Introduction to How Cancer Begins
Simply put, cancer is the result of unregulated cell division. Cancer cells divide when they are not supposed to, don't stop dividing when they are supposed to and don't die when they should. In the worst cases, the cancer cells leave the area in which they arose and travel to other parts of the body.
Cancer cells do not look or act like the normal cells from which they originate. It is reasonable, then, to ask 'Why do cancer cells behave so badly?'. It turns out the the answers lie in the genes of the affected cells. In cancer cells, changes to key genes cause the cells to act abnormally. The changes are often the result of changes to the DNA (mutations) in the cells. Because there are many different things that are capable of causing mutation, there are an equally large number of causes of cancer.
The development of cancer takes place in a multi-step process. As the cells become more abnormal, they gain new capabilities, such as the ability to release growth factors and digestive enzymes. The cells continue to divide, impacting nearby normal cells, often reducing the function of the affected organ. Even abnormal cancer cells die sometime and a tumor that is large enough to feel can take years to reach that size. Although not all cancers share exactly the same steps, there are some general features that are shared in the development of many types of cancer. Another critical step in the growth of a tumor is the development of a blood supply (angiogenesis). Blood provides nutrients, carries away waste and the blood vessels provide a way for cancer cells to move around the body. The stages in the development of a solid tumor (i.e. breast cancer, or skin cancer) and the process of angiogenesis are described in the following pages.
The following sections describe some chemicals and other agents that are known to cause cancer and discuss how they are thought to cause changes in normal cells.
Below is a list of topics covered in this section.
Cancer Initiation, Promotion, and Progression
In the eighteenth century, London physician Percival Pott made the first link between cancer and environmental agents when he noted a high incidence of scrotal cancer among chimney sweeps. He hypothesized that it was caused by exposure to coals and tars. Out of this observation grew the two-stage model of cancer development by 1) initiators and 2) promoters. In the years since Pott's observations a wide range of chemicals, radiation sources, viruses and bacteria have been implicated in the development of cancer. (1)
The initial experimental studies of carcinogenesis were conducted in animals. Chemicals able to react with DNA and non-reactive compounds were both tested for their ability to cause cancer. The model used was mouse skin carcinogenesis. In this system researchers painted test chemicals on the skin and observed the growth of tumors. Researchers found that application of a DNA reactive substance only resulted in tumor formation when the animals were further treated with another non-reactive substance. A compound that reacts with DNA and somehow changes the genetic makeup of the cell is called a mutagen. The mutagens that predispose cells to develop tumors are called initiators and the non-reactive compounds that stimulate tumor development are called promoters. Approximately 70% of known mutagens are also carcinogens--cancer-causing compounds. (2) A compound that acts as both an initiator and a promoter is referred to as a 'complete carcinogen' because tumor development can occur without the application of another compound. (3)
Initiation
Initiation is the first step in the two-stage model of cancer development. Initiators, if not already reactive with DNA, are altered (frequently they are made electrophilic) via drug-metabolizing enzymes in the body and are then able to cause changes in DNA (mutations). (3) Since many initiators must be metabolized before becoming active, initiators are often specific to particular tissue types or species. (4) The effects of initiators are irreversible; once a particular cell has been affected by an initiator it is susceptible to promotion until its death. Since initiation is the result of permanent genetic change, any daughter cells produced from the division of the mutated cell will also carry the mutation. (3) In studies of mouse skin carcinogenesis, a linear relationship has been observed between the dose of initiator and the quantity of tumors that can be produced, thus any exposure to the initiator increases risk and this risk increases indefinitely with higher levels of exposure. (4)
Initiation is the first step in the two-stage model of cancer development. Initiators, if not already reactive with DNA, are altered (frequently they are made electrophilic) via drug-metabolizing enzymes in the body and are then able to cause changes in DNA (mutations). (3) Since many initiators must be metabolized before becoming active, initiators are often specific to particular tissue types or species. (4) The effects of initiators are irreversible; once a particular cell has been affected by an initiator it is susceptible to promotion until its death. Since initiation is the result of permanent genetic change, any daughter cells produced from the division of the mutated cell will also carry the mutation. (3) In studies of mouse skin carcinogenesis, a linear relationship has been observed between the dose of initiator and the quantity of tumors that can be produced, thus any exposure to the initiator increases risk and this risk increases indefinitely with higher levels of exposure. (4)
