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SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor–stromal interactions

Oncogene volume 22, pages 5021–5030 (2003)Cite this article

Abstract

Deregulated expression of SPARC/osteonectin, a secreted glycoprotein with multiple biological functions, has been associated with the progression of various cancers. Using microarrays, we previously identified SPARC as one of the genes induced by treatment with a DNA methylation inhibitor in pancreatic cancer cells. We therefore analysed the expression pattern and methylation status of the SPARC gene in pancreatic cancer. Gene expression profiling by oligonucleotide microarray and reverse transcription–PCR analyses demonstrated that SPARC mRNA was expressed in non-neoplastic pancreatic ductal epithelial cells, but was not expressed in a majority of pancreatic cancer cell lines. The loss of SPARC expression was associated with aberrant hypermethylation of its CpG island. Immunohistochemical labeling revealed that the SPARC protein was overexpressed in the stromal fibroblasts immediately adjacent to the neoplastic epithelium in primary pancreatic cancers, but rarely expressed in the cancers themselves. Primary fibroblasts derived from pancreatic cancer strongly expressed SPARC mRNA and secreted SPARC protein into the conditioned media, and treatment of pancreatic cancer cells with exogenous SPARC resulted in growth suppression. SPARC expression in fibroblasts from noncancerous pancreatic tissue was augmented by coculture with pancreatic cancer cells. These findings suggest that SPARC is a frequent target for aberrant methylation in pancreatic cancer and that SPARC expression in fibroblasts adjacent to pancreatic cancer cells is regulated through tumor–stromal interactions.

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Abbreviations

SAGE:

serial analysis of gene expression

5Aza-dC:

5-aza-2′-deoxycytidine

RT–PCR:

reverse transcription–polymerase chain reaction

MSP:

methylation-specific polymerase chain reaction

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Acknowledgements

This work was supported by the SPORE in Gastrointestinal Malignancies (CA62924), the Michael Rolfe Foundation, and a gift to support pancreatic cancer research from Susan Gurney. We thank Dr Scott E Kern (The Johns Hopkins Medical Institutions, Baltimore, MD, USA) for providing the DNA samples from pancreatic cancer xenografts, and Professor Masao Tanaka and Dr Kazuhiro Mizumoto (Kyushu University, Fukuoka, Japan) for providing primary fibroblasts.

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Authors and Affiliations

  1. Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Norihiro Sato, Noriyoshi Fukushima, Naoki Maehara, Hiroyuki Matsubayashi, Jens Koopmann, Gloria H Su, Ralph H Hruban & Michael Goggins

  2. Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Gloria H Su, Ralph H Hruban & Michael Goggins

  3. Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Michael Goggins

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  1. Norihiro Sato
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Correspondence to Michael Goggins.

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Sato, N., Fukushima, N., Maehara, N. et al. SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor–stromal interactions. Oncogene 22, 5021–5030 (2003). https://doi.org/10.1038/sj.onc.1206807

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