The Veterinary Journal 185 (2010) 1–3

Contents lists available at ScienceDirect

The Veterinary Journal

journal homepage: www.elsevier .com/ locate/ tv j l

Introduction

Biomarkers in veterinary medicine: Towards targeted, individualised therapiesfor companion animals

Ali Mobasheri a,*, Joseph P. Cassidy b

a School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Sutton Bonington Campus, Leicestershire, UKb Veterinary Sciences Centre, School of Agriculture, Food Science and Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland

A biomarker is a biochemical entity used to measure the pro-gress of a disease or the effects of treatment on clinical outcome.In medicine the term refers to a protein measured in blood, whoseconcentration reflects the presence or severity of a disease state.The National Cancer Institute (NCI)1 defines a biomarker as ‘a bio-logical molecule found in blood, other body fluids, or tissues that is a signof a normal or abnormal process, or of a condition or disease’, and theterms ‘molecular markers’ or ‘signature molecules’2 have also beenused to describe such markers.

A diverse array of samples may be assayed for the presence ofbiomarkers including blood, urine, faeces, tissue sections, isolatedcells and cell smears, and even exhaled breath. Biomarker researchin ‘Big Pharma’ is a multi-million dollar enterprise and the pharma-ceutical industry has traditionally used biomarkers at every stageof the drug development pipeline, from the discovery and clinicaltrial phases to the validation and approval processes. This stream-lined approach ensures that biomarkers can be used in diseaseprognosis and diagnosis as well as in assessing responses to treat-ment and in drug safety/efficacy monitoring.

The recent proliferation of post-genomic technologies has re-sulted in rapid growth and progress in human biomarker research(Mobasheri et al., 2004). In addition to the applications outlinedabove, such research has also focussed on the development of per-sonalised treatments to reduce levels of attrition in clinical trials(Ilyin et al., 2004). A similar interest in biomarkers is now emerg-ing in veterinary medicine, where there is enormous potential fortheir development and application. Research is not only relevantto the health and welfare of companion and food-production ani-mals, but also to broader themes such as global food security. Asin human medicine, biomarkers may have applications in the tai-loring of ‘individualised medicine’ for companion animals.

This Special Issue of The Veterinary Journal is dedicated toreviewing the ‘state of play’ of biomarkers in veterinary science.The issue is aimed at veterinarians and the broader biomedical re-search community interested in learning more about the back-ground and application of biomarkers in a series of reviewarticles and experimental studies contributed by internationally

1090-0233/$ - see front matter � 2010 Elsevier Ltd. All rights reserved.doi:10.1016/j.tvjl.2010.04.003

* Corresponding author. Tel.: +44 115 951 6449; fax: +44 115 951 6440.E-mail address: ali.mobasheri@nottingham.ac.uk (A. Mobasheri).

1 See: www.cancer.gov/.2 See: www.cancer.gov/dictionary/.

renowned scientists. Many of the contributors attended an interna-tional conference at Nottingham in July 2009 entitled ‘Biomarkersin Veterinary Medicine’, which show-cased the use of biomarkersin cancer, neurological, cardiovascular, respiratory and systemicinflammatory disease, as well as in metabolic diseases such asobesity and diabetes mellitus. The multi-disciplinary nature ofthe meeting made it highly relevant to both clinical and basic sci-entists involved in the leading-edge post-genomic technologiesbeing applied in this area of research. Key outcomes of the 2009conference included the identification of challenges that lie aheadin biomarker development, and the technical difficulties associatedwith assay standardisation in a rapidly expanding field (Matharoo-Ball et al., 2008). There was however a general consensus that vet-erinary biomarker research was now beginning to ‘catch-up’ on itshuman medical counterpart. A report outlining the content of thepresentations at the Nottingham conference has been published(Eckersall et al., 2009), and a follow-up conference is planned in2011.

In this Special Issue, a broad range of biomarker themes are ad-dressed. A review by German et al. (2010) focuses on the medicalconsequences of obesity in companion animals. Obesity leads toa multitude of adverse health effects such as decreased life-span,diabetes mellitus, orthopaedic and respiratory disease and neopla-sia. The article assesses the endocrine function of adipose tissue indisease pathogenesis, highlighting the potential role of adipokinesas biomarkers of obesity-associated disease. The evidence suggeststhat adipokines act as pro-inflammatory cytokines and can influ-ence various body systems, perturbing normal endocrine functionand resulting in insulin resistance and metabolic disease (Bulcãoet al., 2006; Maury and Brichard, 2010).

