Modelling the consequences of interactions between tumour cells.

Classical models of tumorigenesis assume that the mutations which cause tumours to grow act in a cell-autonomous fashion. This is not necessarily true. Sometimes tumour cells may adopt genetic strategies that boost their own replication and which also influence other cells in the tumour, whether directly or as a side-effect. Tumour growth as a whole might be enhanced or retarded. We have used mathematical models to study two non-autonomous strategies that tumour cells may use. First, we have considered the production by tumour cells of an angiogenesis growth factor that benefits both the cell from which it originates and neighbouring cells. Second, we have analysed a situation in which tumour cells produce autocrine-only or paracrine-only growth factors to prevent programmed cell death. In the angiogenesis model, stable genetic polymorphisms are likely to occur between cells producing and not producing the growth factor. In the programmed cell death model, cells with autocrine growth factor production can spread throughout the tumour. Production of paracrine-only growth factor is never selected because it is 'altruistic' (that is of no benefit to the cell that makes the growth factor), despite being potentially beneficial to tumour growth as a whole. No polymorphisms can occur in the programmed cell death model. Production of angiogenesis and other growth factors in tumours may be under stable genetic, rather than epigenetic, control, with implications for therapies aimed at such targets. Many of the mutations observed in tumours may have non-autonomous effects

Allele loss occurs frequently at hMLH1, but rarely at hMSH2, in sporadic colorectal cancers with microsatellite instability.

Mutations at the hMSH2 and hMLH1 mismatch repair loci have been implicated in the pathogenesis of colorectal cancer. Tumours with two allelic mutations at a mismatch repair locus develop replication errors (RERs). In the hereditary non-polyposis colorectal cancer (HNPCC) syndrome, one mutation is inherited and the other acquired somatically: in RER+ sporadic colorectal cancers, both mutations are somatic. RER+ tumours tend to have a low frequency of allele loss, presumably because they acquire most mutations through RERs. However, before a second mismatch repair mutation has occurred somatically, there is no reason to suppose that allele loss occurs less frequently in tumours that are to become RER+. Indeed, this second mutation might itself occur by allele loss. We have searched for allele loss at the hMSH2 and hMLH1 loci in RER+ and RER- sporadic colorectal cancers. Loss occurred at the hMLH1 locus in 7/17 (41%) RER+ tumours, compared with 6/40 (15%) RER- cancers (chi2=3.82, P approximately 0.05). At hMSH2, 2/22 RER+ sporadic cancers (9%) had lost an allele, compared with 2/40 (5%) RER- cancers (chi2=0.03, P>0.5). Taken together with previous studies which focused on colorectal cancers from HNPCC families, the data suggest that allele loss at hMLH1, but not at hMSH2, contributes to defective mismatch repair in inherited and sporadic colorectal cancer

Mutations in Bcl10 are very rare in colorectal cancer

Bcl10 is a recently identified gene reported to be involved commonly in human malignancy (Willis et al (1999) Cell 96: 1-20). To investigate whether it is frequently mutated in colorectal cancer we have analysed a series of 132 colorectal cancers and eight colorectal cancer cell lines for mutations in Bcl10. One feature of the Bcl10 gene is that it harbours two polyadenine tracts. These repeating elements in genes can be prone to a high rate of mutation if there is defective mismatch repair. To examine the possibility that Bcl10 may be preferentially mutated in mismatch repair-deficient cancers, 49 of the tumours and cell lines were known to be replication error (RER)-positive and, of these, ten were from individuals harbouring germline mutations in hMLH1 or hMSH2. No pathogenic mutations were detected in the tumours and only one mutation was found in the colorectal cancer cell lines. These results indicate that Bcl10 is unlikely to be involved in the pathways of colorectal carcinogenesis

The Psy-Security-Curriculum ensemble: British Values curriculum policy in English schools

Framed as being in response to terrorist attacks and concerns about religious bias in some English schools, ‘British Values’ (BV) curriculum policy forms part of the British Government’s Counter-Terrorism and Security Act, 2015. This includes a Duty on teachers in England to actively promote British Values to deter students from radicalisation. This paper, first, traces the history of Britishness in the curriculum to reveal a prevalence of nationalistic, colonial values. Next, an ensemble of recent policies and speeches focusing on British Values is analysed, using a psycho-political approach informed by anti-colonial scholarship. Finally, we interrogate two key critiques of the British Values curriculum discourse: the universality of British Values globally, and concerns over the securitisation of education. Findings indicate that the constitution of white British supremacist subjectivities operate through curriculum as a defence mechanism against perceived threats to white privilege, by normalising a racialised state-controlled social order. The focus is on ‘British’ values, but the analytic framework and findings have wider global significance

Comprehensive analysis of common mitochondrial DNA variants and colorectal cancer risk

Several lines of evidence implicate mitochondrial dysfunction in the development of cancer. To test the hypothesis that common mtDNA variation influences the risk of colorectal cancer (CRC), we genotyped 132 tagging mtDNA variants in a sample of 2854 CRC cases and 2822 controls. The variants examined capture ∼80% of mtDNA common variation (excluding the hypervariable D-loop). We first tested for single marker associations; the strongest association detected was with A5657G (P=0.06). Overall the distribution of association P-values was consistent with a null distribution. Next, we classified individuals into the nine common European haplogroups and compared their distribution in cases and controls. This analysis also provided no evidence of an association between mitochondrial variation and CRC risk. In conclusion, our results provide little evidence that mitochondrial genetic background plays a role in modifying an individual's risk of developing CRC

CASP8 variants D302H and −652 6N ins/del do not influence the risk of colorectal cancer in the United Kingdom population

