Page 151 - Concise Pathology for Exam Preparation ( PDFDrive )

136 SECTION I General Pathology

(miRNAs)—small RNAs 21–25 nucleotides in length that control gene expression by
downregulating them. Mutations in such miRNAs (known as oncomirs) can lead to
the activation of oncogenes.
• Oncoproteins are products of oncogenes, which resemble products of proto-oncogenes,
but are devoid of important regulatory mechanisms. They include:
(a) Growth factors (GFs):
• These are polypeptides elaborated by many cells that normally act on another
cell to stimulate its proliferation (paracrine action), eg, PDGF in glioblastomas,
TGF-a in sarcomas and FGF in carcinoma of bowel and breast.
• Many cancer cells are capable of synthesizing the same growth factors that stimulate
their growth. An oncogene may cause a cell to secrete growth factors, even though
it does not normally do so, thus inducing its own uncontrolled proliferation
(autocrine loop) and proliferation of neighbouring cells, eg, osteosarcomas encode
b-chain of PDGF and the same tumours also express receptors for PDGF.
• A group of related oncogenes that encode homologues of fibroblast growth factors
(FGFs), eg, HSTF-1 (heparin-binding secretory transforming factor-1) and INT-2
(also known as fibroblast growth factor-3) are activated in several gastrointestinal
and breast tumours; b FGF, a member of the fibroblast growth factor family, is ex-
pressed in human melanomas but not in normal melanocytes. Hepatocyte growth
factor and its receptor c-MET are overexpressed in follicular carcinoma of thyroid.
(b) Growth factor receptors: Receptor kinases add phosphate groups to receptor
proteins at the surface of the cell (which receive protein signals from outside the cell
and transmit them to the inside of the cell). Tyrosine kinases add phosphate groups
to the amino acid tyrosine in the target protein. They can cause cancer by turning
the receptor on permanently (constitutively), even without signals from outside the
cell (Flowchart 6.4).

Receptors for growth factors undergo mutations or are overexpressed

Mutant receptor proteins deliver continuous signals

Continuous activation of signal-transducing proteins on the inner leaflet of plasma membrane

Signal transduced from cytosol to nucleus via second messengers

Activation of nuclear regulatory factors

DNA transcription
FLOWCHART 6.4. Role of growth factor receptors in evolution of carcinogenesis.

Examples
• Point mutations in ERB-B1 (EGF receptor) found in a subset of lung adenocarci-
nomas and squamous cell carcinoma result in constitutive activation of EGFR
tyrosine kinase.
• Amplification of ERB-B2 results in overexpression of HER2 receptor and its
constitutive tyrosine kinase activity leading to carcinomas of breast, lung, ovary
and stomach.
• Gene rearrangements may activate other receptor tyrosine kinases, eg, ALK.tyrosine
kinase.
(c) Signal transduction proteins
• Normal signal transduction proteins, which transduce signals from the growth
factor receptors on the cell surface to the nucleus, may get mutated, eg, mutated
RAS (rat sarcoma) gene.
• Point mutations involving RAS family genes (HRAS, KRAS and NRAS; HRAS and
KRAS were named after their discoverers, namely Jennifer Harvey and Werner

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