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Cancer has been one of the leading causes of death in the developed world for decades. As such, many studies have been done to find a more effective therapeutic intervention for cancer treatment (Ghotra, Puigvert and Danen, 2009). Patients are currently treated with chemotherapy, radiotherapy, surgery and anti-angiogenic therapy and generally respond well to treatment. However, development of new tumors after successful initial intervention leads to relapse of the disease and metastasis. Evidence points to the presence of a subset of cells present within the tumor that have the ability to self-sustain and are responsible for the initiation and progression of cancer (Cho and Clarke, 2008). These cells are termed cancer stem cells.
Cancers stem cells (CSCs) are cancer cells possessing characteristics similar to normal stem cells and are able to differentiate into any form of cancer cells in a heterogenous tumor population. They are also capable of self-renewal and are tumorigenic. CSCs have mechanisms for active telomerase expression, antiapoptotic pathways and common stem cell genes. Their ability to survive and resist multiple drugs make them difficult to treat with conventional chemotherapy that target cells that are proliferating rapidly (Matoso and Nikitin, 2008). CSCs have been isolated in leukemia and in malignant solid tumors such as the brain, lungs and gastrointestinal cancers.
The cancer stem cell hypothesis is suggested to be responsible for the growth and maintenance of tumors and is supported by two observations. The first observation suggests that tumors are derived from a single cell, but the cells within the tumor are not all identical (Park, Bergsagel and McCulloch, 1971). Some cells are cancerous; some make up the tumor bulk while others support tumor growth. It is thought that the different cells that develop is a result of selection of cells that can adapt to the tumor microenvironment (Heng et al., 2006) allowing for tumor heterogeneity. The second observation was based on a stochastic model that suggests every CSC has the ability to become a tumor. However, the chances of a CSC to enter the cell cycle and differentiate into cancer cells are very low, therefore decreasing formation of new tumor.
Why target cancer stem cells? How can we target them?
The proposed existence of a small proportion of CSCs in tumors results in incomplete tumor ablation during chemotherapy. The drugs used in conventional chemotherapy target terminally differentiated or differentiating cells and not stem cells. Therefore, the CSCs still remain and can cause a relapse of the disease.
In the quest to rapidly reduce tumor size, drugs required to target CSCs have been overlooked. Successful cancer intervention therefore involves drugs capable of targeting proliferating cells as well as inducing differentiation of CSCs and then eliminating them. Blocking of signal cascade pathways such as Wnt/Î²-catenin, Notch and Sonic hedgehog up-regulated during cancer may be potential therapy in leukemic and solid cancers (Ischenko et al., 2008). An example of such blocking compound is cyclopamine (James et al., 2004). It binds and prevents proliferation of cells and tumors that has an active hedgehog signal. Another approach for elimination was targeting of CSC surface molecules using antibodies or other proteins (Ischenko et al., 2008). However, these molecules have to be expressed only by CSCs or cancer progenitor cells and not on normal stem cells. An example of such drug is gemtuzumab ozogamicin (MylotargÂ®), an anti-CD33 monoclonal antibody used in the treatment of CD33+ acute myeloid leukemia.
There have been reports suggesting that inflammatory lesions sustained prior may cause some cancer types such as gastrointestinal and ovarian cancers. Therefore, the use of non-steroidal anti-inflammatory drugs like cyclooxygenase (COX) -1 and -2 inhibitors would decrease the occurrence of these types of cancer by targeting tumor microenvironment.
Differentiation of cancer stem cells into its mature differentiated phenotype, termed differentiation therapy, has been used in the treatment of leukemia. Patients are treated with an all-trans-retinoic acid which causes promyelocytes to mature thus making the use of conventional chemotherapy possible.
Change from current therapy to stem cell tergetting
What are the different stem cell targets?
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