Polymorphisms in CASP8 at 2q33.1 have been associated with the risk of developing cancer, specifically, the D302H variant (rs1045485) with breast cancer in the European population and the −652 6N ins/del promoter variant (rs3834129) with multiple tumours including colorectal cancer (CRC) in the Chinese population. We evaluated the relationship between −652 6N ins/del and D302H variants and risk of developing CRC in the UK population by genotyping 4016 cases and 3749 controls. Both variants showed no evidence of an association with risk of developing CRC (P=0.42 and 0.22, respectively). In contrast, the recently identified CRC susceptibility allele rs6983267 mapping to 8q24 was significantly associated with disease risk (P=8.94 × 10−8). It is thus very unlikely that variation in CASP8 defined by −652 6N ins/del or D302H influences the risk of CRC in European populations. The implications of our findings both in terms of population-specific effects and publication bias are discussed

Evolutionary Games with Affine Fitness Functions: Applications to Cancer

We analyze the dynamics of evolutionary games in which fitness is defined as an affine function of the expected payoff and a constant contribution. The resulting inhomogeneous replicator equation has an homogeneous equivalent with modified payoffs. The affine terms also influence the stochastic dynamics of a two-strategy Moran model of a finite population. We then apply the affine fitness function in a model for tumor-normal cell interactions to determine which are the most successful tumor strategies. In order to analyze the dynamics of concurrent strategies within a tumor population, we extend the model to a three-strategy game involving distinct tumor cell types as well as normal cells. In this model, interaction with normal cells, in combination with an increased constant fitness, is the most effective way of establishing a population of tumor cells in normal tissue.Comment: The final publication is available at http://www.springerlink.com, http://dx.doi.org/10.1007/s13235-011-0029-

A novel selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor prevents human adipogenesis

Glucocorticoid excess increases fat mass, preferentially within omental depots; yet circulating cortisol concentrations are normal in most patients with metabolic syndrome (MS). At a pre-receptor level, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates cortisol from cortisone locally within adipose tissue, and inhibition of 11β-HSD1 in liver and adipose tissue has been proposed as a novel therapy to treat MS by reducing hepatic glucose output and adiposity. Using a transformed human subcutaneous preadipocyte cell line (Chub-S7) and human primary preadipocytes, we have defined the role of glucocorticoids and 11β-HSD1 in regulating adipose tissue differentiation. Human cells were differentiated with 1·0 μM cortisol (F), or cortisone (E) with or without 100 nM of a highly selective 11β-HSD1 inhibitor PF-877423. 11β-HSD1 mRNA expression increased across adipocyte differentiation (P<0·001, n=4), which was paralleled by an increase in 11β-HSD1 oxo-reductase activity (from nil on day 0 to 5·9±1.9 pmol/mg per h on day 16, P<0·01, n=7). Cortisone enhanced adipocyte differentiation; fatty acid-binding protein 4 expression increased 312-fold (P<0·001) and glycerol-3-phosphate dehydrogenase 47-fold (P<0·001) versus controls. This was abolished by co-incubation with PF-877423. In addition, cellular lipid content decreased significantly. These findings were confirmed in the primary cultures of human subcutaneous preadipocytes. The increase in 11β-HSD1 mRNA expression and activity is essential for the induction of human adipogenesis. Blocking adipogenesis with a novel and specific 11β-HSD1 inhibitor may represent a novel approach to treat obesity in patients with MS

Observation of surface gap solitons in semi-infinite waveguide arrays

We report on the first observation of surface gap solitons, recently predicted to exist at the interface between uniform and periodic dielectric media with defocusing nonlinearity [Ya.V. Kartashov et al., Phys. Rev. Lett. 96, 073901 (2006). We demonstrate strong self-trapping at the edge of a LiNbO_3 waveguide array and the formation of staggered surface solitons with propagation constant inside the first photonic band gap. We study the crossover between linear repulsion and nonlinear attraction at the surface, revealing the mechanism of nonlinearity-mediated stabilization of the surface gap modes.Comment: 4 pages, 5 figure

Allele loss and mutation screen at the Peutz-Jeghers (LKB1) locus (19p13.3) in sporadic ovarian tumours

Germline mutations in the LKB1 (STK11) gene (chromosome sub-band 19p13.3) cause characteristic hamartomas and pigmentation to develop in patients with Peutz-Jeghers syndrome. Peutz-Jeghers syndrome carries an overall risk of cancer that may be up to 20 times that of the general population and Peutz-Jeghers patients are at increased risk of benign and malignant ovarian tumours, particularly granulosa cell tumours. Loss of heterozygosity (allele loss, LOH) has been reported in about 50% of ovarian cancers on 19p13.3. LKB1 is therefore a candidate tumour suppressor gene for sporadic ovarian tumours. We found allele loss at the marker D19S886 (19p13.3) in 12 of 49 (24%) sporadic ovarian adenocarcinomas. Using SSCP analysis, we screened ten ovarian cancers with LOH, 35 other ovarian cancers and 12 granulosa cell tumours of the ovary for somatic mutations in LKB1. No variants were detected in any of the adenocarcinomas. Two mutations were detected in one of the granulosa cell tumours: a mis-sense mutation affecting the putative 'start' codon (ATG --&gt; ACG, M1T); and a silent change in exon 7 (CTT --&gt; CTA, leucine). Like BRCA1 and BRCA2, therefore, it appears that LKB1 mutations can cause ovarian tumours when present in the germline, but occur rarely in the soma. The allele loss on 19p13.3 in ovarian cancers almost certainly targets a different gene from LKB1