RESUMEN
Modern cancer research on prognostic and predictive biomarkers demands the integration of established and emerging high-throughput technologies. However, these data are meaningless unless carefully integrated with patient clinical outcome and epidemiological information. Integrated datasets hold the key to discovering new biomarkers and therapeutic targets in cancer. We have developed a novel approach and set of methods for integrating and interrogating phenomic, genomic and clinical data sets to facilitate cancer biomarker discovery and patient stratification. Applied to a known paradigm, the biological and clinical relevance of TP53, PICan was able to recapitulate the known biomarker status and prognostic significance at a DNA, RNA and protein levels.
Asunto(s)
Biomarcadores de Tumor , Bases de Datos Genéticas , Genómica , Neoplasias , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologíaRESUMEN
Digital pathology and the adoption of image analysis have grown rapidly in the last few years. This is largely due to the implementation of whole slide scanning, advances in software and computer processing capacity and the increasing importance of tissue-based research for biomarker discovery and stratified medicine. This review sets out the key application areas for digital pathology and image analysis, with a particular focus on research and biomarker discovery. A variety of image analysis applications are reviewed including nuclear morphometry and tissue architecture analysis, but with emphasis on immunohistochemistry and fluorescence analysis of tissue biomarkers. Digital pathology and image analysis have important roles across the drug/companion diagnostic development pipeline including biobanking, molecular pathology, tissue microarray analysis, molecular profiling of tissue and these important developments are reviewed. Underpinning all of these important developments is the need for high quality tissue samples and the impact of pre-analytical variables on tissue research is discussed. This requirement is combined with practical advice on setting up and running a digital pathology laboratory. Finally, we discuss the need to integrate digital image analysis data with epidemiological, clinical and genomic data in order to fully understand the relationship between genotype and phenotype and to drive discovery and the delivery of personalized medicine.
Asunto(s)
Biomarcadores/química , Procesamiento de Imagen Asistido por Computador/métodos , Bancos de Muestras Biológicas , Neoplasias de la Mama/metabolismo , Neoplasias Colorrectales/metabolismo , Biología Computacional/métodos , ADN/química , Femenino , Colorantes Fluorescentes/química , Genotipo , Humanos , Inmunohistoquímica/métodos , Hibridación Fluorescente in Situ , Masculino , Microscopía Fluorescente/métodos , Reconocimiento de Normas Patrones Automatizadas , Fenotipo , Medicina de Precisión/métodos , Neoplasias de la Próstata/metabolismo , Programas Informáticos , Análisis de Matrices TisularesRESUMEN
Stromal-derived growth factors are required for normal epithelial growth but are also implicated in tumour progression. We have observed inactivation of the retinoblastoma protein (Rb), through phosphorylation, in cancer-associated fibroblasts in oro-pharyngeal cancer specimens. Rb is well known for its cell-autonomous effects on cancer initiation and progression; however, cell non-autonomous functions of Rb are not well described. We have identified a cell non-autonomous role of Rb, using three-dimensional cultures, where depletion of Rb in stromal fibroblasts enhances invasive potential of transformed epithelia. In part, this is mediated by upregulation of keratinocyte growth factor (KGF), which is produced by the depleted fibroblasts. KGF drives invasion of epithelial cells through induction of MMP1 expression in an AKT- and Ets2-dependent manner. Our data identify that stromal fibroblasts can alter the invasive behaviour of the epithelium, and we show that altered expression of KGF can mediate these functions.