Science: Cancer stem cells can be reversed by drugs
March 14, 2016 Source: Bio Valley
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)]; Scientists have long believed that there are a group of highly invasive cancer cells in solid tumors: tumor-initiating cells (also called tumor stem cells, Tumor-initiaing cells or cancer stem cells). These cells are highly resistant to conventional chemotherapy, and their presence promotes tumorigenesis, progression, and metastasis to other organs. In recent years, they have been regarded as an important target for cancer treatment. If this type of cells are controlled in the patient's body, then the cancer's progression and metastasis can be effectively controlled to achieve cancer control.
Epithelial-mesenchymal transition (EMT) is a cellular biological characteristic shift that allows normal and tumor epithelial cells to acquire the characteristics of "interstitial" state stem cells. In the pre-metastasis stage of the tumor, the tumor cells in the primary tumor lose their polar epithelial cell characteristics (adhesive, lamellar structure) and transform into interstitial cell characteristics with migration and invasion ability (cell-free Sexuality, loss of tight junctions between cells and cells), high resistance to various conventional chemotherapy drugs.
A team led by renowned cancer biologist Robert A. Weinberg recently published a wonderful research work in Science magazine. They try to find targeted drugs that specifically kill these cancer cells that cause cancer or inhibit these highly aggressive cancer cells. Weinberg hypothesized that by targeting drugs, it can induce the transformation of tumor stem cells from mesenchymal-to-epithelial transition (MET), so that tumor stem cells with high metastatic ability can be recovered under the targeted induction of drugs. "Become a cell with polar epithelial properties. Thus, cancer stem cells lose the ability to be highly invasive and metastasized in patients.
First, the researchers identified a drug that activates the transcription of the CDH1 gene, CDH1 is the gene for the E-cadherin protein, and E-cadherin is a key cell-linked marker membrane protein on the epithelial cell membrane, confirming that these drugs can promote MET. Conversion. Then, through this screening result, it was found that these inducers mainly activated adenylate cyclase, including cholera toxin and forskolin. Researchers have discovered that after treatment of stromal cells with cholera toxin or forskolin, these cells differentiate into benign epithelial cells, thereby losing the ability to produce tumors. Moreover, in in vitro experiments, these treated cells lost resistance to conventional chemotherapeutic drugs. Finally, the researchers further found that these drugs can increase the concentration of cAMP in the cells, thereby activating the PKA signal more strongly. One of the key H3K9 histone demethylases, PHF2, is a substrate for PKA, a key molecule in the process of cAMP-promoting MET. By genomic epigenetic analysis of the function of PHF2, they also compared the epigenetic changes in cells before and after PKA activation. It was finally determined that PHF2 promotes the demethylation of intracellular epithelial-related genes, thereby abolishing the transcriptional repression of these genes and finally promoting the transformation of cells into epithelial cells.
In fact, in the end they did find such a class of drugs that target tumor-initiating cells for MET conversion. They activate the PKA signaling pathway, which in turn activates histone demethylases for epigenetic modification in tumor-initiating cells. The cancer cells with high invasive ability are forced to return to the characteristic cells of the epithelial cells, and then turn into benign tumors.
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