Dr. Ziad W JaradatDr. Ziad W Jaradat

Cancer Stem Cells

Recently biologically distinct and Recently biologically distinct and relatively rare populations of tumor-relatively rare populations of tumor-initiating cells have been identified in initiating cells have been identified in cancers of the hematopoietic system, cancers of the hematopoietic system, brain and breast. Cells of this type have brain and breast. Cells of this type have the capability of: the capability of: Self renewalSelf renewal Potential to develop into any cell in the Potential to develop into any cell in the

overall tumor populationoverall tumor population The proliferative ability to drive continued The proliferative ability to drive continued

expansion of the population of malignant expansion of the population of malignant cells.cells.

Given these features, it is possible that Given these features, it is possible that cancer stem cells arise by mutation from cancer stem cells arise by mutation from normal stem cells or mutated progenitor normal stem cells or mutated progenitor cells. cells.

These progenitors are also called These progenitors are also called transit transit amplifyingamplifying cells which possess substantial cells which possess substantial replicative activity, but do not usually have replicative activity, but do not usually have the self renewal capacity of the stem cells. the self renewal capacity of the stem cells. Those cells also to become cancer cells Those cells also to become cancer cells they must they must acquire mutationsacquire mutations that cause that cause them to gain the property of self renewal.them to gain the property of self renewal.

Cancer stem cells can be the source of all Cancer stem cells can be the source of all the malignant cells in primary tumor, they the malignant cells in primary tumor, they can compose the small reservoir of drug-can compose the small reservoir of drug-resistant cells that are responsible for the resistant cells that are responsible for the relapse after chemotherapy induced relapse after chemotherapy induced remission or can give rise to distant remission or can give rise to distant metastasis.metastasis.

It is becoming evident that a cancer It is becoming evident that a cancer treatment regimen that fails to eliminate treatment regimen that fails to eliminate cancer stem cells may allow re-growth of cancer stem cells may allow re-growth of the tumor. Therapeutic strategies that the tumor. Therapeutic strategies that specifically target cancer stem cells should specifically target cancer stem cells should eradicate tumors more effectively than eradicate tumors more effectively than current treatments and reduces the risk of current treatments and reduces the risk of relapse and metastasis.relapse and metastasis.

Cancer Stem Cells in the Hematopoietic, Brain Cancer Stem Cells in the Hematopoietic, Brain

and Breast Systemsand Breast Systems In various types of leukemia, cancer stem cells In various types of leukemia, cancer stem cells

have been unequivocally identified and several have been unequivocally identified and several biologic properties of these stem cells have been biologic properties of these stem cells have been found to have direct implications for therapy. found to have direct implications for therapy.

Stem cells responsible for certain leukemia’s are Stem cells responsible for certain leukemia’s are mostly quiescent, suggesting that conventional mostly quiescent, suggesting that conventional anti-proliferativeanti-proliferative cytotoxic regimens are unlikely cytotoxic regimens are unlikely to be effective against them. to be effective against them.

Some of those cells (hematopoietic system) have surface Some of those cells (hematopoietic system) have surface markers such as interleukin-3 receptor alpha chain that are markers such as interleukin-3 receptor alpha chain that are not present on normal stem cells. Other unique molecular not present on normal stem cells. Other unique molecular features of leukemia stem cells such as nuclear factor kB features of leukemia stem cells such as nuclear factor kB (NF-kB) or phosphatidylinositol 3’ kinase (PI3). (NF-kB) or phosphatidylinositol 3’ kinase (PI3).

None of those is detected in resting normal hematopoietic None of those is detected in resting normal hematopoietic stem cells. These markers may be useful for antibody-stem cells. These markers may be useful for antibody-based or related therapeutic regimens as they could be based or related therapeutic regimens as they could be tumor specific targets. tumor specific targets.

Similarly, it has been recently proved that normal neural Similarly, it has been recently proved that normal neural stem cells (Brain system) express a cell surface protein stem cells (Brain system) express a cell surface protein that can be detected with an antibody against CD 133 that can be detected with an antibody against CD 133 epitope.epitope.

