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Colon cancer is the third most frequently diagnosed cancer in the UK and is often associated with a "Westenf' style of eating, high in fat and low in vegetables and fruits. There is strong epidemiological evidence that more physical activity is associated with reduced risk of colon cancer, but the amount or type of activity necessary to invoke this protection is disputed, and the mechanism responsible has not been elucidated. In this project, Min mice were used in studies of the impact of physical activity on development of intestinal neoplasia. These mice have a mutation at codon 850 in the Apc gene and develop multiple intestinal polyps spontaneously. The numbers, sizes and anatomical distribution of these lesions can be altered by dietary and pharmacological agents. From 5 weeks of age, male and female Min mice were exercised by running on a treadmill at up to 21 m/min for 30-60 min on a 5% slope for 5d/week for 10 weeks (TR). Additional groups of mice were provided with an exercise wheel (WH) or with no exercise (CON). Throughout the study, mice had ad libitum access to a Western-style high fat diet. Interleukin (IL)-6, IL-10, caecal transit time, colonic short chain fatty acids and natural killer cell cytotoxicity were investigated as potential protective mechanisms. On average, WH mice ran 2.99km/d (maximum 18.35km/d) compared with a maximum 0.96km/d for TR mice. Female mice were more willing treadmill runners and ran further in the wheels than did males. There was no significant reduction in total number of turnours or tumour burden in TR or WH compared with CON mice. Molar proportion of butyrate was significantly greater in TR mice compared with CON (P = 0.002). None of the other investigated mechanisms were different between exercise groups, although sex differences were observed for transit time. Non-exercise physical activity (NEPA) undertaken by the TR and CON mice was quantified for 23h per day (i. e. excluding period associated with treadmill running) using an Inframot device. NEPA was significantly higher for TR compared with CON mice (P=0.00 1), and for females compared with males (P<0.00 1). This study demonstrates that the turnour load in Min mice fed a high fat diet is not modulated by an exercise regime.

ASPP2 has been identified as a haploinsufficient tumour suppressor in mice, and an activator of the apoptotic function of the p53 family. Yeast two-hybrid experiments have also shown that ASPP2 interacts with a large number of proteins involved in other major signalling pathways. The mechanism(s) of action of ASPP2 are therefore complex, and likely to involve more than just the stimulation of the apoptotic programme. Since a study previously conducted in our laboratory revealed that the deletion of ASPP2 in vivo leads to severe hydrocephalus in the J129/C57BL6 background (Vives et al., 2006), it can be hypothesised that ASPP2 safeguards the normal development of the mammalian central nervous system (CNS), in addition to its role as a tumour suppressor. Deletion of ASPP2 leads to the development of hydrocephalus, most probably by affecting tight junctions (TJs) in the choroid plexus, thereby impairing its blood-cerebrospinal fluid (CSF) barrier function. TJ defects are likely to be the underlying cause of the loss of cell polarity observed in the neuroepithelium of several areas of the CNS. As cell polarity plays a key role in multiple aspects of CNS development, ASPP2 appears to be required for the proper lamination of the cerebral cortex and retina.