Representación de imágenes de histopatología utilizada en tareas de análisis automático: estado del arte

This paper presents a review of the state-of-the-art in histopathology image representation used in automatic image analysis tasks. Automatic analysis of histopathology images is important for building computer-assisted diagnosis tools, automatic image enhancing systems and virtual microscopy systems, among other applications. Histopathology images have a rich mix of visual patterns with particularities that make them difficult to analyze. The paper discusses these particularities, the acquisition process and the challenges found when doing automatic analysis. Second an overview of recent works and methods addressed to deal with visual content representation in different automatic image analysis tasks is presented. Third an overview of applications of image representation methods in several medical domains and tasks is presented. Finally, the paper concludes with current trends of automatic analysis of histopathology images like digital pathology

The Spatial Distribution and Dynamics of CXCL13 in Lymphoid Tissues

Morphogens are soluble signalling molecules that regulate a broad spectrum of biological processes. However, the distances and scales over which this regulation occurs are unclear. To date, many studies have highlighted source-sink mechanisms for morphogen gradient formation but fail to take the role of the tissue microenvironment into account. Using a systems-based approach we show that the chemokine CXCL13 is regulated by the B-cell microenvironment on distinct but interconnected levels of biological organization. CXCL13 is a key determinant of humoral immune responses, regulating the localisation of lymphocytes within lymphoid tissues. Due to a complex and dynamic interaction network occurring over broad spatiotemporal scales, mapping the spatial distribution of CXCL13 in situ is challenging. To address this we have mapped the 3-dimensional organisation of CXCL13+ stromal cells in situ using a fluorescent reporter system, identifying three distinct but interconnected stromal subsets that are unique in their network properties. We quantify CXCL13 dynamics using high-speed narrowfield microscopy in collagen matrix and lymph node tissue sections with results suggesting that diffusion is highly constrained by local tissue microanatomy. However, this data alone is insufficient to describe CXCL13 gradient formation. To consolidate this data we employ a quantitative modelling approach hybridising different techniques into a high fidelity in silico representation of the B-follicle, where immune cells can interact with stroma capable of creating and shaping complex physiological gradients. Simulation analyses and immunohistochemistry suggest that chemokine fields within the follicle are dynamic and non-uniform, with multiobjective optimization analysis suggesting that this spatial configuration is designed to promote scanning rates. Taken in concert, our data suggests that CXCL13 acts over short distances creating a complex landscape of expression. Importantly, this study provides a basis for understanding the spatial distribution of morphogens with complex binding behaviours

Targeting tumor microenvironment crosstalk through GPCR receptors and PI3K pathway

