In order for cells to start dividing uncontrollably, genes that regulate cell growth must be dysregulated.
Proto-oncogenes are genes that promote cell growth and
mitosis, whereas
tumor suppressor genes discourage cell growth, or temporarily halt cell division to carry out
DNA repair. Typically, a series of several
mutations to these genes is required before a normal cell transforms into a
cancer cell. provides most of the building blocks required to duplicate the cellular components of a dividing cell and, therefore, is also essential for carcinogenesis. Ras was originally identified in the Harvey sarcoma virus genome, and researchers were surprised that not only is this gene present in the human genome but also when ligated to a stimulating control element, it could induce cancers in cell line cultures. New mechanisms were proposed recently that the cell transformation during carcinogenesis was decided by the overall threshold of the oncogene networks (such as Ras signaling) but not by the status of the individual oncogene.
Proto-oncogenes Proto-oncogenes promote cell growth in a variety of ways. Many can produce
hormones, "chemical messengers" between cells that encourage mitosis, the effect of which depends on the
signal transduction of the receiving tissue or cells. Some are responsible for the signal transduction system and signal
receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. They often produce
mitogens, or are involved in
transcription of DNA in
protein synthesis, which create the
proteins and
enzymes responsible for producing the products and
biochemicals cells use and interact with. Mutations in proto-oncogenes can modify their
expression and function, increasing the amount or activity of the product protein. When this happens, they become
oncogenes, and, thus, cells have a higher chance of dividing excessively and uncontrollably. The chance of cancer cannot be reduced by removing proto-oncogenes from the
genome, as they are critical for growth, repair and
homeostasis of the body. It is only when they become mutated that the signals for growth become excessive. It is important to note that a gene possessing a growth-promoting role may increase the carcinogenic potential of a cell, under the condition that all necessary cellular mechanisms that permit growth are activated. This condition also includes the inactivation of specific tumor suppressor genes (see below). If the condition is not fulfilled, the cell may cease to grow and can proceed to die. This makes identification of the stage and type of
cancer cell that grows under the control of a given oncogene crucial for the development of treatment strategies.
Tumor suppressor genes , also known as "programmed cell death".
Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally, tumor suppressors are
transcription factors that are activated by cellular
stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways that lead to the activation of
tumor suppressor genes. The functions of such genes is to arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. The
p53 protein, one of the most important studied tumor suppressor genes, is a transcription factor activated by many cellular stressors including
hypoxia and
ultraviolet radiation damage. Despite nearly half of all cancers possibly involving alterations in p53, its tumor suppressor function is poorly understood. p53 clearly has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in regulating the cell cycle, cell division, and apoptosis. The
Warburg effect is the preferential use of glycolysis for energy to sustain cancer growth. p53 has been shown to regulate the shift from the respiratory to the glycolytic pathway. However, a mutation can damage the tumor suppressor gene itself, or the signal pathway that activates it, "switching it off". The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer. Mutations of tumor suppressor genes that occur in
germline cells are passed along to
offspring, and increase the likelihood for cancer diagnoses in subsequent generations. Members of these families have increased incidence and decreased latency of multiple tumors. The tumor types are typical for each type of tumor suppressor gene mutation, with some mutations causing particular cancers, and other mutations causing others. The mode of inheritance of mutant tumor suppressors is that an affected member inherits a defective copy from one parent, and a normal copy from the other. For instance, individuals who inherit one mutant
p53 allele (and are therefore
heterozygous for mutated
p53) can develop
melanomas and
pancreatic cancer, known as
Li-Fraumeni syndrome. Other inherited tumor suppressor gene syndromes include
Rb mutations, linked to
retinoblastoma, and
APC gene mutations, linked to
adenopolyposis colon cancer. Adenopolyposis colon cancer is associated with thousands of polyps in colon while young, leading to
colon cancer at a relatively early age. Finally, inherited mutations in
BRCA1 and
BRCA2 lead to early onset of
breast cancer. Development of cancer was proposed in 1971 to depend on at least two mutational events. In what became known as the
Knudson two-hit hypothesis, an inherited, germ-line mutation in a
tumor suppressor gene would cause cancer only if another mutation event occurred later in the organism's life, inactivating the other
allele of that
tumor suppressor gene. Usually, oncogenes are
dominant, as they contain
gain-of-function mutations, while mutated tumor suppressors are
recessive, as they contain
loss-of-function mutations. Each cell has two copies of the same gene, one from each parent, and under most cases gain of function mutations in just one copy of a particular proto-oncogene is enough to make that gene a true oncogene. On the other hand, loss of function mutations need to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one mutated copy of a
tumor suppressor gene can render the other,
wild-type copy non-functional. This phenomenon is called the
dominant negative effect and is observed in many p53 mutations. Knudson's two hit model has recently been challenged by several investigators. Inactivation of one allele of some tumor suppressor genes is sufficient to cause tumors. This phenomenon is called
haploinsufficiency and has been demonstrated by a number of experimental approaches. Tumors caused by
haploinsufficiency usually have a later age of onset when compared with those by a two hit process.
