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  • Oncogenomics
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Identification of VEGF-regulated genes associated with increased lung metastatic potential: functional involvement of tenascin-C in tumor growth and lung metastasis

Oncogene volume 27, pages 5373–5384 (2008)Cite this article

Abstract

Metastasis is the primary cause of death in patients with breast cancer. Overexpression of c-myc in humans correlates with metastases, but transgenic mice only show low rates of micrometastases. We have generated transgenic mice that overexpress both c-myc and vascular endothelial growth factor (VEGF) (Myc/VEGF) in the mammary gland, which develop high rates of pulmonary macrometastases. Gene expression profiling revealed a set of deregulated genes in Myc/VEGF tumors compared to Myc tumors associated with the increased metastatic phenotype. Cross-comparisons between this set of genes with a human breast cancer lung metastasis gene signature identified five common targets: tenascin-C(TNC), matrix metalloprotease-2, collagen-6-A1, mannosidase-α-1A and HLA-DPA1. Signaling blockade or knockdown of TNC in MDA-MB-435 cells resulted in a significant impairment of cell migration and anchorage-independent cell proliferation. Mice injected with clonal MDA-MB-435 cells with reduced expression of TNC demonstrated a significant decrease (P<0.05) in (1) primary tumor growth; (2) tumor relapse after surgical removal of the primary tumor and (3) incidence of lung metastasis. Our results demonstrate that VEGF induces complex alterations in tissue architecture and gene expression. The TNC signaling pathway plays an important role in mammary tumor growth and metastases, suggesting that TNC may be a relevant target for therapy against metastatic breast cancer.

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Acknowledgements

We would like to thank Ms Mercedes Calvo for manuscript preparation, Victor Segura and Elizabeth Guruceaga (CEIT and Tecnun, Pamplona, Spain) for their help in bioinformatic analysis, GlaxoSmithKline for the GW654652 compound, Dr René Bernards (The Netherlands Cancer Institute) for the pMSCV-△31LTR vector, Dr Linda Metheny-Barlow (at the LCCC) for helpful discussions, Edward C Rosfjord and Sandra L Deming and Gloria Chepko for contributions to the initial Myc/VEGF crossbreeding study. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, with funds from NIH (to GM) under Contract No. NO1-CO-12400, a grant from the Susan G Komen Foundation (to RBD), a grant from the DOD Breast Cancer Program DAMD17-01-1-0255 (to MDJ), NIH R01 CA72460 (to RBD), NIH 2R01 CA104963 (to RBD) ISCIII-RETIC (RD06/0020, to AC) and a Fulbright-MEC fellowship (AC); O G-M was supported by a Spanish MEC fellowship, and RBD by an NIH grant 2 R01 AG14963-06.

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Author notes

  1. A Calvo, R Catena and M S Noble: These authors contributed equally to this work.

  2. R B Dickson and J E Green: This paper is dedicated to the memory of Dr Robert Dickson.

  3. M D Johnson and J E Green: Contributed equally as senior authors.

Authors and Affiliations

  1. Laboratory of Cancer Biology and Genetics, NCI, NIH, Bethesda, MD, USA

    A Calvo, J-I Huh, R Sharp, T-H Qiu, G Merlino & J E Green

  2. Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    A Calvo, R Catena, I Gil-Bazo & O Gonzalez-Moreno

  3. Department of Histology and Pathology, University of Navarra, Pamplona, Spain

    A Calvo, R Catena, I Gil-Bazo & O Gonzalez-Moreno

  4. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA

    M S Noble, D Carbott, R B Dickson & M D Johnson

  5. Department of Oncology, University Clinic of Navarra, Pamplona, Spain

    I Gil-Bazo

  6. Pathology and Histology Laboratory, Frederick Cancer and Research Development Center, SAIC, Frederick, MD, USA

    M R Anver

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  1. A Calvo
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Correspondence to M D Johnson or J E Green.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Calvo, A., Catena, R., Noble, M. et al. Identification of VEGF-regulated genes associated with increased lung metastatic potential: functional involvement of tenascin-C in tumor growth and lung metastasis. Oncogene 27, 5373–5384 (2008). https://doi.org/10.1038/onc.2008.155

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