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Integrin α9β1 promotes malignant tumor growth and metastasis by potentiating epithelial-mesenchymal transition.

Gupta SK, Oommen S, Aubry MC, Williams BP, Vlahakis NE - Oncogene (2012)

Bottom Line: In addition, we found that α9β1 forms a tri-partite protein complex with β-catenin and E-cadherin, which dissociates following integrin activation and subsequent src and β-catenin phosphorylation.These in vitro results are biologically significant as α9β1-expressing cancer cells induce greater tumor growth and metastases in mice as compared to the cells without α9β1 expression or when integrin expression is suppressed.Furthermore, integrin α9β1 is expressed in primary human small cell lung cancer and patients having a high expression of α9β1 demonstrated significantly worse long-term survival compared with patients with low α9β1 expression.

View Article: PubMed Central - PubMed

Affiliation: Thoracic Disease Research Unit, Division of Pulmonary & Critical Care Medicine, Mayo Clinic, Rochester 55905, MN, USA.

ABSTRACT
The integrin α9β1 binds a number of extracellular matrix components to mediate cell adhesion, migration and tissue invasion. Although expressed in a variety of normal human cells including endothelium, it is also expressed in cancer cells. We have previously shown that α9β1 binds VEGF-A to facilitate angiogenesis, an important component of the tumor microenvironment. As α9β1 induces accelerated cancer cell migration, we wished to determine what role it played in cancer growth and metastasis. In this study, we show that α9β1 expression induces molecular changes consistent with epithelial-mesenchymal transition. In addition, we found that α9β1 forms a tri-partite protein complex with β-catenin and E-cadherin, which dissociates following integrin activation and subsequent src and β-catenin phosphorylation. These findings were consistent in cells in which: α9β1 was exogenously over-expressed, or when its expression was suppressed in cancer cells endogenously expressing α9β1. These in vitro results are biologically significant as α9β1-expressing cancer cells induce greater tumor growth and metastases in mice as compared to the cells without α9β1 expression or when integrin expression is suppressed. Furthermore, integrin α9β1 is expressed in primary human small cell lung cancer and patients having a high expression of α9β1 demonstrated significantly worse long-term survival compared with patients with low α9β1 expression. These findings highlight a novel mechanism of integrin α9β1 function in human cancer.

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α9β1 is associated with increased tumor growth, EMT and cancer metastasisA, Volume of mouse flank tumors formed following subcutaneous injection of SW480-mock (n=5) or SW480-α9 (n=5) cells. B, Top panel: representative photomicrographs of tumor sections stained for the endothelial cell marker CD31 or the lymphatic marker, D2-40; Bottom panel: quantitative analysis of intra-tumoral blood vessels counted in 1 view field (10X) (n=3 per cell type). C, Immunoblots showing relative expression of α9, CD31, EMT-associated cadherin proteins and vimentin in 3 separate tumors derived from SW480-mock or α9 cells. D, Left panel: representative images of lymph nodes from mice injected with SW480-mock or α9 cells; Right top panels: photomicrographs showing lung metastases grossly (arrow) or H&E stained; Bottom right panels: H&E stained liver sections demonstrating metastases at low (40x) and high power (400X).
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Figure 3: α9β1 is associated with increased tumor growth, EMT and cancer metastasisA, Volume of mouse flank tumors formed following subcutaneous injection of SW480-mock (n=5) or SW480-α9 (n=5) cells. B, Top panel: representative photomicrographs of tumor sections stained for the endothelial cell marker CD31 or the lymphatic marker, D2-40; Bottom panel: quantitative analysis of intra-tumoral blood vessels counted in 1 view field (10X) (n=3 per cell type). C, Immunoblots showing relative expression of α9, CD31, EMT-associated cadherin proteins and vimentin in 3 separate tumors derived from SW480-mock or α9 cells. D, Left panel: representative images of lymph nodes from mice injected with SW480-mock or α9 cells; Right top panels: photomicrographs showing lung metastases grossly (arrow) or H&E stained; Bottom right panels: H&E stained liver sections demonstrating metastases at low (40x) and high power (400X).

Mentions: We next performed tumor experiments to determine the pro-carcinogenic effects of α9β1 in-vivo. Tumors formed in mice from flank injection of SW480-α9 cells were up to 3 times larger than tumors formed from SW480-mock cells (Fig 3A), were associated with increased intra-tumoral angiogenesis and lymphangiogenesis (Fig 3B) and displayed altered cadherin and vimentin expression consistent with EMT (Fig 3C).


