Winter Meeting 2011 - The Pathological Society of Great Britain ...

Foyer
08.00 Registration and Coffee
Detailed Programme – Friday 7 January 2011
Presenter = P · Abstract numbers are shown in bold and square brackets eg [S123]
Rosalind Franklin Pavilion
09.00–17.00 Slide seminar Case viewing: The Partnership between Molecular and Conventional
Histopathology
Francis Crick Auditorium
09.00–12.15 Symposum: The Involution of Normal and Cancer Tissue
Chair: Dr MJ Arends, University of Cambridge
Dr A Ibrahim, Addenbrooke’s Hospital, Cambridge (to be confirmed)
09.00–09.30 [S4] How do Tissues React to Injury?
P Prof AH Wyllie
University of Cambridge, Cambridge, United Kingdom
This symposium draws together several speakers who, collectvely, are unfolding the still poorly-understood story
of tissue involution. The now familiar intracellular events of apoptosis account for some, but not all of this process,
and even this part of the story continues to recruit new molecular players. Just as significant as death through
apoptosis and other routes is the process of autophagy, an adaptive response to restriction in energy and nutrient
supply that frequently occurs in injured tissues but, unlike apoptosis, is reversible. How these processes interlock
in whole tissues, where stromal and parenchymal cells constantly signal to each other, presents a further level of
complexity. This relatively new field is of great importance to pathologists and oncologists today, as it encompasses
the increasingly accessible goal of therapy-induced tumour regression.
09.30–10.00 [S5] Many Roads to Apoptosis
P Prof S Grimm
Imperial College London, London, United Kingdom
As apoptosis is genetically regulated, many efforts have been made to isolate the components of apoptosis
signalling pathways. Our own approach was motivated by a conspicuous correlation: most of the genes involved
in apoptosis exert their activity also upon over-expression. At first, it seemed impractical to use this dominant
effect for isolating such genes because their activity leads to cell death instead of cell proliferation as in the case of
oncogenes. However, using a genetic screen we have been able to discover dominant, apoptosis-inducing genes.
This assay, which we named RISCI (robotic single cDNA investigation), is now executed in a high-throughput
format by custom-made transfection- and DNA isolation-robots. Using additional information from extensive
literature studies and careful sequence analysis we have chosen several genes from the screen for further studies.
The components of the mitochondrial “permeability transition pore”, which is important for cell death by anticancer
drugs, is a focus of the laboratory as is the respiratory chain complex II, which contains tumour suppressor
proteins such as cybL, whose gene was isolated in the screen. With one of the mitochondrial fission genes we
have detected a novel caspase-activating complex at the interface between mitochondria and the ER. Moreover,
the metastasis suppressor KAI1 at the plasma membrane is studied in our group. How the ubiquitin/proteasome
system regulates cell death is explored with a gene that functions as a ubiquitin-specific protease for apoptosis
induction. Besides this, an interesting aspect of the screen is presently another focus of our work: we have found a
tumour-specific gene, i.e. a gene that induces apoptosis only in transformed tumour cells. This indicates that our
screen provides a systematic way to uncover such synthetic lethal “anti-cancer genes”.
10.00–10.30 [S6] Cell Death Pathways in the Mammary Gland
P Prof C Watson 1 ; PA Kreuzaler 1 ; AS Staniszewska 1 ; W Li 1 ; RA Flavell 2
University of Cambridge, Cambridge, United Kingdom; 2 Yale University, New Haven, United Kingdom
Post-lactational regression of the mammary gland epithelium (involution) is one of the major cell death events
in the adult mammalian organism. Extensive cell death occurs within 12 hours of forced weaning and is nearing
completion by 6 days in the mouse. Using genetically engineered mice, we have identified a number of the essential
mediators of involution including the transcription factors Stat3 and NF-κB and their upstream regulators such as
the cytokines LIF, OSM and TWEAK. Since activation of executioner caspases and translocation of cytochrome C
into the cytosol have been reported during involution, the modality of programmed cell death is presumed to be
apoptosis. However, so far this has not been unequivocally demonstrated. Contrary to this view, we have recently
discovered that mammary gland epithelium undergoes cell death through a non classical, lysosomal mediated
pathway. During involution, lysosomes in the mammary epithelium undergo widespread lysosomal membrane
permeabilisation (LMP), releasing cysteine cathepsins into the cytosol. This cell death is independent of executioner
caspases 3, 6 and 7 but requires Stat3, which up-regulates the expression of cathepsins B and L while down
regulating the cathepsin inhibitor Serine Protease Inhibitor 2A (Spi2A). This is the first time that such a lysosomal
mediated programmed cell death pathway (LM-PCD) pathway has been shown to control physiological cell death
16 Visit our website: www.pathsoc.org | Winter Meeting (199 th ) 6 – 7 January 2011 | Scientific Programme