9th May 2007 Prof Pignatelli
Reasons for doing research for the trainee
Limited scope during clinical training and exams but can be done!
Clinical or lab-based
Tissue based and cell based (beta-catenin transgenic mouse, hairy with big feet!)
B-catenin cell cell adhesion molecule also proto-oncogene. Pilomatricoma has mutation in beta-catenin gene. Also intestinal dysplasia and adenomas. Liver hyperplasia and hepatomegaly. Polycystic kidneys.
Important for pathologist to correlate gene function with morphology.
Accumulation of genetic and epigenetic events (eg. adenoma to carcinoma progression in colorectum)
Catenins in cell adhesion, cytoplasmic protein associated with actin cytoskeleton of epithelial cells. Regulation of E-cadherin (transmembrane protein lost in lobular carcinoma breast probably responsible for change in morphology of cells, more rounded, less cohesive groups).
B-catenin expression in carcinoma cells (note change in morphology when B-catenin overexpressed in culture, cells less cohesive and more spindled).
B-catenin nuclear localisation in dysplasia (defect in degradation of the protein). Metaplastic polyps show membrane localisation. Some benign processes get nuclear localisation eg. prolif endometrium.
Widespread nuclear localisation and Dukes staging independent predictors of short survival after curative resection (>75% nuclear localisation <20% 5 year survival; 60% survival when <75% nuclear!! Multivariate analysis including staging as a confounding factor).
Gene transfection experiment with E-cadherin WT into mutant cells leads to increasingly cohesive groups.
Other cell adhesion molecules involved in cancer
Fascin - another protein involved in polymerisation of actin cytoskeleton. Can be used to identify RS cells.
Cell transfection experiment - fascin transfection and overexpression leads to increase in finger-like projections in intially smooth rounded cells; and altered cell motility (increased "invasion" into in vitro matrix).
Integrins - also important in cell adhesion, proliferation, differentiation, polarity, survival and migration.
Integrin expressed on cell surface and can be detected in benign and malignant cells. Integrin is downregulated when cells are induced to undergo apoptosis. Happens before the cells undergo apoptosis so probably an initiating factor rather than just consequence of cell destruction.