Page 226 - Textbook of Pathology, 6th Edition

210

SECTION I

Figure 8.19 Schematic representation of major properties of cancer in terms of molecular carcinogenesis.

By mutation in the protooncogene which alters its iii) Gene amplification i.e. increasing the number of copies of
structure and function. DNA sequence in protooncogene leading to increased
By retroviral insertion in the host cell. mDNA and thus increased or overexpressed gene product.
General Pathology and Basic Techniques
By damage to the DNA sequence that normally regulates Examples of gene amplification are found in some solid
growth-promoting signals of protooncogenes resulting in its human tumours e.g.
abnormal activation. Neuroblastoma having n-MYC HSR region.
By erroneous formation of extra copies of protooncogene ERB-B1 in breast and ovarian cancer.
causing gene amplification and hence its overexpression or Most of the oncogenes encode for components of cell
overproduction that promotes autonomous and excessive signaling system for promoting cell proliferation. Possible
cellular proliferation. effects of oncogenes in signal transduction for cell
In general, overactivity of oncogenes enhances cell proliferation in human tumours are discussed below in
proliferation and promotes development of human cancer. relation to the role of protooncogenes in mitosis in normal
About 100 different oncogenes have been described in cell cycle and are listed in Table 8.4 and schematically shown
various cancers. Transformation of proto-oncogene (i.e. in Fig. 8.20:
normal cell proliferation gene) to oncogenes (i.e. cancer cell
proliferation gene) may occur by three mechanisms: i) Growth factors (GFs). GFs were the first protoonocgenes
i) Point mutations i.e. an alteration of a single base in the to be discovered which encode for cell proliferation cascade.
DNA chain. The most important example is RAS oncogene They act by binding to cell surface receptors to activate cell
carried in many human tumours such as bladder cancer, proliferation cascade within the cell. GFs are small
pancreatic adenocarcinoma, cholangiocarcinoma. polypeptides elaborated by many cells and normally act on
ii) Chromosomal translocations i.e. transfer of a portion of one another cell than the one which synthesised it to stimulate
chromosome carrying protooncogene to another its proliferation i.e. paracrine action.
chromosome and making it independent of growth controls. However, a cancer cell may synthesise a GF and respond
This is implicated in the pathogenesis of leukaemias and to it as well; this way cancer cells acquire growth self-
lymphomas e.g. sufficiency. Most often, growth factor genes are not altered
Philadelphia chromosome seen in 95% cases of chronic or mutated but instead growth factor genes are overexpressed
myelogenous leukaemia in which c-ABL protooncogene on to stimulate large secretion of GFs which stimulate cell
chromosome 9 is translocated to chromosome 22. proliferation. The examples of such tumour secreted GFs are
In 75% cases of Burkitt’s lymphoma, translocation of c- as under:
MYC proto-oncogene from its site on chromosome 8 to a a) Platelet-derived growth factor- (PDGF-β): Overexpression of
portion on chromosome 14. SIS protooncogene that encodes for PDGF-β and thus there