Etiology and pathogenesis of lung cancer

Etiology and background processes

The overwhelming majority of cases are associated with exogenous carcinogens. Genetic factors as an independent cause play a role only in isolated instances. Geographic factors exert a tremendous influence on incidence.

A special role in the morphogenesis of peripheral cancer is played by pneumosclerosis of any etiology. The association between the tumor and a scar was first described by C. Friedrich (1939) using tuberculous pneumosclerosis as an example. Scar tissue acts as a problastomatous (background) process.

Mechanisms of carcinogenesis in the scar:

• Deposition: accumulation of exogenous and endogenous carcinogens.
• Genetic shifts: activation of proto-oncogenes (ras, fos, bcl-2) and loss of anti-oncogenes (p53).
• Microenvironment alteration: development of local hypoxia, immunosuppression, and uncoupling of intercellular contacts.
• Matrix remodeling: type III collagen (characteristic of embryonic tissue and the regeneration phase) accumulates in the scar area, while the amount of mature type I collagen decreases. This disrupts the balance between epithelial proliferation and differentiation.

General pathogenesis and morphogenesis

Carcinogenesis in the lungs is the result of impaired cell division, maturation, and programmed cell death (apoptosis). The key event is always damage to the epithelial cell DNA (chromosomal aberrations and mutations).

Sequence of tissue changes: Hyperplasia foci $\rightarrow$ Metaplasia $\rightarrow$ Dysplasia (intraepithelial neoplasia) $\rightarrow$ Cancer.

Pathogenesis has specific features depending on localization:

1. Central cancer (large bronchi): Carcinogens enter with inhaled air. They destroy the mucociliary barrier and damage basal layer cells. This leads to squamous cell metaplasia, dysplasia, and subsequent malignant transformation.
2. Peripheral cancer (small bronchi, alveoli): Toxins enter not only via the aerogenic route but also via the bloodstream or lymphatics. However, the concentration of substances delivered solely by hematogenous or lymphogenous routes is usually insufficient to induce a tumor—a combination of factors is required.

Role of cellular oncogenes

Four families of oncogenes (myc, ras, bcl, erb-B) are critical for the development of lung cancer. They determine the tumor profile, which is essential for diagnosis and targeted therapy selection.

• myc family (c-myc, L-myc, N-myc): These are immediate-early response genes. They encode proteins that induce proliferation and suppress differentiation. c-myc amplification occurs in various forms of cancer (10–25%), whereas L-myc and N-myc expression is characteristic only of neuroendocrine tumors. In small cell lung cancer, the activity of these genes significantly correlates with tumor size and the presence of metastases.
• ras family: Responsible for growth signal transduction (p21 protein synthesis). K-ras mutations are specific to non-small cell lung cancer (up to 30% in adenocarcinoma). They are detected as early as the precancerous stage (atypical hyperplasia) and in surrounding tissue, forming a "field of carcinogenesis".
• bcl-2 family: Apoptosis regulators. Cell fate depends on balance. Pro-proliferative factors (bcl-2, bclXL) block apoptosis, while pro-apoptotic factors (bax, bclXS) trigger it. A shift in this balance determines the direction of tumor growth.

Tumor Suppressor Genes

Normally, suppressor genes (such as p53 and Rb) block the proliferation of cells with a damaged genome and trigger apoptosis. A mutated suppressor gene is recessive, so development of cancer requires damage to both alleles (e.g., mutation of one allele and deletion of the other). These changes occur at the very earliest stages.

The p53 gene is the most frequently altered gene in tumor growth:

• Wild-type (normal): Functions as a transcription factor. Regulates the transition of the cell from the G1 to the S phase, handles DNA repair, and triggers apoptosis. Interacts with p21, Mdm2, and bax proteins.
• Mutant type: Undergoes a conformational change, accumulates in nuclei (detected by IHC methods), and begins to act as an oncogene, stimulating division. Causes the production of specific antibodies in the blood.

Accumulation of mutant p53 in precancerous conditions reliably predicts tumor development. However, about 50% of lung cancer cases develop without a p53 mutation, indicating the existence of alternative molecular pathways of carcinogenesis.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Morphological differences between squamous cell metaplasia and dysplasia of the bronchial epithelium
• Mechanisms of p53 protein interaction with cell cycle regulators (p21, Mdm2, bax)
• Basics of targeted therapy upon detection of K-ras mutations
• Features of erb-B family oncogene expression in lung tumors
• Adenomatous atypical hyperplasia as a precancerous condition

Other topics in the "Lung Diseases" section

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.