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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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High expression of α9β1 in human SCLC predicts shorter patient survivalA, Immunoblot of lysates from fresh frozen SCLC samples for detection of α9β1; densitometric quantification from 3 separate immunoblots. B, Representative photomicrographs (20X) of SCLC samples (3 patients) stained to detect α9β1. Bottom panels are normal lung controls. C, Patient characteristics of tumors with high or low α9β1 expression. D, Kaplan-Meyer plot comparing survival in patients with high or low α9β1 expression.
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Figure 6: High expression of α9β1 in human SCLC predicts shorter patient survivalA, Immunoblot of lysates from fresh frozen SCLC samples for detection of α9β1; densitometric quantification from 3 separate immunoblots. B, Representative photomicrographs (20X) of SCLC samples (3 patients) stained to detect α9β1. Bottom panels are normal lung controls. C, Patient characteristics of tumors with high or low α9β1 expression. D, Kaplan-Meyer plot comparing survival in patients with high or low α9β1 expression.

Mentions: Based on our in vitro and in vivo data, we postulated that the extent of α9β1 expression in SCLC might correlate with the severity of disease. We analyzed SCLC tissue from fifteen patients and found variable α9β1 expression both by immunoblot (Fig 6A) and RT-PCR (data not shown). Tumors from three separate patients, were also used for immunohistochemistry which confirmed the expression of α9β1 on the surface of SCLC cells (Fig 6B). Subsequently, we were able to separate patients based on the extent of α9β1 expression in their tumor tissue: eleven high expressers and four low expressers. Fig 6C tables the characteristics of the patients in relation to the degree of α9β1 activity and is highlighted by significant differences in stage of disease and survival time. The average survival for patients with high α9β1 was 19 mo compared to 30 mo in patients with low α9β1 expression (p<0.001), (Fig 6D).


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)

High expression of α9β1 in human SCLC predicts shorter patient survivalA, Immunoblot of lysates from fresh frozen SCLC samples for detection of α9β1; densitometric quantification from 3 separate immunoblots. B, Representative photomicrographs (20X) of SCLC samples (3 patients) stained to detect α9β1. Bottom panels are normal lung controls. C, Patient characteristics of tumors with high or low α9β1 expression. D, Kaplan-Meyer plot comparing survival in patients with high or low α9β1 expression.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368989&req=5

Figure 6: High expression of α9β1 in human SCLC predicts shorter patient survivalA, Immunoblot of lysates from fresh frozen SCLC samples for detection of α9β1; densitometric quantification from 3 separate immunoblots. B, Representative photomicrographs (20X) of SCLC samples (3 patients) stained to detect α9β1. Bottom panels are normal lung controls. C, Patient characteristics of tumors with high or low α9β1 expression. D, Kaplan-Meyer plot comparing survival in patients with high or low α9β1 expression.
Mentions: Based on our in vitro and in vivo data, we postulated that the extent of α9β1 expression in SCLC might correlate with the severity of disease. We analyzed SCLC tissue from fifteen patients and found variable α9β1 expression both by immunoblot (Fig 6A) and RT-PCR (data not shown). Tumors from three separate patients, were also used for immunohistochemistry which confirmed the expression of α9β1 on the surface of SCLC cells (Fig 6B). Subsequently, we were able to separate patients based on the extent of α9β1 expression in their tumor tissue: eleven high expressers and four low expressers. Fig 6C tables the characteristics of the patients in relation to the degree of α9β1 activity and is highlighted by significant differences in stage of disease and survival time. The average survival for patients with high α9β1 was 19 mo compared to 30 mo in patients with low α9β1 expression (p<0.001), (Fig 6D).

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