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BMC Genomics Biomed Central BMC Genomics BioMed Central Research article Open Access Expression analysis of secreted and cell surface genes of five transformed human cell lines and derivative xenograft tumors Robert A Stull1, Roya Tavassoli1, Scot Kennedy1, Steve Osborn1, Rachel Harte1, Yan Lu1, Cheryl Napier2, Arie Abo*1 and Daniel J Chin*1 Address: 1PPD Discovery, 1505 O'Brien Street, Menlo Park, California 94025, USA and 2Piedmont Research Center, Morrisville, North Carolina 27560, USA Email: Robert A Stull - [email protected]; Roya Tavassoli - [email protected]; Scot Kennedy - [email protected]; Steve Osborn - [email protected]; Rachel Harte - [email protected]; Yan Lu - [email protected]; Cheryl Napier - [email protected]; Arie Abo* - [email protected]; Daniel J Chin* - [email protected] * Corresponding authors Published: 18 April 2005 Received: 20 September 2004 Accepted: 18 April 2005 BMC Genomics 2005, 6:55 doi:10.1186/1471-2164-6-55 This article is available from: http://www.biomedcentral.com/1471-2164/6/55 © 2005 Stull et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Since the early stages of tumorigenesis involve adhesion, escape from immune surveillance, vascularization and angiogenesis, we devised a strategy to study the expression profiles of all publicly known and putative secreted and cell surface genes. We designed a custom oligonucleotide microarray containing probes for 3531 secreted and cell surface genes to study 5 diverse human transformed cell lines and their derivative xenograft tumors. The origins of these human cell lines were lung (A549), breast (MDA MB-231), colon (HCT-116), ovarian (SK-OV-3) and prostate (PC3) carcinomas. Results: Three different analyses were performed: (1) A PCA-based linear discriminant analysis identified a 54 gene profile characteristic of all tumors, (2) Application of MANOVA (Pcorr < .05) to tumor data revealed a larger set of 149 differentially expressed genes. (3) After MANOVA was performed on data from individual tumors, a comparison of differential genes amongst all tumor types revealed 12 common differential genes. Seven of the 12 genes were identified by all three analytical methods. These included late angiogenic, morphogenic and extracellular matrix genes such as ANGPTL4, COL1A1, GP2, GPR57, LAMB3, PCDHB9 and PTGER3. The differential expression of ANGPTL4 and COL1A1 and other genes was confirmed by quantitative PCR. Conclusion: Overall, a comparison of the three analyses revealed an expression pattern indicative of late angiogenic processes. These results show that a xenograft model using multiple cell lines of diverse tissue origin can identify common tumorigenic cell surface or secreted molecules that may be important biomarker and therapeutic discoveries. Background formation and increased proliferation, many pathways The process of tumorigenesis has long been recognized to are activated both in the growing tumor and its environ- depend upon complex interactions of a tumor with its ment to culminate in an established solid tumor. For non-transformed tissue environment [1]. Beyond trans- example, adhesive pathways are activated to enable Page 1 of 20 (page number not for citation purposes) BMC Genomics 2005, 6:55 http://www.biomedcentral.com/1471-2164/6/55 transformed cells to aggregate and form a microtumor. migration include the chorioallantoic membrane [17], Subsequently, microtumors must avoid destruction by the matrigel migration assays [18] or 3D-collagen assays [19]. immune system and elicit vasculature formation for con- However, the limits of studying the angiogenic process tinued growth [2,3]. In support of these events, cell-matrix with established endothelial cells in vitro have been rec- adhesion proteins, cell surface antigens, angiogenic fac- ognized. Tumorigenesis involves both heterophilic and tors and modulatory agents have been found differentially homophilic cellular communication and adhesion expressed in several experimental models of tumorigene- between not only endothelial cells but also pericytes and sis [4-6] and in tumor biopsy samples relative to control smooth muscle cells; hence other cell surface proteins and tissues [7,8]. Experimental models with established tum- secreted factors are absent from such assays [3]. origenic human cell lines have compared the gene expres- sion profiles between the cultured parental cells and after A search for tumorigenic genes common to tumors of implantation into immune-deficient murine hosts [6]. In diverse origin should be as broad as possible and hence this study, we examined this problem with a more focused should not