Cancerous tumors and embryonic tissues have been found to share many of the same antigens, which are detected by the immune system through antibodies. This group of antigens is called oncofetal antigens. Consequently, animals can be vaccinated with embryonic tissues/cells (most recently done with human embryonic stem cells) and develop an immune response against cancer.

Interestingly, this state of immune tolerance is similar to what happens during pregnancy, and, more specifically, it’s been found that the body’s response to a tumor is very similar to its response to embryonic tissues. While much recent research has not been published in this area, there is actually a long history of studies that show: (1) there is a significant number of antigens shared between tumors and embryonic tissues (called “oncofetal antigens”) and, consequently, antibodies made against tumors can also recognize embryonic tissues, and vice versa; (2) pregnancy confers some immunity against cancer (accompanied by antibody production against oncofetal antigens), not only against its occurrence but also against its growth; (3) similar to pregnancy, an immune response against cancer can be generated by vaccinating animals with embryonic tissues. These studies and the recent re-visitation will be explored below (for a more detailed review, see Brewer et al., 2009).

The first published suggestion that tumors may have an embryonic nature came in the early 1800s (Muller, 1838). Tumors were suspected to be tissues that had been triggered to become embryonic-like again, and it is now generally accepted that tumors are indeed more “embryonic” than the tissues they are derived from, due to the re-expression of embryonic-related genes. By the late 1800s, researchers understood cancer enough to realize that they must better understand normal development in order to better combat cancerous tumors and their embryonic-like cells (Brewer et al., 2009). In the 1880s, these studies shifted focus; the field of immunology was born (from research conducted by Louis Pasteur, at the University of Strasbourg, and Robert Koch, as a medical officer in Poland) and many researchers focused on creating vaccines to cure diseases. Cancer was no exception.

The Discovery and Establishment of Oncofetal-Antigens

As the field of immunology blossomed, in the 1920s and 1930s researchers found that tumors express antigens that are also found on embryonic tissues (an antigen is a molecule that the immune system recognizes, usually a protein on the cell’s surface). Specifically, it was found that antibodies made against tumors in the digestive track reacted with the tumors as well as tissues from embryonic and fetal gut and pancreas (Hirzfeld, 1929; Hirzfeld et al., 1932). Later in the early 1970s, several studies reported that antibodies developed against a variety of animal tumors reacted against embryos (as well as the original tumor)(Brewer et al., 2009).

While it was becoming clear that antibodies made against tumors could recognize embryonic tissues, researchers wondered whether the reverse was true: Could antibodies made against embryonic tissues react against tumors? In the 1960s, it was found that about 80% of blood sera (which normally contains antibodies) from pregnant women in the first two trimesters contained antibodies that reacted with tumors (as well as embryonic tissue) (Alexdander and Fairley, 1967). These and following studies led to the idea of universal “oncofetal antigens,” antigens that are expressed by tumors and fetal/embryonic tissues.

Pregnancy Confers Some Cancer Immunity

As the concept of oncofetal antigens developed, researchers explored a hypothesis with very practical applications: Because pregnant animals develop antibodies that can recognize tumor tissues, pregnancy may “immunize” an animal against cancer. Some early observations that supported this theory were nearly 300 years old, when celibate nuns were thought to have increased incidences of breast, uterine, and ovarian cancer (Brewer et al., 2009). While some hypothesized that this was due to a lack of “hormonal stimulation” (as has been suspected to be a factor in breast cancer), others thought it might be due to a lack of antibodies generated against embryonic tissues. Further evidence to support the latter explanation was published in the 1960s to 1980s, as multiple studies reported that women and animals that were multiparous (pregnant multiple times) not only had less spontaneous cancers, but multiparous animals also had fewer carcinogen-induced cancers and were somewhat resistant to transplanted tumors (Brewer et al., 2009). In the early 1970s, researchers further dissected this immune response and found that pregnant women produced cytotoxic T lymphocytes that could kill tumor cells but not normal, benign cells (Ambrose et al., 1971).

(As an interesting side note, a decrease in pregnancy rate has been found to correlate with the presence of antibodies against oncofetal antigens, and the effect can be replicated by immunizing with embryonic or tumor tissues. For women who have spontaneous abortions, it has been found that [at the time of a spontaneous abortion] antibodies are detectable in their sera that react against tumors; when these antibodies were injected into rats, there was a significant decrease in tumor growth [Buttle et al., 1964]. This effect has been repeated in animals; when animals were immunized with embryonic or tumor tissues, their pregnancy rate also significantly decreased [Parmiani and Della Porta, 1973].)

