From Normal to Pathology
Proto-oncogenes are natural structural elements of the genome. In a healthy organism, they strictly control the cell cycle, being responsible for proliferation and differentiation. In mature tissues, these genes are predominantly in an inactive state. Their physiological activation occurs only under specific conditions: during embryogenesis or in foci of reparative regeneration when tissues need to recover.
However, under the influence of exogenous (chemical, physical, biological) or endogenous carcinogens, primary damage to the DNA of a somatic cell occurs. If this process is accompanied by a failure in repair systems, mutations become fixed in the genome. As a result, the normal proto-oncogene transforms into a cellular oncogene—the main promoter of tumor growth.
Mechanisms of Proto-Oncogene Activation
For a cell to begin dividing uncontrollably, a proto-oncogene must be activated. This process is implemented through several pathways:
- Point mutations: local structural alterations in the DNA sequence.
- Amplification: a multiple-fold increase in the copy number of a specific gene. Additional small chromosomes may even appear in cells. A prime example is c-neu amplification in breast cancer or N-myc in neuroblastoma.
- Translocation: the transfer of a chromosome segment containing a proto-oncogene to an active zone, closer to strong enhancers (transcription amplifiers).
- Insertional activation: a viral mechanism. Retroviruses (RNA viruses) integrate into the host cell genome and modulate the activity of neighboring cellular proto-oncogenes with their own genes.
- Epigenetic alterations: changes in gene expression without breaking the DNA itself (e.g., gene demethylation or histone acetylation).
Classification and Functions of Oncoproteins
Activated cellular oncogenes encode the synthesis of specific molecules—oncoproteins (oncoproteins). Their main task in a tumor cell is the continuous transmission of mitogenic signals from the cell membrane to the nucleus. In structure and function, they are homologous to normal elements of signaling pathways:
- Growth factor analogs: e.g., c-sis.
- Growth factor receptor analogs: c-erb-B, c-fms.
- Proteins with tyrosine kinase activity: c-abl, c-src.
- Low-molecular-weight G-protein analogs: c-ras. They interact with GTP and affect the adenylate cyclase system.
- Proteins with serine-threonine kinase activity: c-raf, associated with protein kinase C.
- Nuclear transcription factors: c-myc, c-fos, c-jun. They localize directly in the nucleus and act directly on DNA.
- Mitochondrial proteins: the c-bcl-2 family, which regulate (block) cellular apoptosis.
Role of Chromosomal Translocations
Translocations play a key role in the development of certain hemoblastoses, as they place a proto-oncogene under the control of powerful cellular stimulators.
- Burkitt lymphoma: a reciprocal translocation occurs between chromosomes 8 and 14. The c-myc proto-oncogene is transferred to the immunoglobulin heavy chain gene locus. Active immunoglobulin genes begin to act as enhancers, causing c-myc overexpression.
- Chronic myeloid leukemia (CML): the so-called Philadelphia chromosome is formed. A segment of chromosome 9 with the c-abl gene is transferred to chromosome 22. A chimeric c-abl-bcr gene is formed, whose protein product possesses pathological tyrosine kinase activity.
Tumor Morphogenesis
The accumulation of genetic errors leads to fundamental disorders: proliferation suffers, apoptosis is blocked, and cell differentiation is disrupted. Morphologically, this manifests in stages:
- Pre-tumor dysplasia: atypical cells appear, tissue structure is disrupted, but there is no invasion yet.
- Non-invasive tumor (Carcinoma in situ): the tumor grows but does not breach the basement membrane.
- Invasive tumor: cells acquire immortality (immortalization) and invade surrounding tissues.
- Metastatic tumor: tumor cells spread to distant organs.
Briefly: answers to topical questions
Which gene groups are targets for mutations in carcinogenesis?
The targets for mutations in carcinogenesis are genes regulating the cell cycle and homeostasis. The following main groups are distinguished:
- Proto-oncogenes — regulators of cell proliferation and differentiation (their activation turns them into oncogenes).
- Tumor suppressor genes (anti-oncogenes) — inhibit cell proliferation (lost or mutated during carcinogenesis).
- Apoptosis-regulating genes — control cell death.
- DNA repair genes — responsible for repairing damaged DNA.
Mutator genes and the enzyme telomerase also play an additional role in carcinogenesis.
Which oncogenes are activated by amplification?
The following cellular oncogenes are activated by amplification—an increase in the number of gene copies:
- c-myc and c-ras — in lung, bladder, colon, and pancreatic cancer.
- N-myc and N-ras — in neuroblastoma; N-myc amplification is associated with a poor prognosis.
- c-neu — in breast cancer; its oncoprotein is homologous to epidermal growth factor receptors and is a criterion for a poor prognosis.
What types of exogenous carcinogens exist?
Exogenous carcinogens are carcinogenic factors entering the external environment from outside. There are three main groups:
- Chemical carcinogens.
- Physical (radiation) carcinogens, including solar and ultraviolet radiation.
- Viral (biological) carcinogens, including oncogenic DNA-containing and RNA-containing viruses: Epstein-Barr virus, human papillomavirus, and HTLV-I.
How does a cellular oncogen differ from a viral oncogenic?
Cellular oncogene is formed from the cell's own normal gene—a proto-oncogene—upon its activation, for example, as a result of a point mutation, amplification, or translocation.
Viral oncogene is a gene introduced into the cell by an oncogenic virus; retroviruses can be carriers of it. Transfer of viral oncogenes into normal cells leads to their malignant transformation.
To memorize translocations: Burkitt's is 8 and 14 (c-myc gene), while CML (Philadelphia chromosome) is 9 and 22 (c-abl gene).
Class and exam questions
What is the difference between a proto-oncogene and an oncogene?
A proto-oncogene is a normal gene that controls cell division and maturation. An oncogene is its mutated form, which synthesizes oncoproteins and triggers uncontrolled tumor growth.
What role do retroviruses play in carcinogenesis?
RNA viruses can integrate into the cell genome. They either bring viral oncogenes themselves or act as enhancers, activating the host cell's own proto-oncogenes.
What is cell immortalization?
This is the process by which tumor cells acquire "immortalization". It occurs at the stage of cellular changes following hyperplasia and dysplasia, preceding invasive growth.
How does the autocrine mechanism work in breast cancer?
During amplification of the c-neu gene, receptor oncoproteins accumulate. They bind growth factors secreted by the tumor itself, thereby continuously stimulating its own growth.
What else to study on this topic
- The role of tumor suppressor genes (anti-oncogenes) in cell cycle regulation.
- Mechanisms of DNA repair impairment upon exposure to carcinogens.
- Epigenetic alterations: methylation and acetylation in oncogenesis.
- Morphological criteria for pre-tumor dysplasia and carcinoma in situ.
- The Bcl-2 gene family and their effect on cellular apoptosis.
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