Promotion
Once a cell has been mutated by an initiator, it is susceptible to the effects of promoters. These compounds promote the proliferation of the cell, giving rise to a large number of daughter cells containing the mutation created by the initiator. (2) Promoters have no effect when the organism in question has not been previously treated with an initiator. (4)
Once a cell has been mutated by an initiator, it is susceptible to the effects of promoters. These compounds promote the proliferation of the cell, giving rise to a large number of daughter cells containing the mutation created by the initiator. (2) Promoters have no effect when the organism in question has not been previously treated with an initiator. (4)
Unlike initiators, promoters do not covalently bind to DNA or macromolecules within the cell. Many bind to receptors on the cell surface in order to affect intracellular pathways that lead to increased cell proliferation. (3) There are two general categories of promoters: specific promoters that interact with receptors on or in target cells of defined tissues and nonspecific promoters that alter gene expression without the presence of a known receptor. Promoters are often specific for a particular tissue or species due to their interaction with receptors that are present in different amounts in different tissue types.
While the risk of tumor growth with promoter application is dose-dependent, there is both a threshold and a maximum effect of promoters. Very low doses of promoters will not lead to tumor development and extremely high doses will not produce more risk than moderate levels of exposure. (4)
Progression
In mice, repeated promoter applications on initiator-exposed skin produces benign papillomas. Most of these papillomas regress after treatment is stopped, but some progress to cancer. The frequency of progression suggests that the papillomas that progress to cancer have acquired an additional, spontaneous, mutation. (5) The term progression, coined by Leslie Foulds, refers to the stepwise transformation of a benign tumor to a neoplasm and to malignancy. Progression is associated with a karyotypic change since virtually all tumors that advance are aneuploid (have the wrong number of chromosomes). This karyotypic change is coupled with an increased growth rate, invasiveness, metastasis and an alteration in biochemistry and morphology. (4)
In mice, repeated promoter applications on initiator-exposed skin produces benign papillomas. Most of these papillomas regress after treatment is stopped, but some progress to cancer. The frequency of progression suggests that the papillomas that progress to cancer have acquired an additional, spontaneous, mutation. (5) The term progression, coined by Leslie Foulds, refers to the stepwise transformation of a benign tumor to a neoplasm and to malignancy. Progression is associated with a karyotypic change since virtually all tumors that advance are aneuploid (have the wrong number of chromosomes). This karyotypic change is coupled with an increased growth rate, invasiveness, metastasis and an alteration in biochemistry and morphology. (4)
Stages of Tumor Development
The growth of a tumor from a single genetically altered cell is a stepwise progression. The process described below is applicable for a solid tumor such as a carcinoma or a sarcoma. Blood cell tumors go through a similar process but since the cells float freely, they are not limited to one location in the body.
Hyperplasia- The altered cell divides in an uncontrolled manner leading to an excess of cells in that region of the tissue. The cells have a normal appearance but there are too many of them!
Dysplasia- Additional genetic changes in the hyperplastic cells lead to increasingly abnormal growth. The cells and the the tissue no longer look normal. The cells and the tissue may become disorganized.
Carcinoma in situ- Additional changes make the cells and tissues appear even more abnormal. The cells are now spread over a larger area and the region of the tissue involved primarily contains altered cells. The cells often 'regress' or become more primitive in their capabilities. An example would be a liver cell that no longer makes liver-specific proteins. Cells of this type are said to be de-differentiated or anaplastic. A key facet of in situ growths is that the cells are contained within the initial location and have not yet crossed the basal lamina to invade other tissues. Cancers of this type are often totally curable by surgery since the abnormal cells are all in one location.
Tumors of this type have not yet invaded neighboring tissue. Based on information about patients with similar growths and microscopic examination, these growths are often considered to have the potential to become invasive and are treated as malignant growths.