Companion animals are exposed to similar environmental car-cinogens as humans and similar genetic changes to those foundin human cancers have been identified in some animal tumours.Dr. Carolyn Henry discusses the controversies, biases and practicalconstraints relating to the clinical application of biomarkers in can-cer screening in animals (Henry, 2010) and indicates how they maybe used in diagnosis, staging and prognosis and in monitoring re-sponse to therapy. Ideally, effective disease-screening biomarkersshould identify sub-clinically affected patients, something that islikely to greatly enhance clinical outcomes. Dr. Henry’s review arti-cle shows that although the techniques of biomarker discovery andclinical application can often be extrapolated from human to ani-

2 A. Mobasheri, J.P. Cassidy / The Veterinary Journal 185 (2010) 1–3

mal, veterinary biomarker research has lagged behind. She arguesthat veterinarians have previously had a flawed understanding ofhow to apply biomarker assays and have not yet fully graspedthe opportunities that such research can offer.

In a separate review, Dr. Lisa Pang and Professor David Argyleassess the use of cancer stem cells and the enzyme telomerase asbiomarkers in veterinary oncology (Pang and Argyle, 2010). Theydemonstrate how such markers should ideally facilitate early-stage tumour detection and so enhance early response to therapyand increased survival times. However, the development of novelcancer therapies requires the parallel application of effective bio-markers to monitor therapy, disease remission and relapse. Dr.Gayathri Selvarajah and Dr. Jolle Kirpensteijn discuss the prognos-tic and predictive biomarkers of canine osteosarcoma (Selvarajahand Kirpensteijn, 2010), a common, aggressive bone tumour thataffects both humans and companion animals. Although chemo-therapy and radiotherapy significantly increase survival rates ofcanine patients, almost 90% of animals develop pulmonary metas-tases (Withrow et al., 1991; O’Day and Gorlick, 2009). Selvarajahand Kirpensteijn (2010) explore the use of biomarkers in the mul-ti-disciplinary management of dogs with osteosarcoma, and pres-ent the few presently known or potential prognostic/predictivemolecular markers which may have value in comparative oncologyas ‘bridging biomarkers’ for human osteosarcoma. The authorsforecast that high-throughput profiling of canine osteosarcomawill have the potential to identify novel markers to enhance diag-nostic and prognostic accuracy and assist in the formulation ofindividually tailored treatments.

A paper by Dr. Melissa Paoloni and her colleagues outlines thecreation of The National Cancer Institute–Comparative OncologyTrials Consortium (NCI–COTC) (Paoloni et al., 2010). The aim of this‘virtual laboratory’ is to inform the development path of noveldrugs and biologicals for human cancer patients through theirevaluation in dogs. It is argued that the establishment of the COTCPharmacodynamic Core has addressed the need for uniform end-point analysis by capitalising on the expertise of the COTC commu-nity of investigators. The authors point out that veterinary bio-marker validation is a secondary benefit of this co-ordinated,streamlined system that harnesses technological advances to themutual benefit of both animal and human health.

Insulinomas are pancreatic b-cell tumours characterised by inap-propriate secretion of insulin, leading to clinical signs associatedwith hypoglycaemia. In a Short Communication, Dr. Floryne Buis-hand and co-workers used uni- and multivariate analyses to evalu-ate the prognostic power of several clinical and histopathologicalcriteria, as well as of the tissue biomarker Ki67 in canine insulinomas(Buishand et al., 2010). The Ki67 ‘index’ proved prognostically usefulin predicting both disease-free interval and overall survival time.

Ion channels, pumps and transporters are increasingly implicatedin the altered molecular and metabolic phenotype of neoplastic cells.In a study by Freeman et al. (2010), immunohistochemistry andsemi-quantitative histomorphometry were used to investigate theexpression of three plasma membrane proteins in canine mammarytumours. They report that the membrane markers GLUT1 and Na, K-ATPase were more highly expressed in neoplastic mammary epithe-lial cells and propose that these proteins could be potentially usefuldiagnostic and prognostic markers.

Two articles highlight the potential application of cardiac bio-markers in veterinary cardiovascular research. Falk et al. (2010)correlated defined pathological features with clinical findings indogs with naturally-occurring congestive heart failure, and Serraet al. (2010) draw attention to the veterinary clinical and toxico-logical applications of cardiac troponin as a biomarker of cardiacinjury.

Elevated concentrations of plasma adrenocorticotrophic hor-mone (ACTH) are frequently associated with pituitary pars inter-

media dysfunction (PPID) in horses, and Lee et al. (2010) presentdata supporting the use of ACTH as a potential biomarker of PPIDand indicate that the reliability of this approach is enhanced ifmultiple samples are assessed throughout the various seasons ina year.