Embryonic Tissues Confer Some Cancer Immunity

While researchers were finding that pregnant animals have some immunity against cancer, researchers started testing whether injecting, or “immunization,” with embryonic tissues alone could similarly trigger an immune response and/or confer cancer immunity. In the late 1960s and early 1970s, many reports were published supporting this theory; anti-tumor antibodies were repeatedly found to be stimulated, and tumors sometimes even prevented, after vaccination with early embryonic tissues or cells (but not adult tissues or cells), even when tested across different species, revealing the presence of conserved antigens (Brewer et al., 2009). In 1970, researchers found that rabbits immunized with homogenized 9-day-old mouse embryos created antibodies that cross-reacted with 72 different mouse tumors from 12 different tissues of origin (created “spontaneously” or induced by viruses or chemicals). The antibodies, as expected, also reacted against embryonic tissues, and, strangely, adult skin (but no other adult tissues) (1970, Stonehill and Bendich). Human embryos also conferred an immune response; again, antibodies produced against the embryos recognized many different types of human tumors and showed no cross-reactivity with adult tissues except skin (Klavins et al., 1971). Immunization with embryonic cells (instead of homogenized embryos) had similar results; immunized mice made antibodies that recognized tumors, embryos, and, again, adult skin (Bendich et al., 1973). These immunized mice were also fairly resistant to tumor induction. Overall, these studies of the late 1960s and early 1970s strongly suggest that vaccination with embryonic tissues not only triggers an immune response against cancer, but may also prevent it to some degree.

(Interestingly, studies like these revealed that even virally-induced cancers [such as SV-40 and Rauscher leukemia virus] are caused by the re-expression of embryonic genes [and not the expression of new, viral genes]; rodents injected with embryonic tissues had an immune response against such virally-induced tumors [Brewer et al., 2009].)

The Problem of Immune Tolerance

But in order to truly harness the potential of using embryonic tissues/cells/proteins to immunize against cancer, the problem of immune tolerance must be better understood. In both patients with cancer and women who are pregnant, immune tolerance takes place in an apparently similar, transient manner. In the 1960s, a study reported that while patients with sarcomas usually did not have detectable antibodies against the tumor, after the tumor was surgically removed, anti-tumor antibodies increased, while this was not seen in patients whose sarcomas were not successfully removed (Ambrose et al., 1971b; Morton et al., 1970). Similarly, antibodies against oncofetal antigens are present in pregnant women in the first two trimesters (presumably while the embryo is seen as “non-self”), then disappear, then reappear after birth (Gold, 1967). (Younger embryos in mice have also been found to be most effective at conferring tumor immunity.) The cause for the transient immune tolerance in both cases is unclear, although “blocking factors” in serum were identified in the early 1970s. The factors most likely (1) prevent recognition of the embryo/cancer (are protective antibodies or antibody/antigen complexes) and/or (2) are immunosuppressive cytokines, e.g. TGF-beta (Brewer et al., 2009). Clearly, to better understand immune tolerance in cancer, it is necessary to better understand it during pregnancy. There are most likely many reasons in common for why pregnancy and tumors are not rejected more often than they are.

Recent Revisiting

While these studies showed many promising findings for fighting cancer, published reports significantly decreased after the mid-1970s, possibly due to decreased funding and infeasibility of progressing the studies further for obvious reasons (Brewer et al., 2009). However, the connection between cancer and embryonic tissues/cells has been revisited recently with the development of human embryonic stem cells.

While it is still largely under debate, much evidence suggests that cancer arises from cancer stem cells. Cancer stem cells share many similarities with human embryonic stem cells (hESCs) (which are stem cells isolated from the inner cell mass of a blastocyst) and induced pluripotent stem cells (iPSCs) (which are adult cells that have been reprogrammed to be hESC-like). These similarities were explored in a previous All Things Stem Cell article: “Better Understanding Cancer and Induced Pluripotent Stem Cells Through Their Similarities.” The basic similarities between iPSCs/hESCs and cancer stem cells are that they can all (1) be potentially pluripotent (or at least multipotent, having an increased potency), (2) avoid apoptosis/cell death (they are proliferative), and (3) express similar cell markers (such as some oncofetal antigens). hESCs and iPSCs can also, due to these traits, create teratoma tumors (a tumor with cells from all three germ layers) when injected into animals.

