Page 228 - Textbook of Pathology, 6th Edition

212 ii) Receptors for GFs. Growth factors cannot penetrate the from its normal location on chromosome 9 is translocated to
cell directly and require to be transported intracellularly by chromosome 22 where it fuses with BCR (breakpoint cluster
GF-specific cell surface receptors. These receptors are region) gene and forms an ABL-BCR hybrid gene which is
transmembrane proteins and thus have two surfaces: the more potent in signal transduction pathway. ABL-BCR hybrid
outer surface of the membrane has an area for binding growth gene is seen in chronic myeloid leukaemia and some acute
factor, and the inner surface of the membrane has enzyme- leukaemias.
activating area which eventually activates cell proliferation iv) Nuclear transcription factors. The signal transduction
pathway. pathway that started with GFs ultimately reaches the nucleus
Most often, mutated form of growth factor receptors where it regulates DNA transcription and induces the cell to
SECTION I
stimulate cell proliferation even without binding to growth enter into S phase. Out of various nuclear regulatory trans-
factors i.e. with little or no growth factor bound to them. cription proteins described, the most important is MYC gene
Various forms of oncogenes encoding for GF receptors located on long arm of chromosome 8. Normally MYC protein
include other mechanisms: overexpression, mutation and binds to the DNA and regulates the cell cycle by
gene rearrangement. Examples of tumours by mutated transcriptional activation and its levels fall immediately after
receptors for growth factors are as under: cell enters the cell cycle.
a) EGF receptors: Normal EGF receptor gene is ERB B1, and MYC oncogene (originally isolated from myelocyto-
hence this receptor is termed as EGFR or HER1 (i.e. human matosis virus and accordingly abbreviated) is seen most
epidermal growth factor receptor type 1). EGFR (or HER1) commonly in human tumours. It is associated with
acts by overexpression of normal GF receptor e.g. in 80% of persistence of or overexpression of MYC oncoproteins which,
squamous cell carcinoma of lung and 50% cases of in turn, causes autonomous cell proliferation. The examples
glioblastomas. of tumours carrying MYC oncogene are as under:
Another EGF receptor gene called ERB B2 (or HER2/neu) a) C-MYC oncogene: Mutated MYC gene due to translocation
acts by gene amplification e.g. in breast cancer (25% cases), t(8;14) seen in Burkitt’s lymphoma.
carcinoma of lungs, ovary, stomach. b) N-MYC oncogene: Mutated MYC gene due to amplification
b) c-KIT receptor: The gene coding for receptor for stem cell seen in neuroblastoma, small cell carcinoma lung.
factor (or steel factor) is c-KIT, that activates tyrosine kinase c) L-MYC oncogene: Mutated MYC gene due to amplification
pathway in cell proliferation. Mutated form of c-KIT by point seen in small cell carcinoma lung.
mutation activates receptor for tyrosine kinase e.g. in v) Cell cycle regulatory proteins. As discussed in Chapter
gastrointestinal stromal tumours (GIST). 3, normally the cell cycle is under regulatory control of cyclins
c) RET receptor: RET (abbreviation of ‘rearranged during and cyclin-dependent kinases (CDKs) A, B, E and D. Cyclins
General Pathology and Basic Techniques
transfection’) protooncogene is a receptor for tyrosine kinase are so named since they are cyclically synthesised during
normally expressed in neuroendocrine cells of different different phases of the cell cycle and their degradation is also
tissues. Mutated form by point mutation is seen in MEN type cyclic. Cyclins activate as well as work together with CDKs,
2A and 2B and in medullary carcinoma thyroid.
while many inhibitors of CDKs (CDKIs) are also known.
iii) Cytoplasmic signal transduction proteins. The normal Although all steps in the cell cycle are under regulatory
signal transduction proteins in the cytoplasm transduce controls, G1 → S phase is the most important checkpoint for
signal from the GF receptors present on the cell surface, to regulation by oncogenes as well as anti-oncogenes (discussed
the nucleus of the cell, to activate intracellular growth below). Mutations in cyclins (in particular cyclin D) and
signaling pathways. CDKs (in particular CDK4) are most important growth
There are examples of oncogenes having mutated forms promoting signals in cancers. The examples of tumours
of cytoplasmic signaling pathways located in the inner having such oncogenes are as under:
surface of cell membrane in some cancers. These are as under: a) Mutated form of cyclin D protooncogene by translocation
a) Mutated RAS gene. This is the most common form of seen in mantle cell lymphoma.
oncogene in human tumours, the abnormality being induced b) Mutated form of cyclin E by overexpression seen in breast
by point mutation in RAS gene. About a third of all human cancer.
tumours carry mutated RAS gene (RAS for Rat Sarcoma gene b) Mutated from of CDK4 by gene amplification seen in
where it was first described), seen particularly in carcinoma malignant melanoma, glioblastoma and sarcomas.
colon, lung and pancreas. Normally, the inactive form of RAS
protein is GDP (guanosine diphosphate)-bound while the 2. REFRACTORINESS TO GROWTH INHIBITION:
activated form is bound to guanosine triphosphate (GTP). GROWTH SUPPRESSING ANTI-ONCOGENES
GDP/GTP are homologous to G proteins and take part in The mutation of normal growth suppressor anti-oncogenes
signal transduction in a similar way just as G proteins act as results in removal of the brakes for growth; thus the
‘on-off switch’ for signal transduction. Normally, active RAS inhibitory effect to cell growth is removed and the abnormal
protein is inactivated by GTPase activity, while mutated RAS growth continues unchecked. In other words, mutated anti-
gene remains unaffected by GTPase, and therefore, continues oncogenes behave like growth-promoting oncogenes.
to signal the cell proliferation. As compared to the signals and signal transduction
b) BCR-ABL hybrid gene. ABL gene is a non-GF receptor pathways for oncogenes described above, the steps in
protooncogene having tyrosine kinase activity. ABL gene mechanisms of action by growth suppressors are not so well