February 22, 2017          Micrograph showing a lymph node invaded by ductal breast    carcinoma, with extension of the tumour beyond the lymph node.    Credit: Nephron/Wikipedia    
      Working with human breast cancer cells and mice, researchers      at Johns Hopkins say they have identified a biochemical      pathway that triggers the regrowth of breast cancer stem      cells after chemotherapy.    
    The regrowth of cancer stem cells is responsible for the    drug resistance that develops in many breast tumors and the    reason that for many patients, the benefits of chemo are    short-lived. Cancer recurrence after chemotherapy is frequently    fatal.  
    "Breast cancer stem cells pose a serious problem for therapy,"    says lead study investigator Gregg Semenza, M.D., Ph.D., the C.    Michael Armstrong Professor of Medicine, director of the    Vascular Biology Program at the Johns Hopkins Institute for    Cell Engineering and a member of the Johns Hopkins Kimmel    Cancer Center. "These are the cells that can break away from a    tumor and metastasize; these are the cells you most want to    kill with chemotherapy. Paradoxically, though, cancer stem    cells are quite resistant to chemotherapy."  
    Semenza says previous studies have shown that resistance to    chemotherapy arises from the hardy nature of cancer stem cells,    which are often found in the centers of tumors, where oxygen    levels are quite low. Their survival is made possible through    proteins known as hypoxia-inducible factors (HIFs), which turn    on genes that help the cells survive in a low-oxygen    environment.  
    In this new study, described Feb. 21 in Cell Reports,    Semenza and his colleagues conducted gene expression analysis    of multiple human breast cancer cell lines grown in the    laboratory after exposure to chemotherapy drugs, like carboplatin, which    stops tumor growth by damaging cancer cell DNA. The team found    that the cancer cells that survived tended    to have higher levels of a protein known as    glutathione-S-transferase O1, or GSTO1. Experiments showed that    HIFs controlled the production of GSTO1 in breast cancer cells when they were exposed    to chemotherapy; if HIF activity was blocked in these lab-grown    cells, GSTO1 was not produced.  
    Semenza notes that GSTO1 and related GST proteins are    antioxidant enzymes, but GSTO1's role in chemotherapy resistance did not    require its antioxidant activity. Instead, following exposure    to chemotherapy, GSTO1 binds to a protein called the ryanodine    receptor 1, or RYR1, that triggers the release of calcium,    which causes a chain reaction that transforms ordinary breast    cancer cells into cancer stem cells.  
    To more directly assess the role of GSTO1 and RYR1 in the    breast tumor response to chemotherapy, the researchers injected    human breast cancer cells into the mammary gland of mice and    then treated the mice with carboplatin after tumors had formed.    In addition to using normal breast cancer cells in the    experiments, the team also used cancer cells that had been    genetically engineered to lack either GSTO1 or RYR1. Loss of    either GSTO1 or RYR1, the researchers report, decreased the    number of cancer stem cells in the primary tumor, blocked    metastasis of cancer cells from the primary tumor to the lungs,    decreased the duration of chemotherapy required to induce    remission and increased the duration of time after chemotherapy    was stopped that the mice remained tumor-free.  
    Although the study showed that blocking the production of GSTO1    may improve the efficacy of chemotherapy drugs, such as    carboplatin, GSTO1 is only one of many proteins that are    produced under the control of HIFs in breast cancer cells that    have been exposed to chemotherapy. The Semenza lab is working    to develop drugs that can block the action of HIFs, with the    hope that HIF inhibitors will make chemotherapy more effective.  
     Explore further:        Toughest breast cancer may have met its match  
    More information: Haiquan Lu et al. Chemotherapy-Induced    Ca2+ Release Stimulates Breast Cancer Stem Cell Enrichment,    Cell Reports (2017). DOI: 10.1016/j.celrep.2017.02.001
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Scientists identify chain reaction that shields breast cancer stem cells from chemotherapy - Medical Xpress