be limited to a single tumor type or tissue approach with respect to the transcripts as well as a source. In order to find common tumorigenic genes broader survey by examining multiple tumor sources in regardless of tissue origin, we chose to study a panel of 5 order to identify differential genes common to multiple adenocarcinoma cell lines from breast, colon, and lung, solid tumors in a xenograft model of tumorigenesis. ovarian and prostate tumors. These cell lines reproducibly yield solid tumors in a standard xenograft assay in To recapitulate the attachment and growth of a micro- or immuno-compromised mice [20-22]. While there may be metastatic tumor, our experimental tumorigenesis model individual differences in capillary branching or density examined human xenograft tumors in nude mice. It is between tumor types, the xenograft assay requires vascular believed that primary or metastatic microtumors about 1 development to support solid tumor formation in a rela- mm3 in size are metastable; they are either (i) resolved by tively avascular subcutaneous site. the immune system, (ii) remain in a steady-state with bal- anced proliferation and apoptosis or (iii) undergo aggres- Since the early tumorigenic events largely rely upon sive growth as long as a vasculature is developed to secreted factors, cell surface receptors or integral mem- provide nutrients to the growing mass [9]. Since the end- brane proteins, we devised a strategy to employ a custom point of the xenograft assay is the formation of a solid microarray to focus on the expression of genes chosen on tumor, genes supporting vasculogenesis and angiogenesis the basis of their cellular localization. Hence, we imple- are likely differentially expressed relative to the parental mented an experimental microarray strategy with high cell lines that were adapted to culture in vitro. However, replication and coverage of all possible secreted and cell the extent of vascularization to support an established surface proteins. Also, focusing on all known and pre- tumor will vary according to the tumor type and tissue dicted cell surface and secreted genes allowed us to design environment as a result of variable levels of proteases, more intra-chip replicates for improved data reliability. receptors or regulators of pericyte and/or endothelial While prioritizing on the 'Function' category of the Gene migration, proliferation, and differentiation [3,10]. Addi- Ontology [23], the range of 'Biological Processes' covered tionally, some tumors such as early grade astrocytomas by the gene selection remained broad. In contrast to early can leverage existing normal brain blood vessels without concerns that a sub-selection of genes might result in a substantial vasculogenesis for subsequent angiogenic systemic bias, relatively small numbers of genes were sprouting of new vessels from preexisting vessels [11]. found to be common to all xenograft tumors due to the Further, vascularization depends upon a tuned interaction robust experimental design and statistical analysis. in the tissue microenvironment between endothelial cells and pericytes [12,13]. Vascularization of solid tumors Results may also be heterogeneous with a rapidly growing margin We developed a custom 60-mer oligonucleotide microar- surrounding a hypoxic core following regression of co- ray to focus on an ontologically restricted set of secreted opted vessels that supported early tumor growth [10]. and cell surface genes for higher data reliability using a Complicating this picture is the potential for Vascular matrix design with intra-chip replicates in addition to rep- mimicry' where breast tumor derived cells express licate chips. Due to the limits of the Gene Ontology clas- endothelial markers and may serve as rudimentary chan- sification, multiple strategies had to be used to derive a nels [14]. relatively complete collection of secreted and cell surface genes. For example, some proteins have multiple localiza- Many angiogenesis studies have used cultured primary tion sites on the basis of newer experimental evidence vascular endothelial cells and shown the significant roles absent from curated databases; e.g. SORCS3, HDGF. For of VEGF, FGF, PDGF, chemokines and cell-matrix adhe- proteins with multiple cellular localizations, the literature sion proteins [3,15,16]. These assays for endothelial cell (PubMed, NCBI) was the annotation source for finding Page 2 of 20 (page number not for citation purposes) BMC Genomics 2005, 6:55 http://www.biomedcentral.com/1471-2164/6/55 GeneFigure ontology 1 of custom chip probes Gene ontology of custom chip probes.
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