Cancer STEM cells – the update (share with your oncologist)

Dr. Weeks Comment:   Distinguished professor of Oncology, Max Wicha, M.D. who also heads the University of Michigan Comprehensive Cancer Center is oft quoted as saying “Chemotherapy and radiation can make your cancer worse.”  These heretical words are not springing from the mouth of an “alternative cancer doctor” but from a thought leader in conventional cancer care – a pioneering researcher.  But the message is highly disruptive since it undermines a huge industry. Fortunately, Science is no respecter or profit motive; Science just reveals the best understanding we have and it is up to ethical doctors to stop the old and start the new.    Corrective Cancer Care doctors have been “doctoring” (instructing and healing) cancer STEM cells while at the same time killing cancer TUMOR cells.  (NOTE: if the distinction between cancer STEM and cancer TUMOR cells is not clear to you,  search “cancer STEM cell” and read the past 20 articles we have posted on – it is a matter of life or death.

Now Professor Wicha adds:  “Inflammatory mediators such as IL-8, IL-6, and Wnt signaling spur CSCs to self-renew or increase in number, thus driving tumor growth.”   Ask your oncologist what he or she is doing to address your cancer STEM cells  and also ask him or her to assure you that your  current  treatment (chemotherapy and or radiation) is NOT  …”driving tumor growth”




Are Cancer Stem Cells Ready for Prime Time?
A flood of new discoveries has refined our definition of cancer stem cells. Now it’s up to human clinical trials to test if they can make a difference in patients.

By Suling Liu, Hasan Korkaya, and Max S. Wicha | April 1, 2012

In the 30-year battle waged since the initiation of the “war on cancer,” there have been substantial victories, with cures for childhood malignancies among the most important. Our ever-expanding understanding of cellular and molecular biology has provided substantial insights into the molecular underpinnings of the spectrum of diseases we call cancer. Yet, while researchers view this as tremendous progress, many patients have seen only limited improvement. In fact, the relatively modest gains achieved in treating the most common malignancies have caused some to say that we are actually losing the war on cancer.1
Based on new intelligence, oncologists are making informed battle plans to attack a particularly pernicious enemy””the cancer stem cell. Controversial though they are, cancer stem cells are an incredibly promising target. If treatment-resistant cancer, and the metastases that transplant the cancer throughout the body, could be attributed to the actions of a single cell type, it could explain many of the treatment failures and provide a novel way to attack the disease.

The idea that cancers are driven by cells with “embryonic features” is an old one. Many cancers regress to a less differentiated state, expressing proteins that are usually expressed only in the embryo or during early development. It is only in the past 20 years or so, however, that additional observations led to the hypothesis that these embryonic-like cells were a separate subpopulation that fueled tumor expansion, much the same way that stem cells churn out the cells that make up a particular organ.

A number of groups, including our own, have identified cancer stem cell markers enabling the isolation and characterization of these cells. In addition, the development of in vitro and mouse functional assays has led to a veritable explosion of research on cancer stem cells from both blood-derived malignancies and solid tumors.2,3 However, the limitations of these markers and assays have generated heated debate regarding which tumors follow a stem cell model, and which do not. New data from our lab and from others is helping to clarify some of these areas of debate with the goal of better understanding how these cells can be identified and characterized.

Clarifying the debate
A cancer stem cell (CSC) is defined as a cell that has the ability to self-renew, dividing to give rise to another malignant stem cell, as well as to produce the phenotypically diverse, differentiated tumor cells that form the bulk of the tumor. Evidence for CSCs was first documented in leukemia, where it was clear that only a small subset of cancer cells was capable of perpetuating the cancer upon serial transplantation from one mouse to another. Extensive knowledge of normal blood stem cells facilitated our recognition and understanding of leukemia stem cells. Evidence for CSCs in solid tumors has been more controversial, because it is more technically challenging to divide a solid mass into individual cells without damage or alteration, and knowledge of the properties of normal-tissue stem cells in these organs is more limited. However, some of the areas of contention may be resolved by continuing research into the biology of these CSCs.

