Cancer Development

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Introduction

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 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 DNAAbbreviation for deoxyribonucleic acid. Composed of very long strings of nucleotides, which are abbreviated as A, C, G and T. DNA is the storage form of our genetic material. All of the instructions for the production of proteins are encoded in our 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 sometimes 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. Further information on the topics on this page can also be found in most introductory Biology textbooks, we recommend Campbell Biology, 11th edition.1

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, radiationIn cancer biology: A cancer treatment in which high energy beams are used to kill cancer cells. Radiation can also cause genetic damage that can lead to cancer. As an example, skin cancer is believed to be greatly increased by exposure to ultraviolet (UV) radiation from the sun. sources, viruses and bacteriaA microscopic organism. Bacteria lack a nucleus. They are found in very large numbers in almost all locations, including the human body. While most bacteria are harmless or necessary, some can cause disease and death. have been implicated in the development of cancer. 2

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 mutagenAn agent that can cause alterations to DNA. If the alterations are not repaired exactly, changes in the DNA can lead to altered gene expression or gene products. Many mutagens are also carcinogens, agents that can cause cancer. Since cancer results from mutations in key genes, an agent that can cause changes has the potential to cause the changes that lead to cancer. Ironically, radiation and many of the chemotherapy agents used to treat cancer also have the potential to cause mutations and lead to cancer themselves.. 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. 3 A compound that acts as both an initiator and a promoterThe portion of a gene that controls when and how much that particular gene will be expressed (transcribed). Promoters are likened to an on/off switch that determines the activity of a gene. Promoters do not control gene activity themselves, they work by binding to proteins called transcription factors. The transcription factors act as flags to wave down the enzymes (RNA polymerases) that make RNA copies of the genes. Changes (mutations) in the promoter portion of a gene can lead to disruptions in the regulation of gene expression. These changes are often seen in cancer. is referred to as a 'complete carcinogenAn agent that is able to cause cancer. Many carcinogens are chemicals that cause changes (mutations) in DNA. Radiation is another type of carcinogen. ' because tumor development can occur without the application of another compound. 4

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). 4 Since many initiators must be metabolized before becoming active, initiators are often specific to particular tissue types or species. 5 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. 4 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. 5

Promotion
Once a cell has been mutated by an initiator, it is susceptible to the effects of promoters. These compounds promote the proliferationRefers to cell division. The proliferation rate is an indicator of how quickly a tumor is growing. The proliferation rate may be represented as a percentage, showing what fraction of the cells are actively involved in the division process. of the cell, giving rise to a large number of daughter cells containing the mutation created by the initiator. 3 Promoters have no effect when the organism in question has not been previously treated with an initiator. 5

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. 4 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 expressionThe act of transcription and, if needed, translation of a gene. Regulation of gene expression is tightly regulated. Genes must only be expressed in the correct cells, at the right time and in the correct amount. Abnormal gene expression is always found in cancer cells. 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. 5

Progression
In mice, repeated promoter applications on initiator-exposed skin produces benignA growth that does not leave its site of origin or invade surrounding tissue. Benign growths can get large and are capable of causing illness or even death, depending on the location of the growth. Technically, benign growths are not cancer. 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. 6 The term progression, coined by Leslie Foulds, refers to the stepwise transformationThe process by which a normal cell is converted to a cell that has the characteristics of cancer cells. The event causing the change can be an alteration in an oncogene or infection with an oncogenic virus. Transformed cells demonstrate several characteristic differences from normal cells including: density independent growth, anchorage independent growth, lack of dependence on growth factors. 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. 5

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 carcinomaCancer of epithelial cells, the cells that cover the outside and inside of body surfaces. This is the most common form of cancer. or a sarcomaA malignant cancer that originates in bone, muscle or connective tissues.. 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!

DysplasiaAn abnormal condition in which cells may have altered shape or divide in a way that alters the appearance of the tissue or organ. This often occurs when cells divide rapidly and may be a precursor to cancerous growth.- Additional genetic changes in the hyperplastic cells lead to increasingly abnormal growth. The cells and 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 malignantA tumor that has invaded neighboring tissue. growths.

Cancer (Malignant tumors)- These tumors have the ability to invade surrounding tissues and/or spread (metastasizeThe movement of a cancer to a location outside its site of origin. The distant growths are termed metastases.) to areas outside the local tissue. These metastaticThe term for a cancer that has spread beyond its point of origin. Metastatic disease is responsible for the majority of cancer deaths. tumors are the most dangerous and account for a large percentage of cancer deaths. The next few sections 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.

More information on this topic may be found in Chapters 13 and 14 of The Biology of Cancer by Robert A. Weinberg.