Osteoarthritis results in the destruction of articular cartilagematrix and the generation of collagen and proteoglycan matrixfragments, which are potential biomarkers that can be detectedin blood, synovial fluid and urine. Two inter-related reviews byGarvican et al. (2010a,b) examine the markers of both collagenand non-collagenous matrix degradation, and the authors under-line the techniques used to measure these compounds and indicatehow the biomarkers can be applied in assessing joint disease.

Acute phase proteins (APPs) have been used as biomarkers ofinflammation, infection and trauma for decades in human medi-cine but have been relatively under-used in veterinary clinics. Dr.Peter Eckersall and Dr. Rory Bell summarise recent progress inthe detection, measurement and application of APP as biomarkersin both companion and production animal medicine (Eckersall andBell, 2010). Their review discusses the application of assays forAPPs (such as C-reactive protein, haptoglobin and serum amyloidA) as diagnostic markers for diseases such as mastitis, and suggeststhat these proteins will be increasingly useful in the future. In aseparate study, Gómez-Laguna et al. (2010) assessed how APPs inthe serum, saliva and meat juice of pigs correlated with a porcinereproductive and respiratory syndrome virus infection. Theauthors point out that their findings indicate that these APPs canbe used as biomarkers of inflammation both ante- and post-mor-tem and that saliva is a readily accessible biological fluid availablefor assessment.

The papers published in this special issue emphasise the currentresearch effort on veterinary biomarkers. As with all protein-basedhuman biomarkers, detection involves the use of biochemical andimmunological assays, although proteomic technologies are nowresulting in the identification and profiling of oncology biomarkers(Matharoo-Ball et al., 2008; Ratcliffe et al., 2009) and this willprobably extend to other areas of disease in the future. Work willbe further enhanced by the additional application of metabolomic,genomic and transcriptomic detection techniques as illustrated bythe elegant study reported by Yang et al. (2010).

The major challenges facing the development of veterinary bio-markers for use in clinical settings will be identification, validationand qualification of each biomarker in a preclinical setting, fol-lowed by assay validation and standardisation using ‘real world’clinical samples. In human medicine, biomarkers are now seen ascentral to the development of personalised medicine, with treat-ments individually tailored to the specific needs of patients. Wepredict similar developments in veterinary clinics, particularly incompanion animal medicine (Mobasheri and Davidson, 2009). Thisis good news for animal health and welfare and will offer fertilenew arenas for collaboration between clinicians and biomedicalscientists as well as with the pharmaceutical industry.

Acknowledgements

We are grateful to The Veterinary Journal for providing us withthe opportunity to promote this exciting area of veterinary re-search. We are particularly indebted to Dr. Andrew Higgins, TheEditor-in-Chief of TVJ, along with scientific editors Dr. Adrian Phil-bey, Dr. Eric Blomme and Dr. Paul Mills and the members of TVJAdvisory Board, for their dedication, patience and support overthe last 15 months. We wish to thank Professor Gary England,Foundation Dean of the School of Veterinary Medicine and Science,University of Nottingham and Dr. Glenn Crocker, Chief Executive of‘BioCity’ Nottingham for their encouragement and leadership. Weare also grateful to Novartis Animal Health, Pfizer Animal Health

A. Mobasheri, J.P. Cassidy / The Veterinary Journal 185 (2010) 1–3 3

and the WALTHAM Centre for Pet Nutrition for sponsoring the ‘Bio-markers in Veterinary Medicine’ international conference.

References

Buishand, F., Kik, M., Kirpensteijn, J., 2010. Evaluation of clinico-pathological criteriaand the Ki67 index as prognostic indicators in canine insulinoma. TheVeterinary Journal 185, 62–67.

Bulcão, C., Ferreira, S.R., Giuffrida, F.M., Ribeiro-Filho, F.F., 2006. The new adiposetissue and adipocytokines. Current Diabetes Reviews 2, 19–28.

Eckersall, P.D., Bell, R., 2010. Acute phase proteins: biomarkers of infection andinflammation in veterinary medicine. The Veterinary Journal 185, 23–27.

Eckersall, P.D., Slater, K., Mobasheri, A., 2009. Biomarkers in veterinary medicine:establishing a new international forum for veterinary biomarker research.Biomarkers 14, 637–641.

Falk, T., Jönsson, L., Olsen, L.H., Tarnow, I., Pedersen, H.D., 2010. Associationsbetween cardiac pathology and clinical, echocardiographic andelectrocardiographic findings in dogs with chronic congestive heart failure.The Veterinary Journal 185, 68–74.

