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Oncogene: The Birth of Malignant Disease

Biotechnology student, Interested in Oncology and Molecular biology.

Abstract

Cancer is an inherited disease that can be attributed to mutations in normal cells. Gene mutations are mainly caused by environmental damage to DNA or by spontaneous errors in cellular processes such as DNA replication and chromosome segregation. Carcinogenesis is not based on the mutation of a single gene, but involves multiple key gene mutations, which synergistically promote the occurrence and development of tumors.

These key genes are divided into two categories: proto-oncogenes and tumor suppressor genes. The former is similar to the accelerator pedal of a car, and the latter can be compared to the braking system of a car. Activation of proto-oncogenes is analogous to an accelerator pedal being pressed all the time. In contrast, inactivation of tumor suppressor genes means that the brake system is not working. In both cases, cancer cells begin to grow uncontrollably.

Defective oncogenes are like the gas pedal is always "on", at this point some kind of signal is no longer needed to activate these genes, the car will move forward with or without the gas pedal.

Use this analogy for cells: cells continue to divide even when there is no signal to divide. We have two sets of each of our genes, and in the case of oncogenes, defects in just one set of genes can lead to constant cell division.

A large number of genes have been identified as proto-oncogenes, many of which are responsible for providing positive signals that lead to cell division. Some proto-oncogenes act to regulate cell death. oncogenes (that is, defective versions of these genes) can cause cells to divide unregulated. This growth can occur even in the absence of normal growth-promoting signals, such as growth factors. A key feature of oncogene activity is that a defective set of versions can cause cells to grow out of control. This is quite different from tumor suppressor genes, which must require defects in both sets of genes to cause cells to divide abnormally.

To date, those proto-oncogenes that have been identified have many different functions in cells. Despite differences in their normal functions, mutant forms (oncogenic versions) of these genes all lead to unregulated cell division. Mutant proteins typically retain some of their original functions, but are less sensitive to regulatory signals that they should respond to in their normal form.

Differences between cancer cells and normal cells

The human body is made up of cells, Cancer is an abnormal mass of cells that originates from normal cells.

Normal cells may or may not grow, depending on the condition of the body and surroundings. For example, skin cells proliferate and close the wound when injured, but stop growing when the wound heals. Cancer cells, on the other hand, continue to grow, ignoring commands from the body. Because it grows on its own, important surrounding tissue

Multistage carcinogenesis

Cancer cells develop when the genes of normal cells are damaged by about 2 to 10 wounds. It has also been found that damage to these genes is not triggered all at once, but gradually over time. It is called "multi-stage carcinogenesis" because it gradually progresses from normal to cancer.

As a type of gene that damages cells, if a gene that acts as an accelerator for cell proliferation remains trampled even when it is not needed (oncogene activation), cell proliferation is stopped. It is also known that there are cases where the gene that acts as a brake is not applied (inactivation of the tumor suppressor gene).

It is becoming known that there are two types of wounds: mutations that cause abnormalities in the DNA code, and epigenetic mutations that change the way they are used even if the code itself does not change.

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When a normal cell undergoes certain abnormalities, it proliferates. If a second abnormality occurs there, it will grow even faster. It is thought that cancer cells are completed by the accumulation of these abnormalities.

Multistage carcinogenesis

Multistage carcinogenesis

Oncogenes

Oncogenes are a class of genes, referring to genes inherent in human or other animal cells (and cancer-causing viruses), also known as transforming genes, which can promote normal cells to become cancerous, invade and metastasize when activated. The ways of oncogene activation include point mutation, gene amplification, chromosomal rearrangement, virus infection and so on. The result of oncogene activation is that its number or function is enhanced, causing cells to proliferate excessively and acquire other malignant characteristics, thereby forming malignant tumors.

A lung tumor cell seen under a scanning electrone microscope , Anne Weston / LRI /CRUK/Welcome image/Flickr CC by nc nd 2.0

A lung tumor cell seen under a scanning electrone microscope , Anne Weston / LRI /CRUK/Welcome image/Flickr CC by nc nd 2.0

How Proto-Oncogenes Become Oncogenes?

Today, more than 40 different human proto-oncogenes are known. But what types of mutations convert these proto-oncogenes into oncogenes? The answer is simple: Oncogenes arise as a result of mutations that increase the expression level or activity of a proto-oncogene. Underlying genetic mechanisms associated with oncogene activation include the following:

  • Point mutations, deletions, or insertions that lead to a hyperactive gene product
  • Point mutations, deletions, or insertions in the promoter region of a proto-oncogene that lead to increased transcription
  • Gene amplification events leading to extra chromosomal copies of a proto-oncogene
  • Chromosomal translocation events that relocate a proto-oncogene to a new chromosomal site that leads to higher expression
  • Chromosomal translocations that lead to a fusion between a proto-oncogene and a second gene, which produces a fusion protein with oncogenic activity
Point mutation

Point mutation

RAS: an example of oncogene

The product of the RAS gene is involved in signaling pathways that control kinases and can control gene transcription, thereby regulating cell growth and differentiation. To "turn on" this pathway, the ras protein must bind to the guanosine triphosphate (GTP) molecule inside the cell. To "turn off" this pathway, the RAS protein must cleave the GTP molecule. Changes in the RAS gene can change the RAS protein so that the RAS protein no longer has the ability to cleave GTP molecules and release GTP molecules. Such changes cause this signaling pathway to remain "on" all the time. 6 This "on" signal causes cells to grow and proliferate. Thus overexpression and expansion of ras leads to sustained cell proliferation, a critical step in tumorigenesis. Cell division is regulated by a balance of "positive" and "negative" signals. When ras transcription increases, excess gene protein accumulates in the cell; at this time, the "positive" signal of cell division is stronger than the "negative" signal.

Point mutations in the RAS gene usually result in the transformation of RAS from a proto-oncogene to an oncogene. The effects of such functional changes on cells are multifaceted because RAS is involved in many signaling pathways that control cell division and death. The antitumor drugs currently developed are aimed at such a RAS-dependent pathway. However, many studies are required before such drugs can be used in the clinic.

Mutated RAS genes have been identified in malignancies of the following organs: pancreas (90%), colon (50%), lung (30%), thyroid (50%), bladder (6%), ovary (15%) , breast, skin, liver, kidney, some types of leukemia. 6 In the future, it may be possible to use ras to identify certain malignancies. Pancreatic tumors have always been difficult to diagnose, but identifying mutations in the RAS gene in the DNA of pancreatic cells excreted in feces could help clinicians distinguish pancreatitis from pancreatic cancer.

© 2006 Nature Publishing Group Weinstein, I. B. et al. Mechanisms of Disease: oncogene addiction - a rationale for molecular targeting in cancer therapy. Nature Clinical Practice Oncology 3, 449 (2006)

Targeted oncogeneCancer cell line

K-ras

Pancreas

beta-Catenin

Colon

Cyclin E

Liver

MITF

Melanoma

Her-2/neu

Breast

Cyclin D1

Esophagus, Squamous, nasopharynx

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