Molecular basis of carcinogenesis

The article was written by Master, Doctor Bui Thi Hong Khang - Pathologist - Laboratory Department - Vinmec Central Park International General Hospital.

Oncogenesis, also known as carcinogenesis or tumorigenesis, is the formation of a cancer; whereby normal cells are transformed into cancerous cells. This process is characterized by changes at the cellular, genetic, epigenetic and abnormal cell division.
The key to carcinogenesis is that non-lethal gene mutations occur in the following four genes:
proto-oncogenes. Tumor suppressor genes. Genes regulate cell apoptosis (apoptosis). DNA repair genes. These non-lethal mutations occur as a result of environmental factors (viruses, chemicals, radiation), passed on from parents (eg, retinoblastoma genes) or have spontaneity.

Under normal physiological conditions, cell proliferation is very tightly controlled. For a cell to have proliferative activity, it must go through the following steps:
Having specific growth factors. Binds the growth factor to the corresponding receptor on the cell surface; This binding sends a proliferative signal to the cell. Signals are transferred from the cell membrane into the nucleus by the action of signal transduction proteins found on the cell membrane and in the cytoplasm. The gene coding for the transcriptional regulatory protein is activated, the transcriptional regulatory protein is synthesized, and enters the nucleus to stimulate the synthesis of DNA, causing the cell to divide.

Pre-oncogenes play an important role in cell proliferation. Because they encode proteins that are necessary for all of the above steps, such as growth factors, signaling proteins, and transcription-regulating proteins in the nucleus.
Therefore, when the structure of the pre-oncogene is altered due to mutations or when its expression is disturbed, the pre-oncogene is activated into the cellular oncogene (c-onc), potentially stimulates transformation cells to proliferate excessively and automatically, escaping from all normal control mechanisms in the body.
The following table presents some of the more than 100 known pre-oncogenes and the types of tumors that can arise when these pro-oncogenes are activated into cellular oncogenes:

Note: PDGF, platelet derived growth factor; FGF, fibroblast growth factor; EGF, epidermal growth factor; SCF, stem cell factor; GDNF, glial cell line derived neurotrophic factor.

Oncogenes are considered to be dominant cancer genes because only one of the two pre-oncogene alleles needs to be activated to become an oncogene to have an oncogenic effect.
When one of the two pro-oncogen sis (simian sarcoma) is activated to oncogen c-sis, its normal product, the growth factor PDGF, is overproduced, capable of stimulating cell proliferation. form a tumor; eg astrocytoma, osteosarcoma. The pro-oncogene erb B-1 (avian erythroblastosis) encodes for the receptor protein for epidermal growth factor (EGF). Activation to the oncogen c-erb-1 causes this receptor protein to be overproduced, resulting in cell proliferation with little effect on growth factors. The activity of this oncogene was noted in 50% of cases of adenocarcinoma of the lung. Likewise, approximately 30% of cases of metastatic breast carcinoma have activation of the erb B-2 preoncogene to the c-erb-2 oncogen (also known as the Her-2/neu oncogen).
The pro-oncogene ras (rat sarcoma) encodes a proliferative signaling protein located on the inner surface of the cell membrane. Point mutations occurring on the pro-oncogene ras will turn it into the oncogen c- ras, which is able to stimulate cells to proliferate to form tumors even without the effect of growth factors. The activity of this oncogene has been reported in approximately 30% of human cancers.
Pre-oncogene myc (myelocytomatosis), which encodes a protein that regulates replication in the nucleus. Chromosomal translocations and gene amplifications can turn pre-oncogene myc into oncogene c-myc. As a result, the above regulatory protein is overproduced, stimulating cells to proliferate to form cancers such as Burkitt lymphoma and small cell lung cancer.

Tumor suppressor genes play a role in inhibiting cell proliferation; They encode growth inhibitors, molecules that regulate cell adhesion, inhibitory signaling molecules, and transcriptional regulators in the nucleus. Mutations that cause deficiency or inactivation of these genes can lead to tumorigenesis because cell proliferation is no longer inhibited. Because both allele suppressor genes must be either deficient or inactivated to have an oncogenic effect, they are also called recessive cancer genes.
The following table introduces some of the more than 30 known tumor suppressor genes:

