Page 152 - Concise Pathology for Exam Preparation ( PDFDrive )

6 Neoplasia 137

Kirsten and NRAS was named so as it was initially identified in neuroblastoma
cells) are the most common form of abnormality affecting a proto-oncogene in
human tumours. As a member of the family of small G proteins, it is mainly im-
plicated in the pathogenesis of carcinoma of colon, lungs and pancreas.
• In the inactive state, RAS proteins bind guanosine diphosphate (GDP); when
cells are stimulated by growth factors or other receptor–ligand interactions, RAS
becomes activated by exchanging GDP for GTP (guanosine triphosphate;
see Flowchart 6.5).
• Activated RAS, in turn, acts on MAP (mitogen-activated protein) kinase pathway by
recruiting cytosolic protein RAF-1 (RAF proto-oncogene serine/threonine-protein
kinase also known as proto-oncogene c-RAF or simply c-Raf). In addition to MAP
pathway, there is activation of the P13K/AKT pathway as well.
• The MAP kinases so activated target nuclear transcription factors, and thus
promote mitogenesis.
• In normal cells, the activated signal-transmitting stage of the RAS protein is
transient because its intrinsic GTPase activity hydrolyses GTP to GDP, thereby
returning RAS to its quiescent ground state.
• Mutations that reduce the GTPase activity of the RAS protein result in an
activated GTP-bound form that receives continuous signals.

Mutated RAS (rat sarcoma) gene
Growth factors bind to extracellular receptor domain and activate the intracellular
domain of the same

Conformational changes and activation of RAS
GDP Intrinsic GTPase activity of RAS may reconvert
GTP into GDP; GAPs (GTPase-activating
GTP proteins) also prevent uncontrolled RAS activation
Stimulation of RAF mitogen-activated protein
(MAP) kinase mitogenic cascade

Cell proliferation
FLOWCHART 6.5. Role of RAS-signalling pathway in cancer.

(d) Nuclear regulatory molecules: Overexpression of MYC gene occurs with t(8;14)
in Burkitt lymphoma or may be a result of amplification of the gene as seen in
carcinoma of lung, breast and colon (dysregulation due to amplification). Normal
MYC protein binds to DNA and regulates the cell cycle by transcriptional activa-
tion, and its levels fall immediately after the cell enters the cell cycle. Persistent
overexpression of MYC oncogene leads to autonomous cell proliferation.
(e) Cell-cycle regulatory proteins: Normal cell cycle is under control of cyclins and
CDK A, B, E and D. Checkpoint is G 1 → S phase. Mutations in cyclins (particularly
cyclin D) and CDKs (in particular CDK4) may aid in induction of cancer, eg, ‘over-
expression of cyclin D’ is implicated in carcinoma of breast, liver and mantle cell
lymphoma, and ‘amplification of CDK4’ in multiple myeloma, glioblastomas and
sarcomas.

Refractoriness to Growth Inhibition
(Loss of Growth-Suppressing Anti-Oncogenes)

Anti-oncogenes or tumour suppressor genes prevent entry of cells in mitotic pool and push
cells into the G 0 phase. Mutated anti-oncogenes behave like growth-promoting genes. The
following are the important tumour suppressor genes involved in growth inhibition:
1. Retinoblastoma (RB) gene:
• Approximately 60% of retinoblastomas are sporadic, and the remaining 40% are
inherited. To explain the inherited and sporadic occurrence of this seemingly
identical tumour, Knudson proposed his now famous ‘two-hit’ hypothesis of
oncogenesis.

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