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Jun 7, 2007

Integrin alpha 7 Mutations Lead to Unchecked Tumor Cell Proliferation

  • Mutations in the cell adhesion molecule known as integrin alpha 7 lead to unchecked tumor cell proliferation and a significantly higher incidence in metastasis in several cancer cell lines, report researchers at the University of Pittsburgh School of Medicine www.medschool.pitt.edu.

    Integrin alpha 7 belongs to a major class of cell membrane proteins that play a role in the attachment of a cell to the extracellular matrix (ECM). Integrins also help cells attach to one another and are involved in transmitting chemical signals between cells and the ECM.

    In this study, the researchers examined whether this gene is mutated in specimens of various human cancers and whether the level of integrin alpha 7 expression is associated with clinical relapse of human cancers. They also investigated whether integrin alpha 7 has tumor suppressor activity.

    To determine whether mutations in integrin alpha 7 contribute to cancer the scientists sequenced the integrin alpha 7 genes from 66 human cancer specimens and cell lines representing a number of different kinds of cancer, including cancer of the prostate, liver, brain, and muscle.

    They found mutations in the integrin alpha 7 gene, particularly those that resulted in a truncation in 16 of 28 prostate cancers. They also found truncation-inducing mutations in five of 24 liver cancer samples, five of six glioblastomas, and one of four leiomyosarcomas.

    Integrin alpha 7 mutations also were associated with a significant increase in the recurrence of cancer among patients. Nine of 13 prostate cancer patients with integrin alpha 7 mutations experienced a recurrence of their cancer after radical prostatectomy versus only one of eight prostate cancer patients without such mutations. There were five recurrences among eight hepatocellular carcinoma patients with integrin alpha 7 mutations versus only one recurrence of cancer among 16 patients without such mutations.

    To examine the effect of alterations in the level of integrin alpha 7 on tumor formation, the researchers assessed the ability of cancer cells to form colonies in a standard growth medium after increasing or decreasing the level of normal integrin alpha 7 in the cell lines.

    In this experiment, control cancer cells formed large colonies with up to 100 cells each. Cancer cells with normal levels of integrin alpha 7 expression formed fewer and smaller colonies. When the investigators decreased the level of integrin alpha 7  in two cancer cells lines using siRNAs, both cell lines formed more colonies and grew better than corresponding control cell lines.

    The researchers then investigated the role of integrin alpha 7 in metastasis by examining the relationship between the level of integrin alpha 7 expression and cell migration by increasing the expression of normal integrin alpha 7 in three cell lines. The migration rate was significantly reduced in all of the cells compared to those in which the expression of integrin alpha 7 remained deficient, suggesting that the level of normal integrin alpha 7 expression is inversely associated with tumor cell migration.

    Finally, to investigate whether normal integrin alpha 7 possesses tumor suppressor activity, the researchers implanted human cancer cells into immune deficient mice. Some mice received tumor cells in which levels of integrin alpha 7 were increased, others received tumor cells in which the levels of normal integrin alpha 7  were decreased.

    Six weeks after mice were implanted with cancer cells in which levels of normal integrin alpha 7 were deficient, they had tumors with an average volume about four times as large as mice with implanted cancer cells in which normal integrin alpha 7  levels were increased. Similarly, the researchers found no visible metastasis in mice with tumors in which levels of normal integrin alpha 7 had been increased. On the



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