Multiple mutations s In general, mutations in both types of genes are required for cancer to occur. For example, a mutation limited to one oncogene would be suppressed by normal mitosis control and tumor suppressor genes, first
hypothesised by the
Knudson hypothesis.
Non-mutagenic carcinogens Many
mutagens are also
carcinogens, but some carcinogens are not mutagens. Examples of carcinogens that are not mutagens include
alcohol and
estrogen. These are thought to promote cancers through their stimulating effect on the rate of cell
mitosis. Faster rates of mitosis increasingly leave fewer opportunities for repair enzymes to repair damaged DNA during
DNA replication, increasing the likelihood of a genetic mistake. A mistake made during mitosis can lead to the daughter cells' receiving the wrong number of
chromosomes, which leads to
aneuploidy and may lead to cancer.
Role of infections Bacterial Helicobacter pylori can cause
gastric cancer. Although the data varies between different countries, overall about 1% to 3% of people infected with
Helicobacter pylori develop gastric cancer in their lifetime compared to 0.13% of individuals who have had no
H. pylori infection.
H. pylori infection is very prevalent. As evaluated in 2002, it is present in the gastric tissues of 74% of middle-aged adults in developing countries and 58% in developed countries. Since 1% to 3% of infected individuals are likely to develop gastric cancer,
H. pylori-induced gastric cancer is the third highest cause of worldwide cancer mortality as of 2018. Infection by
H. pylori causes no symptoms in about 80% of those infected. About 75% of individuals infected with
H. pylori develop
gastritis. Thus, the usual consequence of
H. pylori infection is chronic asymptomatic gastritis. Because of the usual lack of symptoms, when gastric cancer is finally diagnosed it is often fairly advanced. More than half of gastric cancer patients have lymph node metastasis when they are initially diagnosed. The gastritis caused by
H. pylori is accompanied by
inflammation, characterized by infiltration of
neutrophils and
macrophages to the gastric epithelium, which favors the accumulation of
pro-inflammatory cytokines and
reactive oxygen species/
reactive nitrogen species (ROS/RNS). The substantial presence of ROS/RNS causes DNA damage including
8-oxo-2'-deoxyguanosine (8-OHdG). In addition to the
oxidative DNA damage 8-OHdG,
H. pylori infection causes other characteristic DNA damages including DNA double-strand breaks.
H. pylori also causes many
epigenetic alterations linked to cancer development. These
epigenetic alterations are due to
H. pylori-induced
methylation of CpG sites in promoters of genes H. pylori infection is associated with epigenetically reduced efficiency of the DNA repair machinery, which favors the accumulation of mutations and genomic instability as well as gastric carcinogenesis. In particular, Raza et al. showed that expression of two DNA repair proteins,
ERCC1 and
PMS2, was severely reduced once
H. pylori infection had progressed to cause
dyspepsia. Dyspepsia occurs in about 20% of infected individuals. In addition, as reviewed by Raza et al., allowing cells with
DNA damage to "run an apoptotic red light" and proceed through the cell cycle.