Recently, a report by professors Yi Li, Zihai Li, and colleagues (at the University of Connecticut School of Medicine) expanded upon the previous embryonic immunization studies by using an established embryonic stem cell line for the first time. This re-visitation was most likely prompted by recent interest in the promising, growing fields of cancer vaccines and embryonic stem cells. Many cancer vaccines target oncofetal antigens, which are present on hESCs and iPSCs as well, lending support to the idea of using hESCs and iPSCs to stimulate an immune response against multiple antigens on a tumor.

Li et al., 2009 reported that immunization of mice with hESCs resulted in an immune response against colon cancer (CT26). The mice were immunized twice, one week apart, with hESCs (line H9), iPSCs, and irradiated colon cancer cells (CT26), and one week later exposed to the CT26 colon cancer cells. The hESCs conferred consistent, cellular and humoral responses against the colon cancer (as did the irradiated CT26 cells, as expected), significantly reducing the tumor size. Surprisingly, the iPSC line appeared to be significantly inferior at producing immunity against the tumor, relative to the hESC and CT26 cells. No significant autoimmunity was observed, which can be a concern. (For a commentary on this report, see Zwaka, 2010.)

With this recent report by Li et al. bringing attention back to the long-standing field of cancer vaccination using embryonic tissues and cells, other groups may also revisit this potentially promising tool for fighting cancer.

References

Alexander, P., and Fairley, G. H. Cellular resistance to tumors. Br. Med. Bull. 1967. 23:86–92.

Ambrose, K. R., Anderson, N. G., and Coggin, J. H. Cytostatic antibody and SV40 tumour immunity in hamsters. Nature. 1971a. 233:321–324.
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Ambrose, K. R., Anderson, N. G., and Coggin, J. H. Interruption of SV40 oncogenesis with human foetal antigen. Nature. 1971b. 233:194–195.
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Bendich, A., Borenfreund, E., and Stonehill, E. H. Protection of adult mice against tumor challenge by immunization with irradiated adult skin or embryo cells. J. Immunol. 1973. 111:284–285.
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Brewer, B. G., Mitchell, R. A., Harandi, A., Eaton, J. W. Embryonic Vaccines Against Cancer: An Early History. Exp. Molec. Path. 2009. 86:192-197.
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Li, Y., Zeng, H., Xu, R., Liu, B., Li, Z. Vaccination with Human Pluripotent Stem Cells Generates a Broad Spectrum of Immunological and Clinical Responses Against Colon Cancer. Stem Cells. 2009. 27:3103-3111.
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Zwaka, T. P. Stem Cell Vaccination Against Cancer: Fighting Fire With Fire? Molec. Ther. 2010. 18.1:8-9.
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Image of “Antibody and Antigens” was taken from Wikipedia and redistributed freely as it is in the public domain.

The most recent article, “Likely Suspects in Cancer Growth,” is on cancer stem cells — it is a modified version of the “All Things Stem Cell” post “Cancer Stem Cells: A Possible Path to a Cure” to fit a more lay public audience.

Tune in to “Biology Bytes” for weekly stories on a wide array of fascinating biology topics, including more accessible explanations of stem cell biology.

The most recent and most publicized link between iPSCs and cancer is p53. p53, also known as protein 53 (53 referring to its molecular mass), is a well-studied protein whose normal function is important in preventing cancer. Though p53 has many different roles, they are quite related. In essence, the job of p53 is to make sure the cell does not accumulate DNA damage, or DNA mutations, which could eventually make the cell cancerous. When a cell has its DNA damaged, often from external stresses, p53 stops the normal cell cycle to fix the DNA damage. If the damage is too great to repair, p53 can prevent the cell from dividing, which would create more damaged cells; p53 initiates programmed cell death, or apoptosis. The potential tumor cell dies. Overall, p53 functions as a “tumor suppressor” to prevent abnormal cells from occurring and multiplying into a cancer (Vazquez et al., 2008). Consequently, it has been found that p53 is mutated in approximately 50% of all human tumors, and other tumors may have mutations in the pathway regulating p53 activity (Vazquez et al., 2008). p53 is therefore well-studied as an oncogene, or a gene that when not functioning normally can contribute to a normal cell becoming cancerous.

