Oncogenes are mutated genes that can contribute to the development of cancer . In an unmutated state, we all have genes called proto-oncogenes. When proto-oncogenes mutate or increase in number (amplification) due to DNA damage (eg, exposure to carcinogens), the proteins produced by these genes can affect cell growth, proliferation, and survival and potentially lead to cancer.
There are many checks and balances, and cancer development often requires mutations or other genetic changes in both oncogenes and tumor suppressor genes (genes that make proteins that repair or kill damaged cells).
How Oncogenes Cause Cancer
Cancer occurs most often when a series of mutations in proto-oncogenes (causing them to become oncogenes) and tumor suppressor genes lead to uncontrolled and uncontrolled cell growth. However, the development of cancer is much easier to understand when you look at the different stages and the lack of regulation that occurs over time.
Proto-oncogenes and oncogenes
Proto-oncogenes are normal genes found in everyone's DNA. These genes are "normal" in the sense that they play an important role in normal cell growth and division, and are especially important for the growth and development of the fetus during pregnancy.
These genes act as protein models that trigger cell growth. The problem arises when these genes mutate or activate at a later age (if they become oncogenes), which can lead to the formation of cancerous tumors.
Most oncogenes start out as normal proto-oncogenes. However, proteins produced by oncogenes differ from proteins produced by proto-oncogenes in that they lack normal regulatory functions.
While the products (proteins) produced by proto-oncogenes depend on growth factors and other signals that stimulate cell growth, the products of oncogenes can lead to cell growth even if these other signals are absent. As a result, the number of cells begins to exceed the number of normal surrounding cells and a tumor forms.
Activation methods (how proto-oncogenes become oncogenes)
There are several ways that normal proto-oncogenes can be activated (changed) to become oncogenes. The process can begin when carcinogens (cancer causing) in the environment cause a mutation or amplification of a proto-oncogene.
Animal studies have shown that chemical carcinogens can cause mutations that convert ras proto-oncogenes to oncogenes. This finding is appropriate because KRAS mutations in lung cancer are more common in smokers than in never-smokers.
However, DNA damage can occur accidentally during normal cell growth; even if we lived in a carcinogen-free world, cancer would arise.
Damage to DNA can take one of several forms:
- Point mutations : changes in a base (nucleotide), as well as insertions or deletions in DNA, can result in the substitution of a single amino acid in a protein that alters function.
- Gene amplification : Additional copies of the gene cause more gene products (proteins that lead to cell growth) to be produced or "expressed".
- Translocations / Permutations : Moving a piece of DNA from one place to another can happen in a number of ways. Occasionally, the proto-oncogene moves to a different region of the chromosome and, due to this location, increased expression is observed (more protein is produced). In other cases, a proto-oncogene can fuse with another gene, making the proto-oncogene (now an oncogene) more active.
Mutations can also occur in the promoter or regulatory region adjacent to the proto-oncogene.
Oncogenes versus tumor suppressor genes
There are two types of genes that, when mutated or altered in some other way, can increase the risk of developing cancer: oncogenes and tumor suppressor genes . A combination of changes in both genes is often implicated in the development of cancer.
Even when DNA damage, such as point mutations, occurs when a proto-oncogene becomes an oncogene, many of these cells repair themselves. Another type of gene, tumor suppressor genes, encode proteins that work to repair damaged DNA or repair damaged cells.
These proteins can help reduce the risk of cancer, even if the oncogene is present. If there are also mutations in tumor suppressor genes, the chance of developing cancer is higher because the abnormal cells are not repaired and continue to survive rather than apoptosis (programmed cell death).
There are several differences between oncogenes and tumor suppressor genes:
Most of the time it is autosomal dominant, which means that only one copy of the gene needs to be mutated to increase the risk of cancer.
Enabled by mutation (improved function)
It can be visualized as an accelerator if we consider the cell as a machine
Very often (but not always), an autosomal recessive mutation must occur in both copies before the risk of cancer increases.
Disabled by mutation
Represented as a brake pedal when viewing the camera as a car.
