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Cancer Stem Cells: A Possible Path to a Cure

July 5th, 2009 by Teisha Rowland

Cancer stem cells (CSCs), as their name implies, are stem cells that have been discovered to reside within cancerous tumors. Tumors are made up of a heterogeneous mixture of cells. Consequently, if the growth comes from a common origin it must be a cell, or cells, capable of becoming many different types of cells. This makes stem cells a very likely suspect as they, by definition, are able to give rise to a variety of cells. CSCs have been broadly defined as cells within a tumor that are able to self-renew, regenerating a population of multipotent CSCs, as well as differentiate into other cells, which can create the heterogeneity seen in tumors (Vermeulen et al., 2008).

Although the theory of cancer stem cells has been around since the 1970s (Hamburger and Salmon, 1977), recently it has gained a spotlight in the scientific community. The first functional identification of CSCs was in 1997 in acute myeloid leukemia (Bonnet and Dick, 1997). Researchers found that although there are many different populations of cells within a tumor, only one population has the ability to generate the tumor. This was determined by separating the populations from each other and engrafting them into an immuno-compromised (NOD/SCID) mouse; the population identified as CSCs was able to recreate the original tumor, including morphology and the specific differentiated cell types observed within the tumor (Vermeulen et al., 2008).

The different populations within a tumor can be separated and identified according to the proteins expressed (or produced) on the surface of a particular cell; cells expressing the same set of proteins are grouped into one population. Because such proteins are commonly used to identify and categorize cells, they are called cell markers. CSCs from the same tumor type usually have the same set of markers expressed, although the markers expressed can vary much more between CSCs from different tissues (Vermeulen et al., 2008). For example, breast cancer CSCs have been found to express a marker called CD44, but are distinct for also not expressing the marker CD24 (making this CSC population be labeled CD44+/CD24) (Al-Hajj et al., 2002). In comparison, pancreatic cancer CSCs express CD44, but also express CD24 (Li et al., 2007). Although there are differences like this in marker expression between CSCs from different tumor types, some markers are present in CSCs from many different types of tumors, such as CD44. CSCs from ovarian tumors (Zhang et al., 2008) and head and neck squamous cell carcinomas (Prince et al., 2006) have also been found to express CD44. Another major marker protein expressed in CSCs across tissue types is CD133; it is expressed by CSCs found in brain (Singh et al., 2003), prostate (Lang et al., 2008), colon (O’Brien et al., 2007), lung (Eramo et al., 2007), and hepatic (Suetsugu et al., 2006) tumors. For a more detailed summary of marker expression of CSCs from the different tumors they have been discovered in, see Table 1.

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Table 1. Cancer Stem Cell Populations Detected in Different Cancerous Tumors (CSC Markers and Percent of the Total Tumor)

The markers expressed by cancer stem cells are also standard markers for many different stem cells from non-cancerous tissues. CD133+ is associated with many different kinds of stem cells: neural (Hill, 2006), hematopoietic (Suetsugu et al., 2006), endothelial, epithelial, and other stem cell types (Eramo et al., 2007). CD44 is expressed in hematopoietic (Morrison et al., 1995) and mesenchymal (Pittenger et al., 1999; Mitchell et al., 2006) stem cells. As becomes apparent when comparing these associations to the CSC markers reported in Table 1, often CSCs share the same markers as stem cells found in normal tissue in the tumor origin, but surprisingly sometimes the CSCs express very different markers from the stem cells normally present in the same healthy tissue (Vermeulen et al., 2008). It is still unclear why this is; these CSCs may be migrating from another tissue to the tumor site where they thrive due to components of the new cellular environment (Vermeulen et al., 2008), or the CSCs may be expressing these markers for other, unknown reasons. Like other stem cells, CSCs can differentiate and change expression of their markers; CSCs most likely have a marker expression profile very different from their progenitor cells (Eramo et al., 2007; Vermeulen et al., 2008).

Another cancer stem cell attribute of note is that CSCs account for only a small percentage of the total number of cells in the tumor. Shown in Table 1, the percentage of CSCs in a tumor can vary from as little as 0.002% to around 30%, depending on the type of tumor, but appears to most often be less than 10% (Singh et al., 2003; O’Brien et al., 2007; Eramo et al., 2007; Zhang et al., 2008; Li et al., 2007; Prince et al., 2006). Additionally, it has been reported that only some of the cells in the CSC population, as identified by their markers, can actually form tumors (Hill, 2006; O’Brien et al., 2007). Consequently, some researchers say that selecting for CSCs on the basis of their markers is only enriching for the true, functional CSC population, but it is not isolating them from cells that cannot form tumors (Hill, 2006). Additionally, there may be cells in the tumors other than CSCs that are capable of creating tumors (Hill, 2006), although they would most likely not be as able to form tumors as the identified CSC populations.

In order to comprehend how cancer stem cells are created it is important to understand the theories behind the creation of cancerous tumors and how this applies to CSCs. Cancer can occur when mutations have accumulated in genes related to controlling cell growth and differentiation. Specifically, such key genes are referred to as oncogenes and tumor suppressor genes. If one of the first mutations affects the regulation of cell growth, this can result in the expansion of an already mutated, potentially cancerous stem cell population. This population can gain mutations that upregulate, or increase, their ability to self-renew, further increasing the population size. The Wnt and BMI1 signaling pathways, which normally regulate cell proliferation and self-renewal, are often mutated in CSCs (Vermeulen et al., 2008). When enough mutations accumulate, a cell can overcome the normal cell growth restrictions and grow out of control, becoming cancerous (Vermeulen et al., 2008).

As more evidence is reported pointing at the key role of cancer stem cells in the creation of cancerous tumors, it becomes more crucial for researchers to have a thorough understanding of these stem cells. Although the CSC populations can be identified by different protein markers and their ability to create tumors in a mouse model, there is still much about them that is not well understood: how they are created, how their origins are related to non-cancerous stem cells, whether they are present in all cancerous tumors, and how they are affected by their cellular environment (Vermeulen et al., 2008; Hill, 2006). As more answers come to light, we will be able to answer the most important question: how can we use our knowledge of CSCs to most effectively combat them?

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  1. July 8th, 2009 at 08:49 | #1

    Your blog is very informative on stem cells.

    It’d be great if the CSC model will allow for better treatment and detection.

  1. October 31st, 2009 at 11:56 | #1