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Apr 25, 2012

Researchers Find Gene Key to Maintaining Lung Cancer Stem Cells, Promoting Tumor Initiation, and Metastases

  • Scientists have identified a single gene that appears to be central to the maintenance of non-small cell lung cancer (NSCLC) cancer stem cells, as well as the initiation of tumor formation, growth and metastasis in vivo. A Mayo Clinic College of Medicine team found that cancer stem cells (CSCs) in oncosphere cultures demonstrated high expression levels of matrix metalloproteinase-10 (Mmp-10; or stromelysin 2), and that knocking down Mmp10 expression in these cells resulted in the loss of stem cell markers and the inhibition of oncosphere growth, clonal expansion, and tumor development. Mmp10-deficient oncospheres were in addition far less able to initiate tumor development than unmodified oncospheres when injected into experimental mice.

    Reporting their findings in PLoS One, Alan P. Fields, M.D., and colleagues say subsequent analysis of gene expression data from human cancers highlighted a strong correlation between tumor Mmp10 expression and metastasis in a range of tumor types. “Our data demonstrate for the first time that Mmp10 is a critical lung cancer stem cell gene and novel therapeutic target for lung cancer stem cells,” they conclude. The investigators’ results are published in a paper titled “Matrix Metalloproteinase-10 Is Required for Lung Cancer Stem Cell Maintenance, Tumor Initiation and Metastatic Potential.”

    MMPs have previously been implicated in lung tumor proliferation, invasion, and metastasis. The Mayo team’s own prior work suggested that Mmp10 is needed for transformed growth and invasion of human NSCLC cells in vitro, and mediates tumor initiation through the control of tumor-initiating bronchio-alveolar stem cell expansion.

    Building on these findings the investigators have now looked more closely at the role of Mmp10 in the maintenance and tumorigenic potential of fully transformed mouse lung CSCs, a cell population characterized by stem-like properties including increased anchorage-independent growth in vitro, and enhanced tumor initiation, growth, and metastatic spread as orthotopic tumors in syngeneic mice.

    The CSCs in these oncosphere cultures were found to express high levels of mRNAs for numerous genes associated with stem cell phenotype, and also high levels of Mmp10, but not other MMPs previously linked with lung cancer. The cultures in addition secreted much higher levels of Mmp10 protein into the medium in comparison with parental or redifferentiated cultures. As expected, oncosphere cultures demonstrated a loss of stem cell markers and Mmp10 expression when allowed to redifferentiate in adherent culture.

    Notably, using an Mmp10-targeting RNAi to knock down Mmp10 mRNA expression in the oncosphere cultures led to an inhibition of transformed growth, loss of stem cell markers, and inhibition of clonal expansion, without impacting on cell viability. These effects could be restored by the addition of exogenous Mmp10.

    Initial tests in vivo showed that while transplanting cells from oncosphere cultures into the lungs of syngeneic mice routinely led to the development of large tumors, cells from Mmp10-knockdown cultures generated fewer and small tumors, and also fewer metastases.

    Importantly, the role of Mmp10 in tumorigenesis related to the gene’s expression by CSCs specifically, and not by other cells in the tumor environment. When the researchers injected unmodified oncospheres into Mmp10 knockout mice, tumor growth, size, and metastasis were equivalent to those resulting from the injection of unmodified oncospheres into wild-type syngeneic mice. This indicates that “Mmp10 expressed by oncospheres, but not from Mmp10 produced by other tumor-associated cells, is critical for tumor formation,” they write.

    In a final set of analyses, the team analyzed publicly available gene-expression datasets of human tumors and found a strong positive correlation between Mmp10 expression and metastatic potential not only in human NSCLC, but also in colorectal cancer, melanoma, breast cancer, renal cell carcinoma, and prostate cancer.

    The observation that Mmp10 appears to play a dual role in cancer, both in terms of maintaining the cancer stem cell population and facilitating metastasis, was an unexpected finding, the investigators note. Most other MMPs are expressed in the tumor microenvironment and cells and tissues surrounding the tumor, where they act to modify the tumor environment and facilitate cancer cell spread, Dr. Field explains. Conversely, “Mmp10 acts to keep these cancer stem cells healthy and self-renewing, which also helps explain why these cells escape conventional chemotherapy that might destroy the rest of the tumor.”

    The team is now trying to define the mechanism by which Mmp10 stimulates the growth of cancer stem cells, and identify the design of inhibitors that block its activity. “Given the dual role in cancer stem cells and metastasis, targeting Mmp10 may be especially effective in treating these tumors,” he concludes. 


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