Gene expression analyses of hepatocellular adenoma and hepatocellular carcinoma from the marine flatfish Limanda limanda

Small, Hamish J.; Williams, Tim D.; Sturve, Joachim; Chipman, J.K.; Southam, Andrew D.; Bean, Tim P.; Lyons, Brett P.; Stentiford, Grant D.

doi:10.3354/dao02148

Cited by 15 publications

(19 citation statements)

References 55 publications

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“…In, for example, the Brunsbuttel samples compared with non-tumour bearing Alde fish, choline, phosphocholine and glycine increased, and lactate decreased. Additionally, transcripts for ribosomal proteins showed co-ordinated induction in bulk tumours from dab, indicative of proliferation [22], but no such induction was apparent from the present samples. The changes in gene expression and metabolites detected in this study do not recapitulate those found in bulk tumours, and may be viewed as indicating either an earlier stage of tumourigenesis or a permissive micro-environment in which hyperplastic tissue may form and lead to tumour formation.…”

Section: Discussioncontrasting

confidence: 69%

Towards a System Level Understanding of Non-Model Organisms Sampled from the Environment: A Network Biology Approach

et al. 2011

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The acquisition and analysis of datasets including multi-level omics and physiology from non-model species, sampled from field populations, is a formidable challenge, which so far has prevented the application of systems biology approaches. If successful, these could contribute enormously to improving our understanding of how populations of living organisms adapt to environmental stressors relating to, for example, pollution and climate. Here we describe the first application of a network inference approach integrating transcriptional, metabolic and phenotypic information representative of wild populations of the European flounder fish, sampled at seven estuarine locations in northern Europe with different degrees and profiles of chemical contaminants. We identified network modules, whose activity was predictive of environmental exposure and represented a link between molecular and morphometric indices. These sub-networks represented both known and candidate novel adverse outcome pathways representative of several aspects of human liver pathophysiology such as liver hyperplasia, fibrosis, and hepatocellular carcinoma. At the molecular level these pathways were linked to TNF alpha, TGF beta, PDGF, AGT and VEGF signalling. More generally, this pioneering study has important implications as it can be applied to model molecular mechanisms of compensatory adaptation to a wide range of scenarios in wild populations.

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Section: Discussioncontrasting

confidence: 69%

Towards a System Level Understanding of Non-Model Organisms Sampled from the Environment: A Network Biology Approach

et al. 2011

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“…In light of data presented in the present study, it will now be important to consider the relationship between elevated liver cancer prevalence and potential causal factors at offshore sites. Studies demonstrating potential offshore endocrine disruption effects in populations of dab from the Dogger Bank region of the North Sea (Stentiford & Feist 2005, Scott et al 2007) and the recent finding of over-expression of vitellogenin mRNA in liver tumours of dab (Small et al 2010) are provocative directors for further research investigating the relationship between liver-cancer formation and the endocrine system of marine fish and their elevated association with particular geographic locations (Stentiford et al 2009). …”

Section: Discussionmentioning

confidence: 99%

Effect of age on liver pathology and other diseases in flatfish: implications for assessment of marine ecological health status

Stentiford¹,

Bignell²,

Lyons³

et al. 2010

Mar. Ecol. Prog. Ser.

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Age at disease onset, a familiar concept in human medicine, has not been commonly discussed in relation to diseases of wildlife. Furthermore, while age has been anecdotally linked with disease susceptibility in aquatic animals (e.g. in aquaculture), little attention has been devoted to health of specific cohorts in wild aquatic animal populations. In an attempt to refine current approaches to marine environmental monitoring programmes that utilise fish diseases as a sentinel for ecological status, we have investigated age at onset for 10 disease variables in the flatfish Limanda limanda, a commonly utilised species in such programmes in Europe. By comparing the prevalence of these variables (including several associated with liver neoplasia) in different age classes from the same sites, we have demonstrated an increased propensity for 'harm' (a cumulative measure of multiple disease variables) with age. Furthermore, a comparison of age-matched cohorts from geographically distinct offshore marine sites revealed that this tendency for increased harm differs in magnitude between sites. In these scenarios, the age at onset for key disease variables (such as pre-neoplastic and neoplastic pathologies of the liver) also differs between sites, with some locations containing populations with apparently increased susceptibility in younger age classes. We conclude that while age is an important variable when assessing fish population health status, it does not explain all of the differences in disease prevalence observed in natural populations, and further, that age-matched cohorts from certain populations have a higher propensity for disease than fish of the same age from other sites. The basis for these differences in susceptibility is discussed in relation to the prevailing burden of anthropogenic contaminants and to other natural factors (such as population genetics and migration) inherent in sampled populations.

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“…UK sites exceeding 20%. [31][32][33][34][35] However, the causative factors of these tumors and the molecular mechanisms involved, especially the balance between epigenetic and genetic factors, is unclear. Previous studies in our laboratory indicated that mutation profiles of oncogenes and tumor-suppressor genes within tumors were different between fish species and humans.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation in liver tumorigenesis in fish from the environment

Mirbahai¹,

Yin²,

Bignell³

et al. 2011

Epigenetics

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The link between environment, alteration in DNA methylation and cancer has been well established in humans; yet, it is under-studied in unsequenced non-model organisms. The occurrence of liver tumors in the flatfish dab collected at certain UK sampling sites exceeds 20%, yet the causative agents and the molecular mechanisms of tumor formation are not known, especially regarding the balance between epigenetic and genetic factors. Methylated DNA Immunoprecipitation (MeDIP) combined with de novo high-throughput DNA sequencing were used to investigate DNA methylation changes in dab hepatocellular adenoma tumors for the first time in an unsequenced species. Novel custom-made dab gene expression arrays were designed and used to determine the relationship between DNA methylation and gene expression. In addition, the confirmatory techniques of bisulfite sequencing PCR (BSP) and RT-PCR were applied. Genes involved in pathways related to cancer, including apoptosis, wnt/β-catenin signaling and genomic and non-genomic estrogen responses, were altered both in methylation and transcription. Global methylation was statistically significantly 1.8-fold reduced in hepatocellular adenoma and non-cancerous surrounding tissues compared with liver from non-cancer bearing dab. Based on the identified changes and chemical exposure data, our study supports the epigenetic model of cancer. We hypothesize that chronic exposure to a mixture of environmental contaminants contributes to a global hypomethylation followed by further epigenetic and genomic changes. The findings suggest a link between environment, epigenetics and cancer in fish tumors in the wild and show the utility of this methodology for studies in non-model organisms.

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Gene expression analyses of hepatocellular adenoma and hepatocellular carcinoma from the marine flatfish Limanda limanda

Cited by 15 publications

References 55 publications

Towards a System Level Understanding of Non-Model Organisms Sampled from the Environment: A Network Biology Approach

Towards a System Level Understanding of Non-Model Organisms Sampled from the Environment: A Network Biology Approach

Effect of age on liver pathology and other diseases in flatfish: implications for assessment of marine ecological health status

DNA methylation in liver tumorigenesis in fish from the environment

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