This marker is commonly found on cancer stem This marker is commonly found on cancer stem cells. The transplantation of as few as 100 cells of cells. The transplantation of as few as 100 cells of this type (CD 133 positive) into the brain of an this type (CD 133 positive) into the brain of an immunocompromised mouse resulted in brain tumor immunocompromised mouse resulted in brain tumor while the transfer of 10while the transfer of 1055 cancer cells that are CD-133 cancer cells that are CD-133 negative did not initiate the tumor. negative did not initiate the tumor.

This proves that although the later cells were taken This proves that although the later cells were taken from the tumor directly ( i.e they are cancerous cells) from the tumor directly ( i.e they are cancerous cells) they fail to develop cancer as only subpopulation they fail to develop cancer as only subpopulation which are the CD133 positive are responsible for the which are the CD133 positive are responsible for the cancer.cancer.

Similar to the brain, studies of specimens Similar to the brain, studies of specimens from patients with advanced stages of from patients with advanced stages of metastatic breast cancer demonstrated the metastatic breast cancer demonstrated the presence of cells with specific cell surface presence of cells with specific cell surface antigen profile (CD 44- positive and CD 24 antigen profile (CD 44- positive and CD 24 negative) could successfully establish negative) could successfully establish themselves as tumor xenografts.themselves as tumor xenografts.

Challenges for therapy Challenges for therapy targeted against cancer stem targeted against cancer stem

cellscells The development of treatments that target The development of treatments that target

cancer stem cells is an important cancer stem cells is an important objective.objective.

To design treatment that selectively To design treatment that selectively eradicate cancer stem cells, it is useful to eradicate cancer stem cells, it is useful to have cognate (related) normal stem cells. have cognate (related) normal stem cells.

This requires the development of assays to This requires the development of assays to characterize the function of normal stem characterize the function of normal stem cells and the means to define their cells and the means to define their physical features i.e cell surface markers physical features i.e cell surface markers that will permit their isolation.that will permit their isolation.

It is critical to understand how cancer stem It is critical to understand how cancer stem cells differ from normal stem cells cells differ from normal stem cells particularly with regard to mechanisms particularly with regard to mechanisms controlling cells survival and response to controlling cells survival and response to injury. injury.

It is necessary to understand how It is necessary to understand how therapies that effectively target the bulk of therapies that effectively target the bulk of the tumor cells fail to eradicate cancer the tumor cells fail to eradicate cancer stem cells.stem cells.

Understand the properties of cancer stem Understand the properties of cancer stem cells that make them difficult to kill by cells that make them difficult to kill by treatment regimens. treatment regimens.

How does some cancer cells survive the How does some cancer cells survive the therapy and re-grow after the treatment?therapy and re-grow after the treatment?

It appears that a variety of cancer cells It appears that a variety of cancer cells particularly during relapse express particularly during relapse express multidrug-resistant proteins thus multidrug-resistant proteins thus providing resistance to many providing resistance to many chemotherapeutic agents. chemotherapeutic agents.

ConclusionConclusion The eradication of bulk disease is not likely to The eradication of bulk disease is not likely to

predict the efficacy of drug regimens for rare predict the efficacy of drug regimens for rare cancer cells as it is pivotal to eradicate the cancer cells as it is pivotal to eradicate the cancer stem cells to insure the efficacy of cancer stem cells to insure the efficacy of such drug. such drug.

Therefore, the development of assays that Therefore, the development of assays that measure the survival of cancer stem cells will measure the survival of cancer stem cells will be important for assessing the potential of be important for assessing the potential of new targeted regimens.new targeted regimens.

Craig T. Jordan, Monica Guzman, and Mark Craig T. Jordan, Monica Guzman, and Mark Noble. (Noble. (20062006). Cancer Stem Cells. The New ). Cancer Stem Cells. The New England Journal of Medicine. 355 (12): 1253-England Journal of Medicine. 355 (12): 1253-1261.1261.

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