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Nature. 2015 Apr 16;520(7547):358-62. doi: 10.1038/nature14403. Epub 2015 Apr 8.

A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis.

Author information

1
Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
2
1] Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [2] CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robininson Way, Cambridge CB2 0RE, UK.
3
Department of Genetics and Pathology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
4
Molecular and Computational Biology, University of Southern California, Los Angeles, California 90089, USA.
5
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.

Abstract

Cancer metastasis requires that primary tumour cells evolve the capacity to intravasate into the lymphatic system or vasculature, and extravasate into and colonize secondary sites. Others have demonstrated that individual cells within complex populations show heterogeneity in their capacity to form secondary lesions. Here we develop a polyclonal mouse model of breast tumour heterogeneity, and show that distinct clones within a mixed population display specialization, for example, dominating the primary tumour, contributing to metastatic populations, or showing tropism for entering the lymphatic or vasculature systems. We correlate these stable properties to distinct gene expression profiles. Those clones that efficiently enter the vasculature express two secreted proteins, Serpine2 and Slpi, which were necessary and sufficient to program these cells for vascular mimicry. Our data indicate that these proteins not only drive the formation of extravascular networks but also ensure their perfusion by acting as anticoagulants. We propose that vascular mimicry drives the ability of some breast tumour cells to contribute to distant metastases while simultaneously satisfying a critical need of the primary tumour to be fed by the vasculature. Enforced expression of SERPINE2 and SLPI in human breast cancer cell lines also programmed them for vascular mimicry, and SERPINE2 and SLPI were overexpressed preferentially in human patients that had lung-metastatic relapse. Thus, these two secreted proteins, and the phenotype they promote, may be broadly relevant as drivers of metastatic progression in human cancer.

PMID:
25855289
PMCID:
PMC4634366
DOI:
10.1038/nature14403
[Indexed for MEDLINE]
Free PMC Article

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