Cell-Based Therapies Soften Up Cancer by Targeting Tumor Stiffness

저자：   업로드：2017-07-31  조회수：

    Scientists in the U.S. have created genetically engineered mesenchymal stem cells (MSCs) that can recognize and target "stiff" metastatic tumor tissue and deliver cancer-killing drugs directly to the tumor site. Tests in mouse models of metastatic breast cancer confirmed that the mechanoresponsive cell system (MRCS) can selectively target and destroy cancer cells and shrink tumors, without harming normal tissue either around the tumor or in other organs.

    The University of California, Irvine team, led by Weian Zhao, Ph.D., associate professor of pharmaceutical sciences, hopes that stiffness-targeting MSCs, and potentially other engineered cell types including chimeric antigen receptor (CAR) T cells, could be developed to treat or diagnose a wide range of cancers, and possibly other disorders characterized by fibrosis.

    It’s a unique approach that hasn’t been attempted before, Dr. Zhao told GEN. “Cancer, including metastatic tissues and their extracellular matrix, become stiff due to abnormal collagen deposition and crosslinking, which is caused by cancer cells and in turn promotes cancer progression and metastasis. The biophysical properties of the cancer tissue have not been targeted before, making our study innovative.”

    The treatment also only targets metastatic tissue, which could avoid some of the unwanted side effects of conventional chemotherapy, suggests Dr.  Zhao, who is a member of the Chao Family Comprehensive Cancer Center and the Sue & Bill Gross Stem Cell Research Center at UC Irvine.

    The rationale behind the therapeutic concept was inspired both by the discovery that the tumor microenvironment has this unique, abnormal biophysical property and also by another recent finding, “that the fate of stem cells is regulated by biophysical properties of the environment where they reside,” Dr. Zhao added. “We also use stem cells because they can preferentially migrate to tumor sites when they are transplanted. Our idea was to engineer stem cells so when they are transplanted into the body, they can sense and respond to the unique stiffness at cancer microenvironment to activate antitumor therapeutics to kill cancer cells.”

    Dr. Zhao’s team engineered bone marrow MSCs to home in on and respond to the stiffness of tumor tissue by producing the prodrug-activating enzyme cytosine deaminase (CD), which converts the inactive prodrug 5-fluorocytosine (5-FC) into its active cancer cell-killing form 5-fluorouracil (5-FU). “Stem cells are engineered with a mechanosensitive promoter that is coupled with downstream therapeutics (or cancer diagnostic reporters),” Dr. Zhao explained to GEN. “These stem cells, when transplanted, will naturally migrate to the me

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