Mediators of vascular remodelling co-opted for sequential steps in lung metastasis

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Abstract

Metastasis entails numerous biological functions that collectively enable cancerous cells from a primary site to disseminate and overtake distant organs. Using genetic and pharmacological approaches, we show that the epidermal growth factor receptor ligand epiregulin, the cyclooxygenase COX2, and the matrix metalloproteinases 1 and 2, when expressed in human breast cancer cells, collectively facilitate the assembly of new tumour blood vessels, the release of tumour cells into the circulation, and the breaching of lung capillaries by circulating tumour cells to seed pulmonary metastasis. These findings reveal how aggressive primary tumorigenic functions can be mechanistically coupled to greater lung metastatic potential, and how such biological activities may be therapeutically targeted with specific drug combinations.

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Figure 1: EREG, MMP1, MMP2 and COX2 cooperate to mediate primary tumour growth.
Figure 2: EREG, MMP1, MMP2 and COX2 mediate tumour angiogenic progression.
Figure 3: Genetic inhibition of EREG, MMP1, MMP2 and COX2 prevents metastatic extravasation.
Figure 4: Pharmacological inhibition of tumour growth and dissemination in orthotopically implanted primary tumours.
Figure 5: Targeted inhibition of metastatic extravasation and lung colonization by LM2 and primary malignant cells.

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Acknowledgements

We thank A. Minn, D. Padua, C. Van Poznak, L. Norton, C. Hudis, Y. Pylayeva, P. Gupta, T. Westbrook and Z. Lazar for insightful discussions and technical suggestions. We also thank S. Tulley and members of the Molecular Cytology Core Facility for expert technical assistance. J.M. was funded by a National Institutes of Health grant, and by grants of the W. M. Keck Foundation and the Kleberg Foundation. G.P.G. is supported by an NIH Medical Scientist Training Program grant and a Department of Defense Breast Cancer Research Program pre-doctoral award. D.X.N. is a Berlex postdoctoral fellow of the Damon Runyon Cancer Research Foundation. A.C.C. was supported by an ASCO Young Investigator Award and by the Charles A. Dana Foundation. J.M. is an Investigator of the Howard Hughes Medical Institute.

Author Contributions J.M. designed and supervised experiments. G.P.G., D.X.N. and A.C.C. designed experiments; G.P.G., D.X.N., A.C.C., P.D.B. and J.Y.K. performed experiments; C.N. and R.R.G. isolated metastatic cells from clinical samples; K.T.-M. supervised histological and confocal microscopy imaging; J.M., G.P.G., D.X.N. and A.C.C. analysed data and wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Joan Massagué.

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Gupta, G., Nguyen, D., Chiang, A. et al. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446, 765–770 (2007) doi:10.1038/nature05760

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