From mutations to cancer
As noted above, cancer generally begins after the accumulation of mutations in the cell, including mutations in several proto-oncogenes and several tumor suppressor genes. It was once thought that the activation of oncogenes, leading to uncontrolled growth, is all that is needed for the transformation of a normal cell into a cancerous one, but we now know that other changes are needed more frequently (for example, changes that prolong the survival of damaged cells).
These changes not only cause cells to grow and divide uncontrollably, but they also do not respond to normal cell death signals, do not respect boundaries with other cells (they lose inhibition on contact) and other characteristics that make cells cancers behave differently. than normal cells.
However, some cancers are associated with a single gene mutation, such as childhood retinoblastoma, caused by a mutation in a gene known as RB1.
Inheritance (germline) versus acquired (somatic) mutations
Talking about mutations and cancer can get confusing because there are two different types of mutations to consider.
- Germline mutations: Hereditary or germline mutations are genetic mutations that are present at birth and exist in every cell in the body. Examples of germline mutations are mutations in the BRCA genes (tumor suppressor genes) and non-BRCA genes that increase the risk of breast cancer .
- Somatic Mutations: Somatic or acquired mutations, on the other hand, occur after birth and are not passed from one generation to the next (not by inheritance). These mutations are not present in all cells, but instead occur in a particular type of cell when that cell becomes cancerous or cancerous. Many of the targeted therapies used to treat cancer are designed to reverse the changes in cell growth caused by these particular mutations.
Oncoproteins are products (proteins) that are encoded by oncogenes and are produced when a gene is transcribed and translated (the process of "writing code" in RNA and making proteins).
There are many types of oncoproteins, depending on the specific oncogene present, but most of them work to stimulate cell growth and division, inhibit cell death (apoptosis), or inhibit cell differentiation (the process by which cells become unique. ). These proteins can also play a role in the progression and aggressiveness of an existing tumor.
The concept of oncogenes has been theorized for more than a century, but the first oncogene was not isolated until 1970, when an oncogene was discovered in a carcinogenic virus called Rous sarcoma virus (chicken retrovirus). It was well known that certain viruses and other microorganisms can cause cancer and, in fact, between 20% and 25% of cancers worldwide and about 10% in the United States are caused by these invisible organisms.
However, most cancers do not arise from an infectious organism, and in 1976 it was discovered that many cellular oncogenes are mutated proto-oncogenes; genes commonly found in humans.
Since then, much has been studied about how these genes (or the proteins they encode) work, and some of the exciting advances in cancer treatment are related to their effects on the oncoproteins responsible for cancer growth.
Types and examples
Different types of oncogenes affect growth in different ways (mechanisms of action), and to understand this, it is helpful to look at what is involved in normal cell proliferation (normal cell growth and division).
Most oncogenes regulate cell proliferation, but some inhibit differentiation (the process of transforming cells into unique cell types) or promote cell survival (inhibit programmed death or apoptosis). Recent research also shows that proteins produced by certain oncogenes suppress the immune system, making abnormal cells less likely to be recognized and killed by immune cells such as T cells.
Cell growth and division
Here is a very simplified description of the cell growth and division process:
- There must be a growth factor that stimulates growth.
- Growth factors bind to the growth factor receptor on the cell surface.
- Activation of the growth factor receptor (due to growth factor binding) activates signaling proteins. A cascade of signals follows for efficient transmission of a message to the cell nucleus.
- When the signal reaches the cell nucleus, transcription factors in the nucleus initiate transcription.
- So, cell cycle proteins influence the progression of the cell through the cell cycle.
Although there are more than 100 different functions of oncogenes, they can be divided into several basic types that transform a normal cell into a self-sustaining cancer cell. It is important to note that several oncogenes produce proteins that function in more than one of these regions.
Some cells with oncogenes become self-sufficient by producing (synthesizing) growth factors to which they respond. An increase in the amount of growth factors does not in itself lead to cancer, but it can cause rapid cell growth, which increases the likelihood of mutations.
An example includes the proto-oncogene SIS, which, when mutated, results in an overproduction of platelet-derived growth factor (PDGF). Elevated levels of PDGF are present in many forms of cancer, especially bone cancer (osteosarcoma) and a type of brain tumor.
Growth factor receptors
Oncogenes can activate or increase the number of growth factor receptors on the cell surface (to which they bind).