So what does p53 have to do with iPSCs? One recently discovered connection is with the generation of iPSCs. Recently, many research groups discovered that when p53 is deleted from, or damaged in, their cells, they could more easily become iPSCs (Hong et al., 2009; Kawamura et al., 2009; Utikal et al., 2009; Li et al., 2009; Zhao et al., 2008). As posted earlier, iPSCs are cells that were originally from adult tissues, but have been “reprogrammed” to be pluripotent stem cells, or stem cells able to become all the adult cells of the body, looking and functioning nearly identical to human embryonic stem cells (hESCs) (Takahashi et al., 2007; Yu et al., 2007).

To create iPSCs, adult cells are exposed to “reprogramming factors,” or transcription factors, thought to be important for pluripotency. Researchers have tested different groups of reprogramming factors, and originally four different factors were found to work best. However, the process is rather inefficient; only a very small percentage of cells exposed to the set of factors actually becomes reprogrammed. Shinya Yamanaka’s group, one of the two that first created human iPSCs, found that iPSC generation increased by up to 20% in cells without p53 (Hong et al., 2009). Other groups have reported similar results; cells with non-functional p53 mutants, or mutations in the p53 pathway, had increased reprogramming efficiencies (Utikal et al., 2009; Li et al., 2009), some even with fewer reprogramming factors than are usually needed (Kawamura et al., 2009). Some researchers speculate that p53 is acting to protect the cells from the DNA damage that the reprogramming factors can cause, as p53 is turned on immediately after the factors are introduced (Kawamura et al., 2009). For a more detailed review of these papers, check out (Dolgin, 2009). Overall, these many separate recent reports clearly show the importance of p53 in creating iPSCs. As a side note, a very interesting remaining question is how exactly these cells become pluripotent after bypassing p53 activity.

What are the implications of the fact that decreasing p53 activity greatly increases iPSC derivation? It could imply that just about any cell in the human body has a greatly increased potential to initiate a cancer by losing p53 activity. Interestingly, this actually runs counter to the cancer stem cell hypothesis, which theorizes that not just any cell, but specifically a rare stem cell, may gain mutations over time and give rise to some cancers (see Figure)(Kawamura et al., 2009). This is a somewhat frightening prospect, suggesting that a far greater number of cells have tumorigenic potential than believed by the stem cell hypothesis, though it may help scientists better understand how cancer develops and consequently how it can be successfully fought.

The cancer stem cell hypothesis (top) theorizes that a (rare) mutated stem cell may gain mutations over time and give rise to cancer. Running counter to this (bottom), some evidence suggests that a mutation in p53, causing it to no longer function, in any given cell (including, but not only, stem cells) may greatly increase the cell’s potential to initiate a cancer.

p53 is not the only cancer-related factor important for the creation of iPSCs; most of the reprogramming factors have actually been suggested to be oncogenes and implicated in the generation of different cancers. C-Myc is a widely-used iPSC reprogramming factor (Takahashi et al., 2008) and is also responsible for the regulation of a very large number of different genes within the cell, including controlling cell proliferation. When c-Myc is over-expressed, or expressed at higher levels than normal, it can cause cancer, and high levels of c-Myc have been detected in many different tumor types (Hermeking, 2003). Other studies have shown that all the other reprogramming factors may also be oncogenes, with one exception (Lin28, which has been shown to not even be required for iPSC generation) (Liu, 2008A). But is this really that surprising? The reprogramming factors are genes expressed in embryonic, pluripotent tissues that are thought to be involved in making the tissue pluripotent. The cells that create cancerous tumors are most likely multipotent, being able to become multiple different cell types, because tumors are heterogenous tissues. Consequently, it is not that surprising that researchers have found connections between these embryonic reprogramming factors, and other embryonic-specific genes, and the creation of tumors and cancer stem cells (Wong et al., 2008; Gunaratne, 2009).

