Overview
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Cancer Stem Cells: Overview
Cancer is caused by a complex interplay of molecular signals. Uncontrolled cellular growth, a hallmark of cancer, may hold the key to understanding the spread of disease. Tumors form and proliferate from the actions of a small population of unique cells. The observation that cancer cells and stem cells share many similar properties has led to the search for “cancer stem cells.”
Cancer Cells Arise From Stem Cells
Stem cells are distinguished from other cells by two characteristics: (1) they can divide to produce copies of themselves, or self-renew, under appropriate conditions, and (2) they can differentiate into more specialized cell types. The ability to self-renew gives stem cells long life spans relative to those of mature, differentiated cells. It has therefore been hypothesized that the limited life span of a mature cell makes it less likely to live long enough to undergo the multiple mutations necessary for tumor formation and metastasis.
Increasing evidence supports a cancer stem cell (CSC) hypothesis—that cancer is initiated by a small population of tumor-initiating cells exhibiting stem cell–like properties. The characterization of CSCs will likely play a role in the development of novel targeted therapies designed to eradicate cells resistant to current chemotherapy regimens. The stem cell theory of cancer proposes that among all cancerous cells, a few act as stem cells that reproduce themselves and sustain the cancer, much like normal stem cells normally renew and sustain our organs and tissues, while cancer cells that are not stem cells cannot sustain an attack on our bodies long term. The idea that cancer is primarily driven by a smaller population of stem cells has important implications. For instance, many new anticancer therapies are evaluated based on their ability to shrink tumors, but if the therapies are not killing the cancer stem cells, the tumor will soon grow back (often with a vexing resistance to the previously used therapy).
What Are Cancer Stem Cells?
CSCs are tumor cells, with properties similar to normal stem cells, such as the ability to give rise to all cell types found in a particular cancer sample. CSCs are tumor-forming cells and may generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. Such cells are proposed to persist in tumors as a distinct population and cause recurrence and spread of tumor by giving rise to new tumors. Cancer stem cell research is focused on developing methods to control the disease by targeting these cells.
CSCs, unlike the other cells that form the bulk of a tumor, can self-perpetuate and produce progenitor cells that can repopulate tumor cells eradicated by treatments such as chemotherapy or radiation. These properties allow cancer stem cells to resist all sorts of treatments including chemotherapy, radiotherapy, and molecular-targeted therapy. Evidence of CSC existence is much stronger for hematologic malignancies because this area is better researched as compared to solid organs.
Figure 1 Stem cell characteristics
There are two models for CSC renewal. The cancer stem cell model refers to a subset of tumor cells (CSCs) that have the ability to self-renew and are able to generate the diverse tumor cells. It is believed that only these cells can generate a tumor. The clonal evolution model postulates that tumor cells with a growth potential are selected and expanded. Cells in the dominant population have a similar potential for initiating tumor growth. In the clonal evolution model, all undifferentiated cells have similar possibility to change into tumorigenic cells.
Figure 2 A normal cellular hierarchy comprising stem cells at the apex, which generate common and more restricted progenitor cells and ultimately the mature cell types that constitute particular tissues
Figure 3 In the cancer stem cell (CSC) model, only the CSCs have the ability to generate a tumor, based on their self-renewal properties and proliferative potential
Figure 4 In the clonal evolution model, all undifferentiated cells have similar possibility to change into a tumorigenic cell
Research Related to Cancer Stem Cells
If cancer stem cells are the primary driver of cancer growth and metastasis, then effective cancer treatments must attack the CSCs in addition to eliminating the bulk of the tumor. Shrinking a cancerous tumor or reducing leukemic cells in the blood may offer temporary relief, but it will not offer a long-term cure if CSCs are not eliminated. Furthermore, if only the CSCs are eliminated, the rest of the cancer cells in the body might be attacked by the immune system or die out naturally. The most effective cancer treatments, therefore, will be those that specifically target CSCs. Discovering such treatments will require that we know as much as possible about the qualities and behavior of CSCs.
Figure 5 Both tumor models may play a role in the maintenance of a tumor. Initially, tumor growth is assured with a specific CSC (CSC 1). With tumor progression, another CSC (CSC 2) may arise due to the clonal selection. The development of a new more aggressive CSC may result from the acquisition of an additional mutation or epigenetic modification.
Researchers at Stanford’s Ludwig Center for Cancer Stem Cell Research and Medicine, for instance, discovered why stem cells, including cancer stem cells, are resistant to the ionizing radiation used in many cancer treatments. This understanding may help researchers find compounds that make CSCs vulnerable to radiation damage. Another example concerns immune therapies in which the body’s immune system is trained to attack cancer cells. Some of these therapies failed in clinical trials of skin cancer, and Stanford researchers demonstrated why: the targets that the immune system were trained to attack belonged not to the CSCs but to slightly different daughter cells. The immune therapies seemed effective at first as they attacked the daughter cells, but they left the skin cancer stem cells untouched and therefore it could not cure the cancer.
The first conclusive evidence for CSCs was published in 1997 in Nature Medicine. Bonnet and Dick isolated a subpopulation of leukemic cells that expressed a specific surface marker CD34, but lacked the CD38 marker. The authors established that the CD34+/CD38– subpopulation is capable of initiating tumors in NOD/SCID mice that are histologically similar to the donor. The first evidence of a solid tumor cancer stem–like cell followed in 2002 with the discovery of a clonogenic, sphere-forming cell isolated and characterized from human brain gliomas. Some researchers favor the theory that the CSC is generated by a mutation in stem cell niche populations during development. These developing stem populations are mutated and then expanded such that the mutation is shared by many of the daughter cells of the mutated stem cell.
Another theory associates adult stem cells with the formation of tumors, most often in tissues with a high rate of cell turnover (such as the skin or gut). In these tissues, stem cells are thought to be responsible for tumor formation as a result of the frequent cell divisions of these stem cells (compared to most adult stem cells) in conjunction with the extremely long life span of adult stem cells. This combination creates the ideal set of circumstances for mutations to accumulate; accumulation of mutations is the primary factor that starts a cancer. Another theory is that the mutated cells de-differentiate into stem cells.
Isolation of Cancer Stem Cells
CSCs are commonly identified and enriched using strategies for identifying normal stem cells, including fluorescence-activated cell sorting (FACS), with antibodies