Cancer (Malignant tumors)- These tumors have the ability to invade surrounding tissues and/or spread (metastasize) to areas outside the local tissue. These metastatic tumors are the most dangerous and account for a large percentage of cancer deaths. The next few pages will go into some detail on the changes and capabilities that allow cancer cells to form large tumors and to metastasize to other parts of the body.
Some tumors do not progress to the point where they invade distant tissues. Such tumors are said to be benign. Because they do not spread beyond their initial location, they are not considered to be cancerous. Benign tumors are less often lethal than malignant tumors, but they can still cause serious health problems. Large benign tumors can put pressure on organs and cause other problems. In the case of brain tumors, the limited space within the skull means that a large growth in the brain cavity can be fatal.
Carcinogens: Cancer Causing Substances
Since the 1940s, scientists have isolated compounds and tested their ability to induce cancer. Substances which can cause cancer are known as carcinogen and the process of cancer development is called carcinogenesis. It was suspected early-on that carcinogens caused cancer indirectly, by causing DNA mutations. One early observation supporting this was that X-rays, which were shown to damage DNA, can cause cancer. Since then, other types of radiation, many chemicals and some bacteria and viruses have been shown to cause cancer.
Environmental Agents and Cancer Development
Environmental Exposure
Population (epidemiological) and laboratory studies have led to the discovery of many potential environmental factors in the initiation, promotion and progression of cancer. Starting with Pott's observations in the 18th century, certain occupations have been associated with an increased risk of cancer development. The recognition of increased scrotal cancer in chimney sweeps due to coal and tar exposure was followed by an observation in a British factory that all men distilling 2-napthylamine developed bladder cancer. (1) Nickel refining, leather working and woodworking have also been associated with an increased risk of specific cancers due to chronic exposure to carcinogenic chemicals. Exposure to mustard gas, used as a chemical warfare agent in World War I has been associated with a higher risk of respiratory tract and lung cancers due to its mutagenic properties.(2) Of interest, some chemotherapy drugs are derivatives of mustard gas and are useful for the very same reason; they are highly mutagenic.
Population (epidemiological) and laboratory studies have led to the discovery of many potential environmental factors in the initiation, promotion and progression of cancer. Starting with Pott's observations in the 18th century, certain occupations have been associated with an increased risk of cancer development. The recognition of increased scrotal cancer in chimney sweeps due to coal and tar exposure was followed by an observation in a British factory that all men distilling 2-napthylamine developed bladder cancer. (1) Nickel refining, leather working and woodworking have also been associated with an increased risk of specific cancers due to chronic exposure to carcinogenic chemicals. Exposure to mustard gas, used as a chemical warfare agent in World War I has been associated with a higher risk of respiratory tract and lung cancers due to its mutagenic properties.(2) Of interest, some chemotherapy drugs are derivatives of mustard gas and are useful for the very same reason; they are highly mutagenic.
Geographical Influences
There have also been associations made between different geographical regions and particular cancers. Stomach cancer is 5-6 times higher among Japanese men, attributed to the consumption of fermented foods; breast cancer is 20 times higher among American women, attributed to the high fat American diet; and liver cancer is 10 times higher in Africa, which correlates with high rates of Hepatitis B infection. (3) Liver cancer may also be caused by aflatoxin, a food contaminant produced by fungi. This compound is prevalent in grain stores in tropical and subtropical regions because moist grain is a very good place for the fungi to live. (4)
There have also been associations made between different geographical regions and particular cancers. Stomach cancer is 5-6 times higher among Japanese men, attributed to the consumption of fermented foods; breast cancer is 20 times higher among American women, attributed to the high fat American diet; and liver cancer is 10 times higher in Africa, which correlates with high rates of Hepatitis B infection. (3) Liver cancer may also be caused by aflatoxin, a food contaminant produced by fungi. This compound is prevalent in grain stores in tropical and subtropical regions because moist grain is a very good place for the fungi to live. (4)
Lifestyle
