Activation of Wnt signalling in stroma from pancreatic cancer identified by gene expression profiling

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic stroma. Interactions between cancer and stromal cells play a critical role in tumour invasion, metastasis and chemoresistance. Therefore, we hypothesized that gene expression profile of the stromal components of pancreatic carcinoma is different from chronic pancreatitis and reflects the interaction with the tumour. We investigated the gene expression of eleven stromal tissues from PDAC, nine from chronic pancreatitis and cell lines of stromal origin using the Affymetrix U133 GeneChip set. The tissue samples were microdissected, the RNA was extracted, amplified and labelled using a repetitive in vitro transcription protocol. Differentially expressed genes were identified and validated using quantitative RT-PCR and immuno-histochemistry. We found 255 genes to be overexpressed and 61 genes to be underexpressed within the stroma of pancreatic carcinoma compared to the stroma of chronic pancreatitis. Analysis of the involved signal transduction pathways revealed a number of genes associated with the Wnt pathway of which the differential expression of SFRP1 and WNT5a was confirmed using immunohistochemistry. Moreover, we could demonstrate that WNT5a expression was induced in fibroblasts during cocultivation with a pancreatic carcinoma cell line. The identified differences in the expression profile of stroma cells derived from tumour compared to cells of inflammatory origin suggest a specific response of the tissue surrounding malignant cells. The overexpression of WNT5a, a gene involved in the non canonical Wnt signalling and chondrocyte development might contribute to the strong desmoplastic reaction seen in pancreatic cancer.

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Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection.

Jason Wong, Linda C. Li (2001)

Recent advances in cDNA and oligonucleotide DNA arrays have made it possible to measure the abundance of mRNA transcripts for many genes simultaneously. The analysis of such experiments is nontrivial because of large data size and many levels of variation introduced at different stages of the experiments. The analysis is further complicated by the large differences that may exist among different probes used to interrogate the same gene. However, an attractive feature of high-density oligonucleotide arrays such as those produced by photolithography and inkjet technology is the standardization of chip manufacturing and hybridization process. As a result, probe-specific biases, although significant, are highly reproducible and predictable, and their adverse effect can be reduced by proper modeling and analysis methods. Here, we propose a statistical model for the probe-level data, and develop model-based estimates for gene expression indexes. We also present model-based methods for identifying and handling cross-hybridizing probes and contaminating array regions. Applications of these results will be presented elsewhere.

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Cancer statistics, 2006.

Ahmedin Jemal, Rebecca Siegel, Elizabeth Ward … (2006)

Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,399,790 new cancer cases and 564,830 deaths from cancer are expected in the United States in 2006. When deaths are aggregated by age, cancer has surpassed heart disease as the leading cause of death for those younger than age 85 since 1999. Delay-adjusted cancer incidence rates stabilized in men from 1995 through 2002, but continued to increase by 0.3% per year from 1987 through 2002 in women. Between 2002 and 2003, the actual number of recorded cancer deaths decreased by 778 in men, but increased by 409 in women, resulting in a net decrease of 369, the first decrease in the total number of cancer deaths since national mortality record keeping was instituted in 1930. The death rate from all cancers combined has decreased by 1.5% per year since 1993 among men and by 0.8% per year since 1992 among women. The mortality rate has also continued to decrease for the three most common cancer sites in men (lung and bronchus, colon and rectum, and prostate) and for breast and colon and rectum cancers in women. Lung cancer mortality among women continues to increase slightly. In analyses by race and ethnicity, African American men and women have 40% and 18% higher death rates from all cancers combined than White men and women, respectively. Cancer incidence and death rates are lower in other racial and ethnic groups than in Whites and African Americans for all sites combined and for the four major cancer sites. However, these groups generally have higher rates for stomach, liver, and cervical cancers than Whites. Furthermore, minority populations are more likely to be diagnosed with advanced stage disease than are Whites. Progress in reducing the burden of suffering and death from cancer can be accelerated by applying existing cancer control knowledge across all segments of the population.

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Molecular characterization of the tumor microenvironment in breast cancer.

Minna Allinen, Rameen Beroukhim, Li Cai … (2004)

Here we describe the comprehensive gene expression profiles of each cell type composing normal breast tissue and in situ and invasive breast carcinomas using serial analysis of gene expression. Based on these data, we determined that extensive gene expression changes occur in all cell types during cancer progression and that a significant fraction of altered genes encode secreted proteins and receptors. Despite the dramatic gene expression changes in all cell types, genetic alterations were detected only in cancer epithelial cells. The CXCL14 and CXCL12 chemokines overexpressed in tumor myoepithelial cells and myofibroblasts, respectively, bind to receptors on epithelial cells and enhance their proliferation, migration, and invasion. Thus, chemokines may play a role in breast tumorigenesis by acting as paracrine factors.

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Author and article information

Journal

Journal ID (nlm-ta): J Cell Mol Med

Journal ID (iso-abbrev): J. Cell. Mol. Med

Journal ID (publisher-id): jcmm

Title: Journal of Cellular and Molecular Medicine

Publisher: Blackwell Publishing Ltd (Oxford, UK )

ISSN (Print): 1582-1838

ISSN (Electronic): 1582-4934

Publication date (Print): 02 December 2008

Publication date (Electronic): 25 February 2008

Volume: 12

Issue: 6b

Pages: 2823-2835

Affiliations

[a ]Department of Visceral-, Thoracic- and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University of Dresden Dresden, Germany

[b ]Division of Molecular Oncology, Clinic for General Surgery and Thoracic Surgery, University Hospital of Schleswig-Holstein Campus Kiel Kiel, Germany

[c ]Department of Pathology, University Hospital of Kiel Kiel, Germany

[d ]Department of Pathology, University of Aachen Aachen, Germany

[e ]Department of Pathology, University of Regensburg Regensburg, Germany

[f ]Department of Internal Medicine II, Medical Faculty Mannheim, University of Heidelberg Heidelberg, Germany

[g ]Molecular Gastroenterology Unit, German Cancer Research Center Heidelberg, Heidelberg, Germany

[h ]Department of Surgery, University of Heidelberg Heidelberg, Heidelberg, Germany

[i ]Institute of Pathology, Charité-Universitätsmedizin Berlin Berlin, Germany

[j ]Department of Surgical Research, University Hospital Carl Gustav Carus, Technical University of Dresden Dresden, Germany

Author notes

*Correspondence to: Christian PILARSKY, PhD, Department of Visceral-, Thoracic- and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University of Dresden, Fetscherstr. 74 01307 Dresden, Germany. Tel.: +49 351 458 6607 Fax: + 49 351 458 7338 E-mail: christian.pilarsky@ 123456mailbox.tu-dresden.de

Article

DOI: 10.1111/j.1582-4934.2008.00289.x

PMC ID: 3828895

PubMed ID: 18298655

SO-VID: 7fde3123-8fa6-4a80-89c5-57626fc954cf

History

Date received : 15 October 2007

Date accepted : 11 February 2008

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Activation of Wnt signalling in stroma from pancreatic cancer identified by gene expression profiling

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Most cited references 44

Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection.

Cancer statistics, 2006.

Molecular characterization of the tumor microenvironment in breast cancer.

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