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Myofibroblasts enable invasion of endothelial cells into three-dimensional tumor cell clusters: a novel in vitro tumor model

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Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

In an effort to study the importance of stromal involvement in angiogenesis, we developed a novel, multicellular model that utilizes three of the primary cell types involved in tumor angiogenesis.

Methods

Fluorescently labeled human microvascular endothelial cells (HMVECs), 10T1/2 cells and myofibroblasts were incubated in the presence of a three-dimensional tumor cell cluster resuspended in collagen and embedded in Matrigel.

Results

HMVECs cultured in the presence of a human SKOV-3 ovarian carcinoma tumor cell cluster, surrounded the tumor cell cluster, while myofibroblasts invaded the cluster, localizing within the tumor cell mass. In contrast, 10T1/2 cells, a pluripotent mouse mesenchymal cell line with pericyte-like properties, did not demonstrate the same invasive phenotype. HMVECs cultured in the presence of myofibroblasts invaded the tumor cell cluster and colocalized with the myofibroblasts as demonstrated by fluorescent microscopy and immunohistochemistry. The angiogenesis inhibitors SU6668 and paclitaxel inhibited stromal invasion, while a broad-spectrum matrix metalloproteinase inhibitor did not.

Conclusions

This model emphasizes the critical interaction between endothelial cells and myofibroblasts and provides a more complete in vitro model for studying angiogenesis and tumor progression.

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Fig. 1.
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Fig. 3A, B.
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Acknowledgements

We thank the Histology Department for help in sample processing and sectioning, Patty Clow for assistance in confocal imaging, Megan O'Brien and Leslie Kurtzberg for technical assistance, Trent Richardson for image processing, and Cecile Rouleau for critical reading of the manuscript.

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Author notes

  1. Jennifer Walter-Yohrling

    Present address: Clinical Pharmacology, Centocor, Inc., 200 Great Valley Parkway, Malvern, PA 19355-1307, USA

Authors and Affiliations

  1. Department of Tumor Biology, Genzyme Molecular Oncology, Genzyme Corporation, Five Mountain Road, Framingham, MA 01701, USA

    Jennifer Walter-Yohrling, Bruce M. Pratt, Steve Ledbetter & Beverly A. Teicher

Authors
  1. Jennifer Walter-Yohrling
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  2. Bruce M. Pratt
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Correspondence to Jennifer Walter-Yohrling.

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Walter-Yohrling, J., Pratt, B.M., Ledbetter, S. et al. Myofibroblasts enable invasion of endothelial cells into three-dimensional tumor cell clusters: a novel in vitro tumor model. Cancer Chemother Pharmacol 52, 263–269 (2003). https://doi.org/10.1007/s00280-003-0664-2

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  • DOI: https://doi.org/10.1007/s00280-003-0664-2

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