).Plasmids after excitation (570 nm). were transfected into Phoenix-Ampho packaging cells (gift of G. Nolan, Stanford University, Palo Alto, CA) using the Quantitative PCR Lipofectamine 2000 reagent (Invitrogen). Supernatants of LCM was repeated to isolate invading and noninvading the retroviruses encoding EGFR, mutant p53, periostin over- EPC-hTERT-EGFR-p53R175H cells grown in organotypic cul- expression, and shRNA vector constructs were collected 48 ture. Amplification and cDNA synthesis was performed using and 72 hours after transfection. Subconfluent EPC-hTERT WT-Ovation RNA Amplification System (NuGen Technolo- cells were infected with retrovirus supernatant in 4mg/mL gies) according to the manufacturer's instructions. Real-time polybrene (Sigma). Forty-eight
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