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p53 - A guardian angel in regulating normal and cancer stem cell states

Sun, October 04 2009, 12:00 AM
Posted By: Sciclips

The p53 is a tumor suppressing proteins that activates DNA repair proteins and apoptosis pathways in response to DNA damages that are not irreparable. Mutations in p53, which affects its activity, are responsible for developing various cancers; 83% of tumors have alterations or defect in p53 (1). The p53 plays crucial role in embryonic stem (ES) cells. p53 represses the expression of Nanog, a transcription that is critical for the self-renewal of ES cells (2). Loss of p53 reduces spontaneous differentiation and apoptosis in human embryonic stem cells (3). It has been proposed that breast cancer tumors can originate from cancer stem cells or cancer cells become stem cells due to p53 deficiency, which favors the expansion of cancer stem cells (4). Recent reports (shown below in boxes) have shown the importance of p53 in various stem cell states. Independent studies from five laboratories have shown that loss ofp53 is needed for the induction of induced pluripotent stem cells (iPS cells) from adult cells (see thumbnails). The role of p53 in cancer stem cells has been shown by a recent study . This study has shown that loss of p53 induces symmetric cell division in breast cancer stem cells and this favors breast cancer tumor growth (see thumbnails).

Here are the few questions that have been raised from these recent studies:
  1. Loss of p53 is necessary for the induction pluripotent stem cells from adult cells. Does this mean stem cells are similar to cancer cells? (7). If so, what are the safety issues in using iPS cells for stem cell therapy and similar therapeutic applications? Is it safe to use iPS cells or iPS cells derived cells/tissues for developing drug discovery screening assays?
  2. Do the studies warrant screening of ES cells for p53 mutations or identify pathways that may trigger p53 loss in later stages? Do we need to screen all the cell/tissue types derived from ES or iPS cells for p53 mutations/stability? There may be protein/s or a metabolite/s in cancer stem cells that alter the function of p53. If this is true, this may be a drug target.
  3. The pathway/s that triggers self-renewal or expansion of cancer stem cells in absence of p53 could be a drug target for cancer. Does this mean, one day we will be able to develop a single drug that can be used for the treatment of all types of cancers? Does cancer stem cells based drug discovery approaches may lead us to achieve this possibility?
  4. A recent report has shown that chemotherapy will selectively enrich cancer stem cells in hepatocellular carcinoma (8). Does this means a combination of chemotherapy and cancer cell stem cell therapy can cure cancer?
  5. How safe is to use drugs that induce ex vivo differentiation of stem cells to desirable tissues? This approach can have significant impact on developing treatment of neurological diseases such as Parkinsons disease. Do we need to look after p53 in these stem cells and stem cell derived tissues?
  6. Do the experimental approaches and the conclusions described in recent articles require more studies and analysis to establish the role ofp53?
  7. What are the possible ways we could utilize recent findings on the role of p53 in cancers tem cells for developing anti-cancer drugs?
Finally, it is tempting to believe that cancer stem cells might help to find answers to tons of unanswered questions on cancer and ultimately finding a cure for all types of cancer.


References:
  1. Nature. 2000;404:2425 Abstract: http://www.nature.com/nature/journal/v404/n6773/full/404024a0.html
  2. Nat Cell Biol. 2005;7:165171 http://www.ncbi.nlm.nih.gov/pubmed/15619621
  3. J Biol Chem. 2007;282:58425852 http://www.ncbi.nlm.nih.gov/pubmed/17179143
  4. Breast Cancer Res. 2008; 10(4): 304 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2575544#B14
  5. Cancer Res. 2008;68:46744682 Full article http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18559513
  6. Cell. 2008;134:6273 Abstract: http://www.ncbi.nlm.nih.gov/pubmed/18614011
  7. Nature 2009 460, 1085-1086 http://www.nature.com/nature/journal/v460/n7259/full/4601085a.html
  8. J Int Med Res. 2009 Jul-Aug;37(4):1046-56 http://www.ncbi.nlm.nih.gov/pubmed/19761687?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

These are additional information - p53 related websites

p53/Cancer stem cells (PubMed)

p53/Stem cells (PubMed)

p53/Breast cancer (PubMed)

p53/Proteomics (PubMed)

p53/Biomarker (PubMed)

Categories: Stem Cells

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