Basics of Morphogenesis and Theories of Carcinogenesis
In studying morphogenesis, pathology addresses four key questions: the source of cells (whether the tumor arises de novo or in stages), the nature of the developmental stages, clonality (monoclonal or polyclonal origin), and how the neoplasm interacts with the host organism.
There are two main theories of cellular transformation:
- Saltatory transformation theory. Proposes tumor development without preceding tissue changes (a single-step model). This is supported by data from experimental viral carcinogenesis.
- Staged transformation theory. Developed by L.M. Shabad and supported by most experimental models. It is based on the accumulation of mutations in somatic cells.
Cancer stem (initiating) cells play a critical role in tumor origin by sustaining the growth of the tumor mass. Their proportion in the population is extremely small (e.g., 0.1–1.0% in acute myeloid leukemia); however, their survival after treatment leads to recurrence. Note: the existence of such cells has not been proven for all tumor types.
Stages of Tumor Development
Historically, L.M. Shabad distinguished four stages: focal hyperplasia, diffuse hyperplasia, benign tumor, and malignant tumor (the first three considered preneoplastic processes). Currently, the classification of morphogenetic stages has been refined:
- Preneoplastic stage. Includes hyperplasia and preneoplastic dysplasia. Pathological processes involve both the stroma and the parenchyma. The main morphological criterion is the appearance of signs of cellular atypia.
- Non-invasive tumor stage (carcinoma in situ).
- Invasive growth stage.
- Metastatic stage.
Features of Non-Invasive Cancer (Carcinoma in situ)
The progression of dysplasia under the influence of additional factors leads to genetic rearrangements and malignant transformation. A malignant cell arises, forming a clone.
At the carcinoma in situ stage (intraepithelial neoplasia), the tumor grows "within itself." The basement membrane is intact, and there are no native blood vessels or stroma. Nutrition is provided exclusively through the diffusion of substances from the tissue fluid of adjacent normal tissues.
Why is there no angiogenesis at this stage? There are two hypotheses. The first attributes this to the small tumor mass (lack of stimulating factors). The second, more probable hypothesis, explains this by the absence of specific genetic rearrangements required to trigger invasive growth.
Invasion and the Genetic Model of Progression
Upon transitioning to the invasive tumor stage, infiltrative growth begins. The neoplasm develops a vascular network, forms a stroma, and clear boundaries with healthy tissue disappear due to cellular infiltration. The pathogenesis of invasion proceeds in 3 phases and is tightly controlled by genetics.
Colorectal carcinogenesis serves as a classic model for the staged accumulation of mutations:
| Morphological Stage | Genetic Alterations | Localization |
|---|---|---|
| Hyperplastic epithelium | Mutations or loss of APC, MCC | Chromosome 5q |
| Early adenoma | Impaired DNA methylation | — |
| Late adenoma | K-ras mutation, loss of DCC | Chromosomes 12q, 18q |
| Carcinoma | p53 mutation and loss | Chromosome 17q |
| Metastatic carcinoma | Accumulation of mutations | Deletion of 17q |