An example includes the HER2 oncogene, which results in a significant increase in the amount of HER2 proteins on the surface of breast cancer cells. In about 25% of breast cancers, the number of HER2 receptors is 40 to 100 times higher than in normal breast cells. Another example is the epidermal growth factor receptor (EGFR) , which is found in approximately 15% of non-small cell lung cancers.
Other oncogenes affect proteins involved in cell receptor signaling to the nucleus. Of these oncogenes, the ras family is the most abundant (KRAS, HRAS, and NRAS), found in approximately 20% of cancers overall. BRAF for melanoma also falls into this category.
Non-receptor protein kinases
Non-receptor protein kinases are also involved in the cascade that carries the growth signal from the receptor to the nucleus.
A well-known oncogene involved in chronic myeloid leukemia is the Bcr-Abl gene ( Philadelphia chromosome ), caused by the translocation of segments of chromosome 9 and chromosome 22. When a protein produced by this gene, tyrosine kinase, is continuously produced , leads to a continuous signal for the cell to grow and divide.
Transcription factors are proteins that regulate the entry and passage of cells through the cell cycle.
An example is the Myc gene, which is too active in cancers such as some leukemias and lymphomas.
Cell cycle control proteins
Cell cycle control proteins are products of oncogenes that can affect the cell cycle in a number of ways.
Some, like cyclin D1 and cyclin E1, work to go through certain stages of the cell cycle, such as the G1 / S checkpoint.
Regulators of apoptosis
Oncogenes can also produce oncoproteins that reduce apoptosis (programmed cell death) and lead to longer cell survival.
An example is Bcl-2, an oncogene that produces a cell membrane-associated protein that prevents cell death (apoptosis).
Oncogenes and Cancer Treatments
Research on oncogenes has played an important role in some of the new cancer treatment options, as well as in understanding why some specific treatments may not work as well for some people.
Cancer and oncogenic addiction
Cancer cells tend to have many mutations that can affect various cell growth processes, but some of these oncogenes (mutated or damaged proto-oncogenes) play a more important role in cancer cell growth and survival than others. For example, there are several oncogenes associated with breast cancer, but only some of them appear to be necessary for its progression. Cancer dependence on these specific oncogenes is called oncogen dependence.
Researchers have used this dependence on certain oncogenes, the notorious "Achilles heel" of cancer, to develop drugs that target the proteins produced by these genes. Examples include:
- Drug gleevec (imatinib) for chronic myeloid leukemia targeting the abl signal transducer
- HER2-targeted therapy targeting HER-2 / neu oncogene cells in breast cancer
- EGFR Targeted Therapy for EGFR Oncogene Dependent Cancer in Lung Cancer
- BRAF inhibitors in melanomas with oncogenic dependence on BRAF
- Drugs such as Vitrakvi (larotrectinib) , which inhibit the proteins produced by the NTRK fusion genes, can be effective in several different cancers that contain the oncogene.
- Other targeted therapies including drugs targeting Kras for pancreatic cancer, cyclin D1 for esophageal cancer, cyclin E for liver cancer, beta-catenin for colon cancer, and more.
Oncogenes and immunotherapy
Understanding the proteins produced by oncogenes also helped researchers begin to understand why some people with cancer may respond better to immunotherapy drugs than others, for example, why people with lung cancer that contain the EGFR mutation have less likely to respond to checkpoint inhibitors.
In 2004, a researcher discovered that cancer cells with RAS mutations also produce a cytokine (interleukin-8) that suppresses the immune response. A large percentage of pancreatic cancers have RAS mutations and it is believed that suppression of the immune response by an oncogene may help explain why immunotherapy drugs have been relatively ineffective in treating these cancers.
Other oncogenes that appear to negatively affect the immune system include EGFR, beta-catenin, MYC, PTEN, and BCR-ABL.
Get the word of drug information
Understanding proto-oncogenes, oncogenes, and tumor suppressor genes helps researchers understand both the processes that lead to cancer formation and progression and cancer treatments based on the specific effects of oncogenic products. As more information becomes available, these discoveries are likely not only to lead to more cancer therapies, but also to help uncover the processes by which cancer begins, so that preventive measures can also be taken.