Cancer Stem Cells

What is a stem cellCells capable of developing into more than one cell type. All of the cells in a human body come from the division and subsequent differentiation of a single cell, formed from the fusion of an egg and sperm. This original cell has the capability to form any cell type and is called totipotent. As tissues develop the cells lose the ability to form all other tissues, and become 'committed' to forming only one or a few cell types. These stem cells are called pluripotent. An example are bone marrow cells that form many different kinds of blood cells. Stem cell replacement allows for the pluripotent stem cells in bone marrow to be replaced after high doses of chemotherapy. Many fully differentiated cells are not capable of cell division and are replaced when they die by the division of stem cells in that tissue. Many forms of cancer are thought to be the result of abnormal division of stem cells.?
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 also play a role in healing damaged tissue.

Below is a video of the process by which stem cells can accomplish both self-renewal and differentiationThe maturation of a stem cell into a fully functional cell. Fully differentiated cells are often not able to divide and many cancers are thought to arise via mutations in the small number of stem cells that remain in the tissue.. The process is called "asymmetric cell division," and it assures that stem cells are always available when needed.7

 


What is a cancer stem cell?
Cancer stem cells (CSCs) are thought to arise from normal stem cells. Sometimes, genetic changes or mutations damage normal stem cells, preventing them functioning properly. If this improper function includes uncontrolled reproduction, then the normal stem cell has the ability to form a tumor; it is now a cancer stem cell. 

The existence of CSCs was predicted decades ago, but recent research has identified cancer stem cells in multiple cancer types, prompting extensive research in this field.7, 8


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 cells9 The researchers used a virusThe smallest type of organism known. A single virus particle (called a virion) is much smaller than a cell. Viruses reproduce by invading cells and forcing the cells to make progeny virions. Viruses generally have specific host cells which they infect. Some virus types are associated with specific cancers and can convert normal cells into cancer cells. Examples of viruses associated with cancer are: papillomavirus-cervical cancer, hepatitis virus-liver cancer, Epstein-Barr virus-Burkitt's lymphoma. Virus-induced transformation of cells was one of the very first model systems for the study of cancer. Viruses have also been a key tool in the identification of many oncogenes. Because of their great ability to enter target cells viruses such as adenoviruses are being examined for their ability to deliver genes to cancer cells. 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, epithelialA type of tissue (epithelium) that covers our exposed surfaces, such as skin. Also lines our hollow or tube-like organs/tissues such as the digestive tract. Since these tissues are often exposed to environmental insults such as chemicals and solar radiation and are often divide rapidly to replace lost cells, many cancers arise in epithelial tissues. 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.7


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. In other words, 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.8

 

The Search for Cancer Stem Cells

What led to the search for cancer stem cells?

There are several reasons why many researchers find the cancer stem cell hypothesis appealing. Cancer stem cells provide one possible explanation for the frequent failure of cancer treatments, the large amount of cells needed to cause cancer growth in model organisms, and gaps in other theories of cancer development. A large challenge has been the identification and isolation of cancer stem cells. Researchers have identified some cell surface proteins (also called markers) found on cancer cells that have some important stem cell capabilities. These markers include CD44, CD133, and ALDH1.8

One of the pieces of evidence that favors the existence of cancer stem cells is the fact that when researchers look at tumors they appear to contain several differentiated cell types. The traditional theory on the development of cancer is able to explain this, but the large number of mutations necessary to create the mixture is unlikely. An illustration,- if tumors form from a single mutated cell the tumor would only contain cells of that type rather than cells of many types:

 



If multiple cells of different types in the same area have mutations this would lead to a tumor of mixed cell types:

 


Cancer stem cells have the ability to produce cells of many different types creating the mixture of cells found in a tumor:

 

The possibility of a stem cell becoming a cancer stem cell is, statistically, more likely to happen than multiple mutations in multiple cells in the same area in order to produce a tumor with multiple cell types.10, 8

 

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 (via apoptosisAlso called programmed cell death. Apoptosis is a natural process that occurs throughout the lives of almost all animals and plants. The death of the cells is a carefully controlled process that does not generate any inflammation.) 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.11

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 proteinAlso: MDR, is a P-glycoprotein and drug efflux pump. MDR is a transmembrane protein that can prevent the entry of some anti-cancer drugs into cells and eject drugs from the cell after they have entered. Increased expression of the MDR protein is a leading cause of chemotherapy failure., 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 chemotherapyTreatment of cancer patients with anticancer drugs. Commonly called 'chemo'. These drugs work by attacking cell growth or division. Often these agents are used in combination to take advantage of their different modes of attack on cell division. cause to lead to death (apoptosis). An excess of antiapoptotic proteins helps stem cells avoid the effects of cancer treatments.11

