Page 155 - Concise Pathology for Exam Preparation ( PDFDrive )

140 SECTION I General Pathology

• Different members of the cadherin family are found in different locations.
E-Cadherins are found in epithelial tissue, N-Cadherins are found in neurons and
P-Cadherins are found in the placenta.
• Reduced cell-surface expression of E-Cadherins is noted in many cancers, eg, oe-
sophagus, colon, breast and ovary. Germline mutations of E-cadherin gene predis-
poses to familial gastric carcinomas.
11. Kruppel-like factor 6 (KLF6): This encodes a transcription factor that has many target genes,
including TGF-a and TGF-b receptors, and is found to be mutated in more than 70% of
primary prostate cancers. It has been proposed that KLF6 inhibits cell proliferation by
increasing the transcription of the Cip/Kip cell-cycle inhibitor p21, independent of p53.
12. Patched (PTCH): It encodes a cell membrane protein (PATCHED1), which functions as
a receptor for a family of proteins called Hedgehog. The Hedgehog–PATCHED pathway
regulates several genes, including TGF-b and PDGF. Mutations in PTCH are respon-
sible for Gorlin syndrome, an inherited condition also known as nevoid basal cell
carcinoma syndrome.
13. Serine/threonine kinase 11 (STK11): Also known as LKB1, this encodes a serine/threo-
nine kinase that is a regulator of cellular metabolism. Mutations in STK11 result in
Peutz–Jeghers syndrome (benign polyps of GIT and GI and pancreatic carcinomas).

Growth-Promoting Metabolic Alterations
• Cancer cells demonstrate high levels of glucose uptake and increased fermentation of
glucose to lactose via the glycolytic pathway even in the presence of adequate oxygen
(Warburg effect).
• Positron emission tomography (PET scan) uses this glucose hunger of cancer cells to
visualize tumour cells. This procedure involves injecting patients with F-fluorodeoxy-
glucose, which is a nonmetabolizable derivative of glucose and is preferentially taken up
by rapidly proliferating tumour cells.
• This preference exhibited for aerobic glycolysis by rapidly proliferating tumour cells
over mitochondrial oxidative phosphorylation is because the former provides the tu-
mour cells with metabolic intermediates necessary for synthesis of cellular components
not provided by the latter.
• Also, while in the rapidly growing normal cells, aerobic glycolysis stops when the cells
are no more proliferating, in cancer cells aerobic glycolysis continues due to enhanced
action of oncogenes and decreased action of tumour suppressor genes (owing to pro-
growth signalling factors like P13K/AKT signalling, upregulated transcription factor
MYC and receptor tyrosine kinase activity).
Evasion of Apoptosis

Cancer cells demonstrate abnormalities of both the intrinsic and extrinsic pathways but
the former are more commonly encountered, eg, overexpression of anti-apoptotic gene
BCL2 in follicular lymphomas.

Stem Cell-Like Replicative Potential
• It has been found that some of the cancer cells behave like stem cells. ‘Cancer stem cells’
can arise either through transformation of normal stem cells or through genetic aberra-
tions in mature cells which make de-differentiate to push them into a stem cell-like state.
• The ability of ‘cancer stem cells’ to continuously replicate is attributed to inactivation of
senescence signals and reactivation of telomerase.
Q. Write briefly on angiogenesis.

Ans. Neoplasms cannot enlarge beyond 2 mm in diameter unless they undergo neovascu-
larization as the maximal distance across which oxygen and nutrients can diffuse from
surrounding blood vessels is 1–2 mm.
• Neovascularization perfuses the tumour and newly formed endothelial cells stimulate
the growth of adjacent tumour cells by secreting polypeptide growth factors such as
insulin-like growth factors (IGFs) and PDGF.

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