The α2β1 integrin is a metastasis suppressor in mouse models and human cancer
Norma E. Ramirez, Zhonghua Zhang, Aasakiran Madamanchi, Kelli L. Boyd, Lynda D. O’Rear, Abudi Nashabi, Zhengzi Li, William D. Dupont, Andries Zijlstra, Mary M. Zutter
Norma E. Ramirez, Zhonghua Zhang, Aasakiran Madamanchi, Kelli L. Boyd, Lynda D. O’Rear, Abudi Nashabi, Zhengzi Li, William D. Dupont, Andries Zijlstra, Mary M. Zutter
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Research Article Oncology

The α2β1 integrin is a metastasis suppressor in mouse models and human cancer

Abstract

Integrins regulate cell-cell and cell-matrix adhesion and thereby play critical roles in tumor progression and metastasis. Although work in preclinical models suggests that β1 integrins may stimulate metastasis of a number of cancers, expression of the β1 subunit alone has not been shown to be a useful prognostic indicator in human cancer patients. Here we have demonstrated that the α2β1 integrin suppresses metastasis in a clinically relevant spontaneous mouse model of breast cancer. These data are consistent with previous studies indicating high expression of α2β1 integrin in normal breast epithelium and loss of α2β1 in poorly differentiated breast cancer. They are also consistent with our systematic analysis of microarray databases of human breast and prostate cancer, which revealed that decreased expression of the gene encoding α2 integrin, but not genes encoding α1, α3, or β1 integrin, was predictive of metastatic dissemination and decreased survival. The predictive value of α2 expression persisted within both good-risk and poor-risk cohorts defined by estrogen receptor and lymph node status. Thus, the α2β1 integrin functionally inhibits breast tumor metastasis, and α2 expression may serve as an important biomarker of metastatic potential and patient survival.

Authors

Norma E. Ramirez, Zhonghua Zhang, Aasakiran Madamanchi, Kelli L. Boyd, Lynda D. O’Rear, Abudi Nashabi, Zhengzi Li, William D. Dupont, Andries Zijlstra, Mary M. Zutter

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Figure 3

α2β1 integrin expression inhibits tumor cell intravasation.

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α2β1 integrin expression inhibits tumor cell intravasation. (A) Ex v...
(A) Ex vivo colonies were derived from circulating tumor cells within the peripheral blood of WT/Neu and α2-null/Neu mice at the time of sacrifice. Scale bar: 100 μm. (B) The number of colonies arising from the blood after 12 days of ex vivo culture is depicted. The mean number (denoted by the black line) of ex vivo colonies was significantly greater in α2-null/Neu mice than in WT/Neu mice. P = 0.002. (C) The relative ratio of Neu mRNA to GAPDH mRNA in the peripheral blood at the time of sacrifice was determined by qRT-PCR. The level of Neu mRNA–expressing cells was significantly increased in the peripheral blood of α2-null/Neu mice (n = 12) compared with WT/Neu mice (n = 12) (P = 0.005). (D) The relative level of Neu mRNA to GAPDH mRNA in the peripheral blood of WT/Neu and α2-null/Neu mice at 26–30 weeks of age when the tumors were first palpable. The α2-null/Neu mice demonstrated significantly increased numbers of circulating cells relative to WT/Neu mice (P = 0.002). (E) The relative number of Neu mRNA–expressing tumor cells in the blood of WT nontransgenic control mice and WT/Neu mice was evaluated. Mice lacking the transgene failed to show evidence of circulating Neu mRNA (P = 0.0003). (F) The number of CD31-positive vessels in 10 high-power fields was quantitated. There was no difference in the vascular density within the tumors of WT/Neu (n = 5) and α2-null/Neu (n = 5) animals (P = 0.55). Error bars represent SEMs in C, E, and F.