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Nov 17, 2009

Targeting a Tumor’s Microenvironment Could Be Used to Treat Cancer

  • Fibroblast activation protein (FAP) expressed by some cells that surround cancerous tumors promotes tumor growth in mice, according to scientists at The Wistar Institute. Genetically deleting or therapeutically targeting FAP reduced the rate of tumor growth, they add.

    Their findings were published online November 16 in The Journal of Clinical Investigation. The paper is titled “Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice.”
     
    The Wistar team focused on fibroblasts and pericytes in stromal cells. Pericytes are important to the function of the new blood vessels that develop in tumors. Fibroblasts synthesize components of the extracellular matrix, and those associated with tumors also express FAP, a protease that cuts up other proteins. FAP is expressed in 90% of all human epithelial cancers and is recognized as a marker for cancer growth, according to the researchers. FAP’s mechanism of action, however, had previously been unknown.

    “Our data clearly demonstrates that FAP indeed promotes the growth of colon cancer as well as lung cancer in animal models and provides insight into how FAP works,” says senior author, Ellen Pur, Ph.D., a professor in the molecular and cellular oncogenesis program at Wistar.

    To explore how FAP promotes tumor growth, lead author, Anglica Santos, Ph.D., and colleagues took two approaches: genetic deletion and pharmacologic targeting of FAP to determine the effects of deactivating FAP in mouse models of lung and colon cancer.

    First, they examined the genetic deletion of FAP. In collaboration with Wistar assistant professor and co-author Joseph Kissil, Ph.D., they mated mice engineered to spontaneously develop lung cancer when their K-Ras gene is activated with mice whose FAP gene had been deleted to develop a new strain of mice with a genetic deletion of FAP and expressing an activated K-Ras gene.

    The Wistar team found that lung tumor growth was substantially inhibited in these mice. In another experiment the investigators transplanted colon cancer cells into FAP-deficient mice and saw a similarly marked inhibition of tumor growth.

    "We found that FAP inactivation disrupts the organization of the collagen fibers, which are a key component of the matrix, and could be critical for many things including cell-to-cell communication, cell-matrix interactions, and development of new blood vessels to feed the tumors,” Dr. Pur says. “The organization or architecture of the matrix is important to supporting both stromal and cancer cells within a tumor. If stromal cells depend on this matrix for structural support and to communicate with the cancer, they can't do that properly if it is drastically modified, as we observed in the absence of FAP activity. "

    To explore the potential for a therapeutic approach, the investigators used a novel peptide agent PT630 to shut down FAP activation in the lung and colon cancer mouse models. Again, they found a significant reduction in tumor growth by inhibiting the enzymatic activity of FAP with this candidate drug agent.

    “This proof of concept is the first step toward the clinic,” Dr. Pur says. “We need more drugs that target the noncancer cells in tumors, which can then be combined with specific chemotherapies and biologic drugs to attack both the tumor and its supporting cells.”

    One of the benefits of such a strategy, Dr. Pur adds, is that a limited number of agents would likely be required to treat many different cancers because stromal cells tend to have common properties and share expression of the FAP protein in most tumor types.

     



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