Viral Furthermore, many cancers originate from a
viral infection; this is especially true in animals such as
birds, but less so in
humans. 12% of human cancers can be attributed to a viral infection. The mode of virally induced tumors can be divided into two,
acutely transforming or
slowly transforming. In acutely transforming viruses, the viral particles carry a gene that encodes for an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly transforming viruses, the virus genome is inserted, especially as viral genome insertion is an obligatory part of
retroviruses, near a proto-oncogene in the host genome. The viral
promoter or other transcription regulation elements, in turn, cause over-expression of that proto-oncogene, which, in turn, induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly transforming viruses have very long tumor latency compared to acutely transforming virus, which already carries the viral-oncogene. Viruses that are known to cause cancer such as
HPV (
cervical cancer),
Hepatitis B (
liver cancer), and
EBV (a type of
lymphoma), are all DNA viruses. It is thought that when the virus infects a cell, it inserts a part of its own DNA near the cell growth genes, causing cell division. The group of changed cells that are formed from the first cell dividing all have the same viral DNA near the cell growth genes. The group of changed cells are now special because one of the normal controls on growth has been lost. Depending on their location, cells can be damaged through radiation, chemicals from cigarette smoke, and inflammation from bacterial infection or other viruses. Each cell has a chance of damage. Cells often die if they are damaged, through failure of a vital process or the immune system, however, sometimes damage will knock out a single cancer gene. In an old person, there are thousands, tens of thousands, or hundreds of thousands of knocked-out cells. The chance that any one would form a cancer is very low. When the damage occurs in any area of changed cells, something different occurs. Each of the cells has the potential for growth. The changed cells will divide quicker when the area is damaged by physical, chemical, or viral agents. A
vicious circle has been set up: Damaging the area will cause the changed cells to divide, causing a greater likelihood that they will experience knock-outs. This model of carcinogenesis is popular because it explains why cancers grow. It would be expected that cells that are damaged through radiation would die or at least be worse off because they have fewer genes working; viruses increase the number of genes working. One thought is that we may end up with thousands of vaccines to prevent every virus that can change our cells. Viruses can have different effects on different parts of the body. It may be possible to prevent a number of different cancers by immunizing against one viral agent. It is likely that HPV, for instance, has a role in cancers of the mucous membranes of the mouth.
Helminthiasis Certain parasitic worms are known to be carcinogenic. These include: •
Clonorchis sinensis (the organism causing
Clonorchiasis) and
Opisthorchis viverrini (causing
Opisthorchiasis) are associated with
cholangiocarcinoma. •
Schistosoma species (the organisms causing
Schistosomiasis) is associated with
bladder cancer.
Epigenetics Epigenetics is the study of the regulation of gene expression through chemical, non-mutational changes in DNA structure. The theory of
epigenetics in cancer pathogenesis is that non-mutational changes to DNA can lead to alterations in gene expression. Normally,
oncogenes are silent, for example, because of
DNA methylation. Loss of that methylation can induce the aberrant expression of
oncogenes, leading to cancer pathogenesis. Known mechanisms of epigenetic change include
DNA methylation, and methylation or acetylation of
histone proteins bound to chromosomal DNA at specific locations. Classes of medications, known as
HDAC inhibitors and
DNA methyltransferase inhibitors, can re-regulate the epigenetic signaling in the
cancer cell.
Epimutations include methylations or demethylations of the
CpG islands of the
promoter regions of genes, which result in repression or de-repression, respectively of gene expression. Epimutations can also occur by acetylation, methylation, phosphorylation or other alterations to histones, creating a
histone code that represses or activates gene expression, and such histone epimutations can be important epigenetic factors in cancer. In addition, carcinogenic epimutation can occur through alterations of chromosome architecture caused by proteins such as
HMGA2. A further source of epimutation is due to increased or decreased expression of
microRNAs (miRNAs). For example, extra expression of miR-137 can cause downregulation of expression of 491 genes, and miR-137 is epigenetically silenced in 32% of colorectal cancers> Furthermore, the
relapse of cancer and the emergence of
metastasis are also attributed to these cells. The
cancer stem cell hypothesis does not contradict earlier concepts of carcinogenesis. The cancer stem cell hypothesis has been a proposed mechanism that contributes to
tumour heterogeneity.
Clonal evolution While genetic and
epigenetic alterations in tumor suppressor genes and oncogenes change the behavior of cells, those alterations, in the end, result in cancer through their effects on the population of
neoplastic cells and their microenvironment. Thus, the process of carcinogenesis is formally a process of Darwinian
evolution, known as
somatic or clonal evolution. Furthermore, in light of the Darwinistic mechanisms of carcinogenesis, it has been theorized that the various forms of cancer can be categorized as pubertal and gerontological. Anthropological research is currently being conducted on cancer as a natural evolutionary process through which natural selection destroys environmentally inferior phenotypes while supporting others. According to this theory, cancer comes in two separate types: from birth to the end of puberty (approximately age 20) teleologically inclined toward supportive group dynamics, and from mid-life to death (approximately age 40+) teleologically inclined away from overpopulated group dynamics. == See also ==