Integrin α9β1 promotes malignant tumor growth and metastasis by potentiating epithelial-mesenchymal transition.

Gupta SK, Oommen S, Aubry MC, Williams BP, Vlahakis NE - Oncogene (2012)

α9β1 is associated with increased tumor growth, EMT and cancer metastasisA, Volume of mouse flank tumors formed following subcutaneous injection of SW480-mock (n=5) or SW480-α9 (n=5) cells. B, Top panel: representative photomicrographs of tumor sections stained for the endothelial cell marker CD31 or the lymphatic marker, D2-40; Bottom panel: quantitative analysis of intra-tumoral blood vessels counted in 1 view field (10X) (n=3 per cell type). C, Immunoblots showing relative expression of α9, CD31, EMT-associated cadherin proteins and vimentin in 3 separate tumors derived from SW480-mock or α9 cells. D, Left panel: representative images of lymph nodes from mice injected with SW480-mock or α9 cells; Right top panels: photomicrographs showing lung metastases grossly (arrow) or H&E stained; Bottom right panels: H&E stained liver sections demonstrating metastases at low (40x) and high power (400X).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3368989&req=5

Figure 3: α9β1 is associated with increased tumor growth, EMT and cancer metastasisA, Volume of mouse flank tumors formed following subcutaneous injection of SW480-mock (n=5) or SW480-α9 (n=5) cells. B, Top panel: representative photomicrographs of tumor sections stained for the endothelial cell marker CD31 or the lymphatic marker, D2-40; Bottom panel: quantitative analysis of intra-tumoral blood vessels counted in 1 view field (10X) (n=3 per cell type). C, Immunoblots showing relative expression of α9, CD31, EMT-associated cadherin proteins and vimentin in 3 separate tumors derived from SW480-mock or α9 cells. D, Left panel: representative images of lymph nodes from mice injected with SW480-mock or α9 cells; Right top panels: photomicrographs showing lung metastases grossly (arrow) or H&E stained; Bottom right panels: H&E stained liver sections demonstrating metastases at low (40x) and high power (400X).
Mentions: We next performed tumor experiments to determine the pro-carcinogenic effects of α9β1 in-vivo. Tumors formed in mice from flank injection of SW480-α9 cells were up to 3 times larger than tumors formed from SW480-mock cells (Fig 3A), were associated with increased intra-tumoral angiogenesis and lymphangiogenesis (Fig 3B) and displayed altered cadherin and vimentin expression consistent with EMT (Fig 3C).

Bottom Line: In addition, we found that α9β1 forms a tri-partite protein complex with β-catenin and E-cadherin, which dissociates following integrin activation and subsequent src and β-catenin phosphorylation.These in vitro results are biologically significant as α9β1-expressing cancer cells induce greater tumor growth and metastases in mice as compared to the cells without α9β1 expression or when integrin expression is suppressed.Furthermore, integrin α9β1 is expressed in primary human small cell lung cancer and patients having a high expression of α9β1 demonstrated significantly worse long-term survival compared with patients with low α9β1 expression.

View Article: PubMed Central - PubMed

Affiliation: Thoracic Disease Research Unit, Division of Pulmonary & Critical Care Medicine, Mayo Clinic, Rochester 55905, MN, USA.

ABSTRACT
The integrin α9β1 binds a number of extracellular matrix components to mediate cell adhesion, migration and tissue invasion. Although expressed in a variety of normal human cells including endothelium, it is also expressed in cancer cells. We have previously shown that α9β1 binds VEGF-A to facilitate angiogenesis, an important component of the tumor microenvironment. As α9β1 induces accelerated cancer cell migration, we wished to determine what role it played in cancer growth and metastasis. In this study, we show that α9β1 expression induces molecular changes consistent with epithelial-mesenchymal transition. In addition, we found that α9β1 forms a tri-partite protein complex with β-catenin and E-cadherin, which dissociates following integrin activation and subsequent src and β-catenin phosphorylation. These findings were consistent in cells in which: α9β1 was exogenously over-expressed, or when its expression was suppressed in cancer cells endogenously expressing α9β1. These in vitro results are biologically significant as α9β1-expressing cancer cells induce greater tumor growth and metastases in mice as compared to the cells without α9β1 expression or when integrin expression is suppressed. Furthermore, integrin α9β1 is expressed in primary human small cell lung cancer and patients having a high expression of α9β1 demonstrated significantly worse long-term survival compared with patients with low α9β1 expression. These findings highlight a novel mechanism of integrin α9β1 function in human cancer.

Show MeSH
Related in: MedlinePlus