The impact of many environmental factors can be reduced by making healthy lifestyle choices. One of the most potent carcinogens in humans is benzo[a]-pyrene, a compound found in cigarette smoke. (1) In fact, the tar in cigarette smoke includes both initiators and promoters, making it especially dangerous. Alcohol is a promoter of carcinogenesis in humans, as is asbestos. Additionally, UV radiation, from exposure to the sun or tanning beds, is a powerful initiator in humans and is a cause of skin cancer. (3)
The impact of many environmental factors can be reduced by making healthy lifestyle choices. One of the most potent carcinogens in humans is benzo[a]-pyrene, a compound found in cigarette smoke. (1) In fact, the tar in cigarette smoke includes both initiators and promoters, making it especially dangerous. Alcohol is a promoter of carcinogenesis in humans, as is asbestos. Additionally, UV radiation, from exposure to the sun or tanning beds, is a powerful initiator in humans and is a cause of skin cancer. (3)
Drugs
Tamoxifen, a chemotherapeutic agent used to combat estrogen receptor positive (ER ) breast cancer, increases the risk of endometrial cancer by increasing the rate of endometrial cell proliferation. For this reason, ss-term tamoxifen treatment is losing popularity in favor of aromatase inhibitors.(5) Estrogens themselves may also dasbe important in the promotion of tumors, particularly in post-menopausal women receiving exogenous estrogens, due to their ability to increase mammary and endometrial cell division rates.(6) This is an area of active research.
Tamoxifen, a chemotherapeutic agent used to combat estrogen receptor positive (ER ) breast cancer, increases the risk of endometrial cancer by increasing the rate of endometrial cell proliferation. For this reason, ss-term tamoxifen treatment is losing popularity in favor of aromatase inhibitors.(5) Estrogens themselves may also dasbe important in the promotion of tumors, particularly in post-menopausal women receiving exogenous estrogens, due to their ability to increase mammary and endometrial cell division rates.(6) This is an area of active research.
There are factors that can predispose an unborn fetus to developing cancer later in life. These include exposure to radiation or the synthetic estrogen diethylstilbestrol (DES).(7)
A Closer Look at Aflatoxin: Physical Impact and Associated Cancer
Exposure: Aflatoxin is produced by Aspergillus flavus and Aspergillus parasiticus fungi. The fungi synthesize aflatoxin when they are living in warm, moist conditions. These fungi are prevalent among crops such as rice, corn, cassava, nuts, peanuts, chilies, and spices. Countries with the highest amounts of these organisms lie within 40 degrees latitude north or south of the equator. Storage of food under warm, moist conditions increases the risk of aflatoxin contamination. Approximately 4.5 billion persons living in developing countries are chronically exposed to uncontrolled amounts of aflatoxin.(8)
Associated Cancer: Aflatoxicosis is the disease that results from ingestion of aflatoxin. This disease can present in one of two forms. The first is an acute illness that results from exposure to large amounts of the toxin over a short period of time. Adult humans have a high tolerance for aflatoxin. Ingestion of large amounts of aflatoxin usually causes liver damage and acute illness but is rarely fatal. However, exposure to high levels of the toxin can cause death in children. The second form of aflatoxicosis is due to low level chronic exposure to aflatoxin. Chronic aflatoxin exposure has an additive effect and can lead to the development of liver cancer. Aflatoxin increases the risk of liver cancer (usually in the form of hepatocellular carcinoma or HCC) in all persons who ingest contaminated food. It can also increase the risk of lung cancer in workers who handle the grain. Infection with either the Hepatitis B or C viruses combined with exposure to aflatoxin can increase a person's risk of developing liver cancer by as much as 30 fold over a person who is exposed to aflatoxin but is not infected with hepatitis virus. Infection with the Hepatitis B virus decreases a person's ability to detoxify aflatoxin via the liver. This can partially account for the greatly increased risk of cancer development in individuals exposed to both aflatoxin and hepatitis virus.(8)
In its initial stages, HCC causes no noticable symptoms. It can grow for up to 3 years before causing physical symptoms.(9)For this reason, most HCC patients present with advanced stages of the disease, making treatment difficult. Non surgical treatments are only minimally effective. HCC patients have shown to have, at best, a 25% response rate to chemotherapy, as most HCC tumors are resistant to chemotherapy. Liver transplantation is the only current cure for HCC. Unfortunately, based on the number, size, location, and severity of the underlying disease, not all patients are candidates for a transplant.(10)
Organisms That Cause Cancer
Although most cancer seems to arise from environmental exposures to chemicals and radiation or lifestyle choices, a large number of cases are caused by infections. As more is learned about different types of cancer, additional links with infectious agents are likely to be found.
