Colorectal Carcinogenesis
The process of malignant transformation from normal tissue to invasive carcinoma comprises several stages:
- Genetic alterations: It is generally believed that the first step towards malignant transformation is the accumulation of genetic alterations in proliferative cells (stem or transit cells).
- Abnormal crypt dynamics: Loss of coordination between the processes of cell proliferation at the bottom of the crypt and differentiation and death at the top of the crypt leads to a net increase in the number of cells in the crypt.
- Crypt deformation and fission (Figures 3B and 3C): The excesive cell number inflicts biomechanical stress on the wall of the crypt, which might cause it to fold and and eventually induce crypt fission.
- Polyp formation (Figure 3D): Successive series of crypt fission usually lead to the formation of a benign polyp.
- Tumour progression: Further genetic alterations are required for progression to malignancy and invasiveness.
- Metastasis: Some colorectal cancers acquire the ability to spread
to other parts of the body, often the liver.
A = normal mucosa
B = deformation
C = crypt fission
D = polyp
Figure 3: Progression towards malignancy.
- In the normal mucosa, a tight coordination of the processes of proliferation, migration, differentiation and cell removal ensures the maintainance of the integrity of the crypt structure.
- Disregulation of the processes involved in crypt dynamics and the consequent increase in cell numbers can cause the surface epithelium to deform and fold.
- Further increase in the cell numbers leads to crypt budding and fission.
- Subsequent series of cell proliferation and crypt fission cause the mass of aberrant tissue to protude from the mucosa, giving rise to a polyp. Image taken from the Department of Pathology (University of Cambridge).