On cancer stem cells

A relatively new approach to looking at and treating cancers is to focus on cancer stem cells, a small subpopulation of cancer cells in a tumor that are capable or reproducing indefinitely and differentiating into mature cancer cells.  “Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample(ref).”

Most cancer therapies are based on killing cancer cells – as many cells as possible.  But cancers frequently and persistently recur after bouts of radiation or chemotherapy.  The culprit is thought to be cancer stem cells, where any surviving ones simply go about making new cancer cells.  A new therapeutic concept is therefore to focus on killing the cancer stem cells. 

For example, there is recent news of research related to cause acute myeloid leukemia (AML), a blood disease that is highly treatment-resistant and prone to relapses.  “Researchers created an antibody (7G3) that recognizes and binds to a molecule called CD123, which is expressed at high levels on leukemia stem cells (LSCs), but not on normal blood cells. —When AML-LSCs from human patients were transplanted into mice, those treated with 7G3 survived longer than mice that didn’t receive the antibody. The researchers found that 7G3 blocked a signaling pathway in tumor cells, impaired migration of AML-LSCs to bone marrow and activated the immune system to destroy AML-LSCs(ref).”

On another front, researchers at the University of Michigan are going after breast cancer stem cells(ref).  “Researchers at U-M were the first to identify stem cells in breast cancer. These cells represent fewer than 5 percent of the cells in a tumor but are believed to be responsible for fueling a tumor’s growth and spread. Researchers believe that the ultimate cure of cancer will require killing these cancer stem cells. — In the current study, researchers looked at a drug called perifosine, which inhibits the Akt pathway. Tumors in mice were treated with perifosine or docetaxel, a standard chemotherapy drug. The docetaxel alone showed no effect on the number of cancer stem cells in the tumor. But adding perifosine reduced the cancer stem cell population by up to 90 percent. What’s more, the cells treated with perifosine – either with or without docetaxel – were less likely to grow a secondary tumor, compared to the cells treated with just docetaxel(ref).”  Perifosine affects pathways associated with the PTEN gene.

In another research study, breast cancer stem cell proliferation and differentiation is linked to faulty regulation in the Notch signaling pathway. “First, Notch helps restrict breast stem cell number, so that when Notch is ‘switched off’, there is a resultant expansion in breast stem cells. Second, Notch is important for ensuring that stem cells produce the sleeve of cells that normally line breast ducts. These ‘luminal’ cells may be the cells that give rise to common types of breast cancer. Thus, Notch helps to orchestrate the formation of breast tissue: it plays an important role in controlling stem cell number and instructs stem cells to produce luminal cells. Significantly, Dr Bouras and colleagues found that errant activation of Notch resulted in uncontrolled growth of luminal precursors, leading to the formation of breast tumours(ref).”  Yet-another related study shows that a protein called cyclin d1 is required for growth of breast cancer in the mouse model and negatively regulating Notch signaling and targeting cyclin d1may block the expansion of breast cancer stem cells(ref).

Research on cancer stem cells is proceeding on a variety of additional fronts.  “Researchers at Yale School of Medicine have identified, characterized and cloned ovarian cancer stem cells and have shown that these stem cells may be the source of ovarian cancer’s recurrence and its resistance to chemotherapy(ref).” ‘Stem cell-like glioma cancer cells that share many characteristics with normal stem cells propel the lethal growth of brain cancers by promoting tumor blood vessel formation, and may hold the key to treating these deadly cancers(ref).” “Brain tumor researchers have found that brain tumors arise from cancer stem cells living within tiny protective areas formed by blood vessels in the brain. Killing those cells is a promising strategy to eliminate tumors and prevents them from re-growing. The researchers have found that drugs that block new blood vessel formation can destroy the protected areas and stop cancer from developing(ref).”  An earlier study had indicated “Brain tumors appear to arise from cancer stem cells (CSCs) that live within microscopic protective “niches” formed by blood vessels in the brain; and disrupting these niches is a promising strategy for eliminating the tumors and preventing them from re-growing  –(ref).”  Existing angiogenesis inhibitors like Avastin might be therapeutically useful.

A few days ago a report appeared indicating  “a molecule called telomerase, best known for enabling unlimited cell division of stem cells and cancer cells, has a surprising additional role in the expression of genes in an important stem cell regulatory pathway, say researchers at the Stanford University School of Medicine. The unexpected finding may lead to new anticancer therapies and a greater understanding of how adult and embryonic stem cells divide and specialize(ref).”  We have known for some time that telomerase promotes the differentiation of somatic stem cells through a mechanism independent of telomere extension(ref). 

My impression of this cancer stem cell research at this point is that:

·        Involved researchers believe this area holds great promise for developing targeted and more-effective cancer therapies.

·        Those therapies will involve targeting cancer stem cells rather than cancer cells in general.

·        Those therapies are likely to be less destructive of healthy tissues than existing radiation and chemotherapies and are less likely to lead to relapse and recurrence of the cancer

.·        Few if any of those cancer stem cell therapies have yet been developed sufficiently to become part of regular clinical practice.  Many are still in the cell-level and small-animal stages of experimentation.