Freeman, A., Hetzel, U., Cripps, P., Mobasheri, A., 2010. Expression of the plasmamembrane markers aquaporin 1 (AQP1), glucose transporter 1 (GLUT1) and Na,K-ATPase in canine mammary glands and mammary tumours. The VeterinaryJournal 185, 90–93.

Garvican, E.R., Vaughan-Thomas, A., Innes, J.F., Clegg, P.D., 2010a. Biomarkers ofcartilage turnover. Part 1: markers of collagen degradation and synthesis. TheVeterinary Journal 185, 36–42.

Garvican, E.R., Vaughan-Thomas, A., Clegg, P.D., Innes, J.F., 2010b. Biomarkers ofcartilage turnover. Part 2: non-collagenous markers. The Veterinary Journal185, 43–49.

German, A.J., Ryan, V.H., German, A.C., Wood, I.S., Trayhurn, P., 2010. Obesity, itsassociated disorders and the role of inflammatory adipokines in companionanimals. The Veterinary Journal 185, 4–9.

Gómez-Laguna, J., Gutiérrez, A., Pallarés, F.J., Salguero, F.J., Cerón, J.J., Carrasco, L.,2010. Haptoglobin and C-reactive protein concentrations in the serum, salivaand meat juice of pigs experimentally infected with porcine reproductive andrespiratory syndrome virus. The Veterinary Journal 185, 83–87.

Henry, C.J., 2010. Biomarkers in veterinary cancer screening: applications,limitations and expectations. The Veterinary Journal 185, 10–14.

Ilyin, S.E., Belkowski, S.M., Plata-Salamán, C.R., 2004. Biomarker discovery andvalidation: technologies and integrative approaches. Trends in Biotechnology22, 411–416.

Lee, Z.-Y., Zylstra, R., Haritou, S.J., 2010. The use of adrenocorticotrophic hormone asa potential biomarker of pituitary pars intermedia dysfunction in horses. TheVeterinary Journal 185, 58–61.

Matharoo-Ball, B., Miles, A.K., Creaser, C.S., Ball, G., Rees, R., 2008. Serum biomarkerprofiling in cancer studies: a question of standardisation? Veterinary andComparative Oncology 6, 224–247.

Maury, E., Brichard, S.M., 2010. Adipokine dysregulation, adipose tissueinflammation and metabolic syndrome. Molecular and Cellular Endocrinology314, 1–16.

Mobasheri, A., Davidson, M., 2009. Exciting future predicted for animal health.European Life Sciences Journal 2, 20–21.

Mobasheri, A., Airley, R., Foster, C.S., Schulze-Tanzil, G., Shakibaei, M., 2004. Post-genomic applications of tissue microarrays: basic research, prognosticoncology, clinical genomics and drug discovery. Histology and Histopathology19, 325–335.

O’Day, K., Gorlick, R., 2009. Novel therapeutic agents for osteosarcoma. ExpertReview of Anticancer Therapy 9, 511–523.

Pang, L.Y., Argyle, D., 2010. Cancer stem cells and telomerase as potentialbiomarkers in veterinary oncology. The Veterinary Journal 185, 15–22.

Paoloni, M., Lana, S., Thamm, D., Mazcko, C., Withrow, S., Khanna, C., 2010. Thecreation of the comparative oncology trials consortium pharmacodynamicscore: infrastructure for a virtual laboratory. The Veterinary Journal 185, 88–89.

Ratcliffe, L., Mian, S., Slater, K., King, H., Napolitano, M., Aucoin, D., Mobasheri, A.,2009. Proteomic identification and profiling of canine lymphoma patients.Veterinary and Comparative Oncology 7, 92–105.

Selvarajah, G.T., Kirpensteijn, J., 2010. Prognostic and predictive biomarkers ofcanine osteosarcoma. The Veterinary Journal 185, 28–35.

Serra, M., Papaconstantinou, S., Adamcova, M., O’Brien, P.J., 2010. Veterinary andtoxicological applications for the detection of cardiac injury using cardiactroponin. The Veterinary Journal 185, 50–57.

Withrow, S.J., Powers, B.E., Straw, R.C., Wilkins, R.M., 1991. Comparative aspects ofosteosarcoma. Dog versus man. Clinical Orthopaedics and Related Research 270,159–168.

Yang, Y., Dahly-Vernon, A.J., Blomme, E.A.G., Lai-Zhang, J., Kempf, D.J., Marsh, K.C.,Harrington, Y.A., Nye, S.H., Evans, D.L., Roman, R.J., Jacob, H.J., Waring, J.F., 2010.Liver transcriptomic changes associated with ritonavir-induced hyperlipidemiain sensitive and resistant strains of rats. The Veterinary Journal 185, 75–82.