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Syndecan-1 expression by stromal fibroblasts promotes breast carcinoma growth in vivo and stimulates tumor angiogenesis

Oncogene volume 25, pages 1408–1412 (2006)Cite this article

Abstract

The induction of the cell surface heparan sulfate proteoglycan syndecan-1 (Sdc1) in stromal fibroblasts is observed in more than 70% of human breast carcinomas. Using a coculture model, we have recently shown that stromal cell-derived Sdc1 stimulates carcinoma cell proliferation in vitro, and that this activity requires Sdc1 glycanation. In the present study, we investigated the effect of stromal cell Sdc1 on breast carcinoma growth in vivo. MDA-MB-231 human breast carcinoma cells were inoculated into the flanks of athymic nude mice either alone, or as mixed suspensions with Sdc1-transfected or mock-transfected 3T3 mouse fibroblasts. The mixed tumors showed an intimate association between carcinoma cells and stromal fibroblasts and histologically closely resembled poorly differentiated human breast carcinomas. The presence of fibroblasts led to significantly accelerated tumor growth, which was further augmented (88% increase) by forced expression of stromal Sdc1. The hyperemic macroscopic appearance of tumors containing Sdc1-positive stromal cells contrasted with pale tumors developing in the presence of mock-transfected fibroblasts, which prompted us to examine tumor microvessels. Stromal Sdc1 expression was associated with a significantly elevated microvessel density (36% increase) and a larger vessel area (153% increase). To evaluate the relevance of this finding in human breast cancer, the relationship between stromal Sdc1 and tumor vascularity was also examined in a tissue array containing 207 human breast carcinoma samples. Similar to the xenografts, stromal Sdc1 expression correlated with both vessel density (P=0.013) and total vessel area (P=0.0026). In conclusion, stromal fibroblast-derived Sdc1 stimulates breast carcinoma growth and angiogenesis in vivo.

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Abbreviations

ECM:

extracellular matrix

CK:

cytokeratin

FGFs:

fibroblast growth factors

HSPGs:

heparan sulfate proteoglycans

HGF:

hepatocyte growth factor

HB-EGF:

heparin-binding EGF-like growth factor

Sdc1:

syndecan-1

VEGF:

vascular endothelial growth factor

FGFR:

FGF receptor

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Acknowledgements

This work was supported by: NIH R01-CA107012, Susan G Komen Foundation Grant BCTR0402969, Cancer Center Core Grant CA14520 and the Translational Research Initiative in Pathology (TRIP) core laboratory. We acknowledge Satoshi Kinoshita and Thomas Pier for their excellent histology and immunohistochemistry work. We also thank Dr Jens Eickhoff, Department of Biostatistics and Medical Informatics, University of Wisconsin, for helpful comments on the appropriate use of statistical tests. Alexander Friedl contributed to computer-assisted image analysis.

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  1. T Maeda

    Present address: Department of Anatomy and Cell Biology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan

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  1. Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA

    T Maeda, J Desouky & A Friedl

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Correspondence to A Friedl.

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Maeda, T., Desouky, J. & Friedl, A. Syndecan-1 expression by stromal fibroblasts promotes breast carcinoma growth in vivo and stimulates tumor angiogenesis. Oncogene 25, 1408–1412 (2006). https://doi.org/10.1038/sj.onc.1209168

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