Parasites
One of the first connections between infections and cancer was provided by Dr. Johannes Fibiger. Dr. Fibiger noticed an association between cancer in his laboratory rats and infection with a parasitic worm (nematode). He named the worm Spiroptera carcinoma. While it was later shown that the worms were not the primary cause of the cancer, the link between infection and cancer has withstood the test of time.(1)
One of the first connections between infections and cancer was provided by Dr. Johannes Fibiger. Dr. Fibiger noticed an association between cancer in his laboratory rats and infection with a parasitic worm (nematode). He named the worm Spiroptera carcinoma. While it was later shown that the worms were not the primary cause of the cancer, the link between infection and cancer has withstood the test of time.(1)
Bacteria
Helicobacter pylori is a bacteria that is able to survive in the mucosa of the gastric (stomach) epithelium for a long time and is a main cause of stomach and duodenal diseases. Epidemiological studies have provided evidence that H. pylori is associated with the development of lymphomain mucosa-associated lymphoid tissue (MALT) and gastric adenocarcinoma (stomach cancer). (2)
Helicobacter pylori is a bacteria that is able to survive in the mucosa of the gastric (stomach) epithelium for a long time and is a main cause of stomach and duodenal diseases. Epidemiological studies have provided evidence that H. pylori is associated with the development of lymphomain mucosa-associated lymphoid tissue (MALT) and gastric adenocarcinoma (stomach cancer). (2)
Recent research suggests that the populations of bacteria that live in a person's instestines can influence their risk of developing colon cancer.XXX
Viruses
Certain viruses and bacteria have also been associated with the initiation and promotion of tumor growth based on both epidemiological and experimental evidence. Some DNA viruses contain genes whose products can take control of cell division in the host cell. They promote the development of tumors by increasing proliferation rates and shutting down the normal systems that prevent cells from dividing. These viruses include human papillomavirus (HPV), the most significant risk factor for the development of cervical cancer. Similarly, an RNA virus, human T-cellleukemia virus type 1 (HTLV-1) leads to adult T-cell leukemia by stimulating the proliferation of infected T-cells. (3) Epstein-Barr virus (EBV) is another virus that increases cell proliferation. This virus also protects infected cells from death (apoptosis). EBV infects more than 90% of the world's adult population and has been implicated as a cause of Burkitt's lymphoma, nasopharyngeal carcinoma and gastric lymphoma. Experimental evidence in rats and from human tumors, has implicated the JC virus (a polyomavirus)in brain tumors, particularly medulloblastomas. Some viruses also have indirect actions on tumor development. Hepatitis B causes damage that leads to increased cell division and inflammation in the liver, potentially promoting the growth of tumors. The human immunodeficiency virus (HIV) greatly reduces the function of the immune system and is the cause of AIDS. HIV infection may also make patients susceptible to infection by a type of human herpes virus 8 (HHV8), a risk factor for Kaposi's sarcoma.
Certain viruses and bacteria have also been associated with the initiation and promotion of tumor growth based on both epidemiological and experimental evidence. Some DNA viruses contain genes whose products can take control of cell division in the host cell. They promote the development of tumors by increasing proliferation rates and shutting down the normal systems that prevent cells from dividing. These viruses include human papillomavirus (HPV), the most significant risk factor for the development of cervical cancer. Similarly, an RNA virus, human T-cellleukemia virus type 1 (HTLV-1) leads to adult T-cell leukemia by stimulating the proliferation of infected T-cells. (3) Epstein-Barr virus (EBV) is another virus that increases cell proliferation. This virus also protects infected cells from death (apoptosis). EBV infects more than 90% of the world's adult population and has been implicated as a cause of Burkitt's lymphoma, nasopharyngeal carcinoma and gastric lymphoma. Experimental evidence in rats and from human tumors, has implicated the JC virus (a polyomavirus)in brain tumors, particularly medulloblastomas. Some viruses also have indirect actions on tumor development. Hepatitis B causes damage that leads to increased cell division and inflammation in the liver, potentially promoting the growth of tumors. The human immunodeficiency virus (HIV) greatly reduces the function of the immune system and is the cause of AIDS. HIV infection may also make patients susceptible to infection by a type of human herpes virus 8 (HHV8), a risk factor for Kaposi's sarcoma.