2.1. Rb gene The first tumor suppressor gene discovered, located on chromosome 13. When both Rb genes are inactivated, it leads to the formation of retinoblastoma, a rare childhood cancer. In many adult cancers such as lung cancer, breast cancer and colon cancer, etc., there is also an inactivation of both Rb genes.
The Rb gene expressed throughout the cell cycle encodes for the protein Rb (pRb). Normally, when cells are at rest in the G0 or G1 stage, pRb in its unphosphorylated form inhibits transcription-regulating proteins, causing cell proliferation to be inhibited. Conversely, when the cell receives a proliferative signal, pRb becomes phosphorylated and is no longer able to inhibit transcription-regulatory proteins, resulting in cell division. Thus, when both Rb genes are mutated and inactivated, the transcription-regulatory protein is not inhibited, causing cells to proliferate freely, leading to tumor formation.
Here it is necessary to explain why retinoblastoma - hereditary is considered an autosomal dominant cancer, while the Rb gene is a recessive cancer gene. In this genetic disease, the child is born with 1 inactivated Rb gene from either parent, the remaining Rb allele is normal, so all somatic cells in the child's body are heterozygous. on the healthy Rb gene.
The children's retinal cells are initially normal because only 1 healthy Rb gene is enough to ensure the function of inhibiting cell proliferation. However, the heterozygosity for the healthy Rb gene of retinal cells is easily lost because a new mutation inactivates the remaining healthy Rb gene (loss of heterozygosity), causing the cell proliferation to cease. controllable, leading to retinoblastoma.
In contrast, in retinoblastoma - sporadic, the child is born with 2 healthy Rb genes from his parents. Therefore, in order to create a tumor, one retinal cell must undergo two consecutive mutations to inactivate both Rb allele genes (Knudson's two-stroke model); this is less likely to happen than a single mutation in the heredity. Thus, the Rb gene is a recessive cancer gene, but in hereditary retinoblastoma, "heterozygous predisposition to retinoblastoma" has been transmitted in an autosomal dominant fashion.
2.2. The p53 gene is another tumor suppressor gene located on chromosome 17. Inactivation of both p53 alleles has been reported in most human cancers.
Unlike the Rb gene, the p53 gene is expressed only when the cell's DNA is damaged; The p53 protein content in the nucleus increases rapidly, helping the cell stop at the G1 stage to have time to repair damage on DNA. After successful repair, the cell resumes normal proliferative activity and the p53 protein rapidly disappears from the nucleus due to degradation. In the event of failure of repair, the p53 protein stimulates the production of Bax and Bak proteins and, at the same time, inhibits bcl-2. As a result, the cell is driven into self-destruction. Thus, when both p53 genes are mutated and inactivated, the p53 protein no longer retains its normal function, even though the cell is damaged, the DNA continues to proliferate and can lead to cancer.

DNA damage still frequently occurs during cell activity, spontaneously or due to environmental factors. However, most of these injuries are repaired in time thanks to the action of available DNA repair genes such as MSH2, MLH1, PMS1, PMS2, XP, etc. Therefore, when these genes are damaged, Deficiency or inactivation increases the risk of developing cancer.
Example: In dermatomyositis, there is a defect in the XP gene. Therefore, the DNA damage caused by ultraviolet radiation is not repaired in time, and patients are more susceptible to skin cancer than the general population.

Consists of two groups of genes with opposite effects:
Genes that promote cell suicide, such as genes bad, bax, bak, bim, bid, bik, bok,... Genes that inhibit apoptosis , eg genes Bcl-2, Bcl-XL, Bcl-X,... Mutations that cause deficiency of the first group of genes or increase the expression of the second group of genes will cause the cells to be damaged despite damage. DNA still cannot destroy itself, continues to survive and proliferate, leading to the formation of cancer.
In summary, the natural process of cancer development consists of 4 successive steps: malignant transformation, tumor growth, invasion and metastasis. Molecularly, this step-by-step progression corresponds to the accumulation of mutations (spontaneously occurring or environmental influences) that activate pro-oncogenes, inactivate tumor suppressor genes. , genes that regulate cell apoptosis and DNA repair genes. In the formation of each type of human cancer, it is estimated that there must be 3 to 7 such mutations.
For example, in adenocarcinoma of the colon; It is assumed that the lesion begins with the transformation and proliferation of epithelial cells forming a benign adenoma; This adenoma grows and eventually becomes malignant, infiltrates locally through the intestinal wall layers and metastasizes. This evolution corresponds to the first inactivation of the APC tumor suppressor genes and the MSH2 DNA repair gene, followed by the activation of the ras pre-oncogene, and then the deficiency mutations of other tumor suppressor genes such as DCC, p53 and many more genes.
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