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

A. Calvo, R. Catena, M. S. Noble, D. Carbott, I. Gil-Bazo, O. Gonzalez-Moreno, J. I. Huh, Richard R Sharp, T. H. Qiu, M. R. Anver, G. Merlino, R. B. Dickson, M. D. Johnson, J. E. Green

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)5373-5384
Number of pages12
JournalOncogene
Volume27
Issue number40
DOIs
StatePublished - Sep 11 2008

Fingerprint

Tenascin
Vascular Endothelial Growth Factor A
Neoplasm Metastasis
Lung
Breast Neoplasms
Growth
Genes
Neoplasms
Transgenic Mice
Mannosidases
Neoplasm Micrometastasis
myc Genes
Metalloproteases
Gene Expression Profiling
Human Mammary Glands
Cell Movement
Cause of Death
Lung Neoplasms
Collagen
Cell Proliferation

Keywords

  • Mammary cancer
  • Metastasis
  • Tenascin-C
  • Transgenic mice
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Identification of VEGF-regulated genes associated with increased lung metastatic potential : Functional involvement of tenascin-C in tumor growth and lung metastasis. / Calvo, A.; Catena, R.; Noble, M. S.; Carbott, D.; Gil-Bazo, I.; Gonzalez-Moreno, O.; Huh, J. I.; Sharp, Richard R; Qiu, T. H.; Anver, M. R.; Merlino, G.; Dickson, R. B.; Johnson, M. D.; Green, J. E.

In: Oncogene, Vol. 27, No. 40, 11.09.2008, p. 5373-5384.

Research output: Contribution to journalArticle

Calvo, A, Catena, R, Noble, MS, Carbott, D, Gil-Bazo, I, Gonzalez-Moreno, O, Huh, JI, Sharp, RR, Qiu, TH, Anver, MR, Merlino, G, Dickson, RB, Johnson, MD & Green, JE 2008, 'Identification of VEGF-regulated genes associated with increased lung metastatic potential: Functional involvement of tenascin-C in tumor growth and lung metastasis', Oncogene, vol. 27, no. 40, pp. 5373-5384. https://doi.org/10.1038/onc.2008.155
Calvo, A. ; Catena, R. ; Noble, M. S. ; Carbott, D. ; Gil-Bazo, I. ; Gonzalez-Moreno, O. ; Huh, J. I. ; Sharp, Richard R ; Qiu, T. H. ; Anver, M. R. ; Merlino, G. ; Dickson, R. B. ; Johnson, M. D. ; Green, J. E. / Identification of VEGF-regulated genes associated with increased lung metastatic potential : Functional involvement of tenascin-C in tumor growth and lung metastasis. In: Oncogene. 2008 ; Vol. 27, No. 40. pp. 5373-5384.
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T2 - Functional involvement of tenascin-C in tumor growth and lung metastasis

AU - Calvo, A.

AU - Catena, R.

AU - Noble, M. S.

AU - Carbott, D.

AU - Gil-Bazo, I.

AU - Gonzalez-Moreno, O.

AU - Huh, J. I.

AU - Sharp, Richard R

AU - Qiu, T. H.

AU - Anver, M. R.

AU - Merlino, G.

AU - Dickson, R. B.

AU - Johnson, M. D.

AU - Green, J. E.

PY - 2008/9/11

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N2 - 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.

AB - 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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KW - Tenascin-C

KW - Transgenic mice

KW - Vascular endothelial growth factor

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