In contrast, other studies have suggested that the EMT state, although associated with tumor invasion, is characterized by cellular quiescence, or an inability to replicate, creating a paradox. How can cells which are associated with aggressive metastatic behavior be quiescent? Recent observations by our group and others have suggested an additional mechanism that could explain both observations: CSCs may in fact flip-flop between an EMT state and its converse, the mesenchymal-to-epithelial transition (MET), in which cells re-attach to the matrix and become highly proliferative, thus generating tumors at sites of metastasis.

These results suggest that CSCs, such as those found in breast cancers, have plasticity and can exist in two alternative states: an EMT-like state of CSCs expressing surface markers CD44 but not CD24 (CD44+CD24-), and an MET-like population expressing the CSC marker ALDH. Previous studies taken together with our current work suggest that CSCs located inside the primary tumor mass exist predominantly in the MET state in which they are highly proliferative and express ALDH. In contrast, tumor cells that migrate into the circulation and metastasize are characterized as CD44+CD24-””highly invasive but quiescent EMT CSCs.5 This scenario is supported by studies showing that in women with breast-cancer-derived, bone micrometastases express the EMT CSC markers CD44+CD24-.5 These micrometastases are largely quiescent, as indicated by their lack of expression of markers of cellular proliferation such as Ki67.5 In order to enter a proliferative state, EMT CSC cells must undergo an MET transition in which they lose their invasive characteristics and acquire self-renewal capacity.

New Horizon for Cancer Treatment
The cancer stem cell (CSC) hypothesis offers explanations for many of the frustrating failures of cancer therapy in the clinic. The resistance of CSCs to chemotherapy, radiation, and many targeted therapies, may explain why cancers come back after the tumor mass has been removed and the patient has gone into remission. As such, CSCs offer a new target for attack.

Chemo catch-22:Although chemotherapy is still considered to be the most effective treatment for many cancers, the drugs may act on a tumor’s surrounding tissue in a way that spurs the production of more stem cells. In fact, increases in CSC numbers have been observed in tumors after chemo or radiation. These treatments can create inflammation in the tissue surrounding the tumor as well as hypoxia, or loss of oxygen, which activates Wnt signaling. Inflammatory mediators such as IL-8, IL-6, and Wnt signaling spur CSCs to self-renew or increase in number, thus driving tumor growth.


Suling Liu, Hasan Korkaya, and Dr. Max S. Wicha, Director, UM Cancer Center, are all at the University of Michigan Comprehensive Cancer Center.


  1. C. Leaf, “Why we’re losing the war on cancer (and how to win it),” Fortune, 149:76-82, 84-86, 88 passim., 2004. â†©
  2. A. Larochelle et al., “Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: Implications for gene therapy,” Nat Med, 2:1329-37, 1996. â†©
  3. M. Al-Hajj et al., “Prospective identification of tumorigenic breast cancer cells,” PNAS, 100:3983-88, 2003. â†©
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  5. S. Liu et al., “Role of microRNAs in the regulation of breast cancer stem cells,” J Mammary Gland Biol Neoplasia, DOI: 10.1007/s10911-012-9242-8, 2012. â†©
  6. L. Li et al., “Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib,” Cancer Cell, 21:266-81, 2012. â†©
  7. H. Korkaya et al., “HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion,” Oncogene, 27:6120-30, 2008. â†©
  8. S. Paik et al., “HER2 status and benefit from adjuvant trastuzumab in breast cancer,” N Engl J Med, 358:1409-11, 2008. â†©
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  10. S.J. Conley et al., “Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia,” PNAS, 109:2784-89, 2012. â†©
  11. H. Korkaya et al., “Breast cancer stem cells, cytokine networks, and the tumor microenvironment,” J Clin Invest, 121:3804-09, 2011. â†©
  12. A. Albini, M.B. Sporn, “The tumour microenvironment as a target for chemoprevention,” Nat Rev Cancer, 7:139-47, 2007. â†©
  13. R. Kochhar et al.,”Statins reduce breast cancer risk: a case control study in US female veterans,” J Clin Oncol, ASCO Annual Meeting Proceedings 23:514, 2005. â†©

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