Can CSCs be targeted with treatment?
Cancer stem cells can cause problems with cancer treatments, but researchers are trying to come up with ways to target them. A potential cancer drug, napabucasin, has been found to target 'stemness.' According to two separate studies, a treatment combining napabucasin with chemotherapy was able to block STAT3 gene transcriptionThe production of an RNA molecule from a DNA template. An RNA copy of a gene is produced by an enzyme, RNA polymerase. The RNA produced can either be used directly in the cell or can be used to direct the production of a protein through the process of translation. Many of the genes that are altered in cancer cells have potent effects on the process of transcription. See transcription factor. in cancer stem cells.12 Napabucasin was shown to kill colorectal stem cells, block their renewal, and kill cancer cells13 Napabucasin could have serious side effects in humans, as it has been shown to cause bone loss in mice.14

It may also be possible to combine two non-lethal drug together in a way that will kill CSCs. An international collaboration looking into this found that combining an antibiotic (doxycycline) with vitamin C was effective at targeting CSC-like breast cancer cells.15

Learn more about MDR and drug resistance.
Learn more about cancer cell death (apoptosis).

 

Cancer Development Summary

Introduction

  • All of our cells have similar structures and share a majority of their functions.
  • Cancers may be categorized into five basic types based on the cell of origin:
    • Carcinoma - epithelial cells
    • Sarcoma - muscle, bone, cartilage, fat, or connective tissue
    • LeukemiaA cancer affecting the cells that develop into white or red blood cells. Both of these cell types originate from stem cells in bone marrow. Red blood cells function to carry oxygen to our tissues and the white cells (leukocytes) are part of our immune system. The cancerous cells often accumulate in the blood. - blood cells or their precursors
    • LymphomaA cancer arising in the lymphatic system. The white blood cells affected are part of the body's immune system. The lymphatic system is a large network of vessels that carry fluid and cells of the immune system around the body. Lymph nodes are regional collection centers in the lymphatic system. See also, 'lymphatic system'. - bone marrow derived cells; cancer affects the lymphatic systemA large network of vessels that carry fluid and cells of the immune system around the body. Lymph nodes are regional collection centers in the lymphatic system. Fluid from the areas surrounding the lymph nodes drains into the lymph nodes. Cells from Tumor cells may break away from the primary tumor and be carried to a nearby lymph node. The lymphatic system is a primary mechanism for tumors to move, or metastasize, to other parts of the body.
    • Myeloma - specific blood cells; B lymphocytes (B-cells)

Stages of Tumor Progression

  • Tumors typically progress is a stepwise fashion:
    • Hyperplasia - cells divide too much but appear normal
    • Dysplasia - the tumor cells and tissue appear abnormal
    • Carcinoma in situFrom the Latin, - tumor contains primarily altered cells and is growing larger; it has not left the site of origin
    • Malignant Cancer - tumor has begun to invade nearby or distant tissues
  • Benign tumors remain in their initial location and do not invade other tissues.

Initiators and Promoters

  • Initiation is the first step in the two-stage model of cancer development.
  • Initiators cause irreversible changes (mutations) to DNA that increase cancer risk.
  • Promotion is the second step in the two-stage model of cancer development.
  • Once a cell has been mutated by an initiator, it is susceptible to the effects of promoters.
  • Promoters increase the proliferation of cells and there are two main types:
    • Specific - interact with receptors on or in particular target cells.
    • Nonspecific - alter gene expression without the presence of a known receptor

Carcinogens

  • Substances that can cause cancer are known as carcinogens.
  • The process of cancer development is called carcinogenesis.
  • Certain carcinogenic chemicals are associated with an increased risk of specific cancers due to chronic exposure.
  • One of the most potent carcinogens in humans is benzo[a]pyrene, a compound found in cigarette smoke.

Viruses and Bacteria

  • Certain viruses and bacteria have also been associated with the initiation and promotion of tumor growth.
  • Some viruses cause cancer directly by affecting cell division while other viruses cause cancer by causing chronic inflammationA reaction to tissue damage or invasion. Small blood vessels become leaky, leading to redness and swelling. Cells of the immune system migrate to the area and can release chemicals and proteins that cause damage to the structures/cells nearby. or reducing immune system function.

Chronic Inflammation

  • Chronic inflammation is an important factor in tumor development.
  • Inflammation can lead to altered behavior of cells, stimulation of blood vessel growth (angiogenesisThe formation of blood vessels. This process is required for a tumor to grow past a small size since the blood delivers nutrients to the cells in the tumor mass.) and tissue remodeling.
  • Markers of inflammation correlate with a worse prognosis for cancer patients.
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