Chronic Inflammation and Cancer Development
Chronic inflammation has been seen, both experimentally and epidemiologically, to be an important factor in tumor development. Chronic inflammation can be caused by viral or bacterial infections, autoimmune diseases and inflammatory conditions of unknown origins. It has been shown that mutation of key inflammatory control genes is associated with a higher risk of cancer progression, and markers of inflammation correlate with a worse prognosis for cancer patients. Inflammation seems to lead to the development of cancer because of the activities of leukocytes, including the production of proteins that alter the behavior of target cells (cytokines and chemokines), stimulation of blood vessel growth (angiogenesis) and tissue remodeling. Immune cells also produce oxygen radicals that can cause mutations in DNA.
Inflammation can both induce carcinogenesis and lead to progression and metastasis. The activation of a specific transcription factor,NF-kB, by pro-inflammatory cytokines has been shown to produce a more aggressive cancer phenotype including resistance to normal growth control mechanisms, angiogenetic capability and metastasis. Tumor associated macrophages (TAM), are also associated with the inflammatory pathway, have been observed to produce pro-angiogenic factors and recruit blood vessels early in tumor development. TAM also increase the growth rate of tumor cells and cause the dissolution of the connective tissue matrix surrounding the tumor, enabling tumor growth and spread. (1)
There are several cancer types associated with chronic inflammatory conditions, including; colon cancer and inflammatory bowel disease, liver cancer and hepatitis C, bladder or colon cancer and schistosomiasis (a chronic parasitic infection) and stomach cancer and H. pylori infection. (2)
Detecting Carcinogens: The Ames Test
Bacteria have proven to be good models for determining the mutagenic potential of compounds. Bruce Ames, a biochemist, developed an assay to identify potential mutagens. The Ames test works 'backwards' from what one might expect. The test starts with mutant bacteria and looks for chemicals that can change them back into normal (wild type) bacteria.
In the Ames test, a potential mutagen is placed on a paper disc in the center of a petri dish on which only bacterial cells that mutate are able to grow. The mutagenic potential of the compound in question is determined by the amount of bacterial growth seen. Information obtained in this way was shown to be comparable to results from tests in rodents.
Researchers have also manipulated mouse cells to make them potential targets for carcinogens and have transferred genes from cancerous cells into healthy mice,--all of which have led to the conclusion that mutations in key genes can lead to the changes that result in cancer. (1)
What are Cancer Stem Cells
What is a stem cell?
A stem cell is a special cell type that has both the ability to reproduce exact copies of itself (also called self-renewal) and the ability to change (differentiate) into one of the many specialized cell types in the body. Examples of specialized cells that arise from stem cells include nerves, muscles and the cells lining our digestive system. In most parts of the body, stem cells are not very active. In some locations, including the gastrointestinal tract, stem cells divide and differentiate constantly to replace cells that are shed or die. Stem cells are also important during healing of damaged tissues. Below is a video of the process by which stem cells can accomplish both self-renewal and differentiation. The process is called asymmetric cell division and it assures that stem cells are always available when needed.(1)
What is a cancer stem cell?
Cancer stem cells are thought to arise from normal stem cells. Normal stem cells become damaged by mutation and no longer function properly. A main difference between normal stem cells and CSC is that CSC have uncontrolled reproduction and may form tumors. The existence of CSCs was predicted decades ago, but recent research has identified cancer stem cells in multiple cancer types prompting large amounts of research in this field.(1)(2)
Where do cancer stem cells come from?