While such reports have caused some researchers to label iPSCs as “man-made cancer stem cells” (Liu, 2008B), it is important to keep in mind the distinct differences between iPSCs and cancer. iPSCs indeed, by definition, can create teratoma tumors when injected into animals and express many embryonic proteins which allow them to differentiate into multiple cell types just like tumors can. However, unlike cancer, iPSCs are grown in laboratories under controlled settings and it is only when they are undifferentiated that they have these tumorigenic potentials. To be used in therapies all cells must be carefully differentiated to the desired, adult cell type. iPSCs must lose their multipotency and consequently their tumorigenic potential. Researchers are currently working on many ways to make iPSCs safer for therapeutic use: using p53 to select for iPSCs that have no introduced DNA damage (Kawamura et al., 2009), optimizing the purification of differentiated populations, improving transient expression of the reprogramming genes, and more. Aside from therapies and regenerative medicine, iPSCs have great potential for creating cellular disease models, creating cell lines from reprogrammed diseased tissue to allow for greater study in laboratories; cancer cells cannot do this in the same fashion. Despite their similarities, iPSCs have the ability to offer scientists many important research opportunities that studying cancer by itself does not.

Understanding the connections between iPSCs and cancer has great potential for improving our treatment of cancer. Because iPSCs are reprogrammed adult cells, it may be possible to think of tumors as reprogrammed adult cells as well. Since iPSCs can be differentiated into specific, desired cell types, some researchers think it may also be possible to differentiate tumors into non-malignant cell types. However, the human body is a much more complicated environment than cells in a controlled laboratory setting (Blelloch et al., 2004; Yang et al., 2008). To potentially improve our abilities to treat cancer, it will take a great open-mindedness and understanding of not only the behavior of these cells in the laboratory, but also of their possible similarities to cancer initiation as it occurs in an organism.

References

Blelloch, R. B., Hochedlinger, K., Yamada, Y., Brennan, C., Kim, M., Mintz, B., Chin, L., and Jaenisch, R. Nuclear cloning of embryonal carcinoma cells. PNAS. 2004. 101(39): 13985-13990.
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Dolgin, E. Immortality improves cell reprogramming: Knocking out genes with a role in cancer prevention helps produce stem cells. Nature News. 2009.
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Gunaratne, P. H. Embryonic Stem Cell MicroRNAs: Defining Factors in Induced Pluripotent (iPS) and Cancer (CSC) Stem Cells? Curr Stem Cell Res Ther. 2009.
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Hermeking, H. The MYC Oncogene as a Cancer Drug Target. Current Cancer Drug Targets. 2003. 3(3): 163-175.
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Hong, H., Takahashi, K., Ichisaka, T., Aoi, T., Kanagawa, O., Nakagawa, M., Okita, K., and Yamanaka, S. Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature 460, 1132-1135 (27 August 2009).
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Kawamura, T., Suzuki, J., Wang, Y. V., Menendez, S., Morera, L. B., Raya, A., Wahl, G. M., and Izpisúa Belmonte, J. C. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature. 2009. 460: 1140-1144.
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Li, H., Collado, M., Villasante, A., Strati, K., Ortega, S., Cañamero, M., Blasco, M. A., and Serrano, M. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature. 2009. 460: 1136-1139.
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Liu, S. V. iPS Cells: A More Critical Review. Stem Cells and Development. 2008A. 17: 391-397.
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Liu, S. V. IPS Cells are Man-Made Cancer Cells. Logical Biology. 2008B. 8(1): 16-18.
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Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts. Cell. 2007. 131: 1-12.
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Utikal, J., Polo, J. M., Stadtfeld, M., Maherali, N., Kulalert, W., Walsh, R. M., Khalil, A., Rheinwald, J. G., and Hochedlinger, K. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature. 2009. 460: 1145-1148.
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Vazquez, A., Bond, E. E., Levine, A. J., and Bond, G. L. The genetics of the p53 pathway, apoptosis and cancer therapy. Nature Reviews Drug Discovery. 2008. 7: 979-987.
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Wong, D. J., Liu, H., Ridky, T. W., Cassarino, D., Segal, E., and Chang, H. Y. Module Map of Stem Cell Genes Guides Creation of Epithelial Cancer Stem Cells. Cell Stem Cell. 2008. 2(4): 333-344.
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Yang, Y., Zhang, L., Wei, Y., Wang, H., Fukuma, M., Xu, H., Xiong, W., and Zheng, J.
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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.

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?

References

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