[eng] The tumor microenvironment (TME) is gaining momentum due to its contribution to cancer progression and therapy resistance. This TME has a direct crosstalk with tumor cells that involves the activation of different pathways. Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Although FL is generally characterized by slow progression and high response rates to therapy, it is still considered incurable, because almost virtually all the patients relapse. FL is probably the NHL with the highest dependence on microenvironment. PI3K is a common denominator transducing the signaling from FL crosstalk with the TME and plays an important role in multiple cellular functions, and also contributes to cancer promoting aspects of the TME, such as angiogenesis and inflammatory cell recruitment. Idelalisib is a first-in-class δ isoform- specific PI3K inhibitor that receive regulatory approval for relapsed CLL, SLL and FL in 2014. Idelalisib blocks PI3K δ which is restricted to leukocytes. BCL2 deregulation is paramount in the pathogenesis of FL, as a consequence of the t(14;18), and therefore it is an attractive target for novel therapeutic approaches. Venetoclax (ABT-199, AbbVie) is a small BCL-2 inhibitors. Even though 85% of FL patients harbor the t(14;18), the results of the first clinical trial with venetoclax were not satisfactory (overall response 38%). From this first study we conclude that Idelalisib modulates key pathways in the germinal center and shapes the FL immune microenvironment by decreasing the recruitment of TFH and Treg to the tumor site leading to less immunesuppresive phenotype. Furthermore Idelalisib induces a moderate cytotoxic effect on FL cells in co-cultures. This co-culture decrease FL dependence on BCL-2 and consequently, venetoclax cytotoxicity, but Idelalisib sensitizes FL co-cultures to venetoclax. In summary, Idelalisib interferes with the crosstalk of FL and its immune microenvironment and potentiates the activity of venetoclax targeting the tumor cells, thus representing a promising combination therapy that may improve FL outcome. Colorectal cancer (CRC) is the third most common cancer in males and the second in females, and the fourth most common cause of cancer-related death worldwide. Patients with advanced and distal metastatic disease (stage IV), the survival rate drops to 10%, which accounts for approximately 18% of cases. The TME in CRC, is a complex structure composed by different type of cells, which are interacting each other’s and secreting a variety of growth factors and other molecules, such as cytokines and chemokines. Tumor development is based on the crosstalk between tumor cells and their surrounding microenvironment, and this crosstalk is mediated by the receptors and its ligand expression in both types of cells. G protein-coupled receptors (GPCRs) are an important family of membrane signaling receptors, which have an important role in cancer growth and development. Originally, GPCRs were considered as monomeric functional entities, nevertheless, in recent years has become evident that GPCRs form dimers and this dimers formation may modify the cellular response. In cancer, CXCR4 (has been studied extensively) plays an important role at different stages of cancer development, and is involved in the metastasis process of tumor cells. The up- regulation of CXCR4 in CRC correlates with a poor prognosis. Another GPCR, CB2 receptor modulates the downstream signaling and it is able to activate a wide range of signaling pathways, including extracellular signal-regulated kinases 1/2 (ERK1/2). In CRC, it has been described an up-regulation of CB2 receptor expression. GPCRs show differential expression in cancer cells and tissues, and they are highly druggable sites. From this second study we concluded that CXCR4 and CB2 expression is increased in primary colon tumor cells and in metastasis cells compared to normal epithelial cells from colon mucosa, and they formed heterodimers in colon tumoral cells and are associated with more aggressive phenotypes. Moreover, a bidirectional cross-antagonism crosstalk is established between these receptors. These heterodimers regulate in vitro CXCL12-induced migration, and in vivo, the simultaneous inhibition of both receptors shows superior anti-tumoral and anti-metastatic activities than the single agent inhibition. In summary, targeting the heterodimerization of CXCR4 and CB2 that are biologically relevant in cancer can be an effective way to reduce proliferation and dissemination in CRC.[spa] El estudio del microambiente tumoral está ganando importancia en las últimas décadas debido a su contribución en la formación y desarrollo del cáncer, además de contribuir en la resistencia de las células tumorales a diferentes terapias. Este microambiente interactúa con las células tumorales y activa diferentes vías. El linfoma folicular (FL), es el linfoma no Hodgkin indolente más común y con mayor dependencia del microambiente tumoral, además es considerado incurable. PI3K desempeña un papel importante en la comunicación con el microambiente, y es importante en múltiples funciones celulares, además de contribuir en la angiogénesis, reclutamiento de células inflamatorias y promover el crecimiento tumoral. Idelalisib es un inhibidor de PI3K (específicamente de la isoforma δ), que se aprobó en 2014 por la FDA. Paralelamente la desregulación de BCL2 es primordial en la patogénesis de FL, como consecuencia de la t (14; 18), presente en un 85% de los pacientes, y por lo tanto es un objetivo atractivo para novedosos enfoques terapéuticos. Venetoclax (ABT-199, AbbVie) es un pequeño inhibidor de BCL2, que mostró unos resultados del primer ensayo clínico no satisfactorios (respuesta global del 38%). De este primer estudio concluimos que Idelalisib interfiere en la comunicación de FL y su microambiente inmune, además potencia la actividad de venetoclax atacando a las células tumorales, lo que representa una terapia de combinación prometedora que puede mejorar el resultado del tratamiento de FL