In theory, CSCs could be formed in more than one way. Mutations could occur in a differentiated cell (i.e. a skin cell) causing the cell to go backwards or 'devolve' into a cell with some stem cell abilities. Cancer stem cells could also be formed by the mutation of a normal stem cell that causes it to become cancerous. Cancer stem cells have been created in research laboratories from skin cells(3) The researchers used a virus to activate specific pathways and give the target cell stem cell-like qualities. The research proves that a normal cell can become a stem cell with the right set of mutations.
The probability of any particular cell developing a set of mutations that leads to cancer is relatively low. The cells types that are affected by the majority of cancers, epithelial cells, have short lives and are even less likely to accumulate all the mutations they need. Normal stem cells, which are long-lived, are more likely to be around long enough to accumulate the necessary mutations and are a good possible source of cancer stem cells.(1)
What is the difference between the cancer stem cell hypothesis of the origin of cancer and traditional views on the origin of cancer?
The cancer stem cell hypothesis suggests that only a small portion of cells are capable of becoming cancerous. A second prediction is that only a small population of cells in a tumor is responsible for the continuous, uncontrolled growth seen in cancer. The traditional views on the origin of cancer predict that any cell is able to acquire mutations that lead to uncontrolled reproduction. Likewise, all of the cells in a tumor would be predicted to be able to divide endlessly.(2)
Cancer Stem Cells and Treatment
What is the impact of CSCs on treatment?
Current treatments target cancer because the drugs act on cells that are actively dividing. Most of these drugs function by inducing the death (viaapoptosis) of the cancer cells. Cancer stem cells carry mutations that lead to cancer, but they do not necessarily divide quickly. This relatively inactive state would allow them to avoid the effects of cancer treatments which would explain the all too frequent recurrences of cancers. CSCs also efficiently repair DNA damage and avoid apoptosis making them hard targets for today's drugs. This evasion of treatment could be likened to a weed in a garden. Cancer stem cells are like the roots of the weed and the majority of the tumor mass is the leaves and stem of the weed. Removing the visible part of the weed appears to kill it, but the roots underground soon sprout another stem and the weed lives on.(1)
Current treatments target cancer because the drugs act on cells that are actively dividing. Most of these drugs function by inducing the death (viaapoptosis) of the cancer cells. Cancer stem cells carry mutations that lead to cancer, but they do not necessarily divide quickly. This relatively inactive state would allow them to avoid the effects of cancer treatments which would explain the all too frequent recurrences of cancers. CSCs also efficiently repair DNA damage and avoid apoptosis making them hard targets for today's drugs. This evasion of treatment could be likened to a weed in a garden. Cancer stem cells are like the roots of the weed and the majority of the tumor mass is the leaves and stem of the weed. Removing the visible part of the weed appears to kill it, but the roots underground soon sprout another stem and the weed lives on.(1)
Why is it difficult to target CSCs?
The problems encountered when clinicians treat cancer are also seen when purified CSCs are treated with anti-cancer drugs. Because normal stem cells and CSCs are very similar, it is difficult to kill CSCs and leave normal stem cells unharmed. Drug resistance is another major obstacle in treating both cancer and CSCs. Stem cells tend to have high levels of particular cellular pumps (i.e. the multiple drug resistance protein, MDR) that are able to eject cancer drugs from the cells making the drugs ineffective. Stem cells are also harder to kill than normal cells because they have an ability to block the signals that drugs like chemotherapy cause to lead to death (apoptosis). An excess of antiapoptotic proteins helps stem cells avoid the effects of cancer treatments.(1)
The problems encountered when clinicians treat cancer are also seen when purified CSCs are treated with anti-cancer drugs. Because normal stem cells and CSCs are very similar, it is difficult to kill CSCs and leave normal stem cells unharmed. Drug resistance is another major obstacle in treating both cancer and CSCs. Stem cells tend to have high levels of particular cellular pumps (i.e. the multiple drug resistance protein, MDR) that are able to eject cancer drugs from the cells making the drugs ineffective. Stem cells are also harder to kill than normal cells because they have an ability to block the signals that drugs like chemotherapy cause to lead to death (apoptosis). An excess of antiapoptotic proteins helps stem cells avoid the effects of cancer treatments.(1)
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