RESUMO
There is a long-standing association between wound healing and cancer, with cancer often described as a "wound that does not heal". However, little is known about how wounding, such as following surgery, biopsy collection or ulceration, might impact on cancer progression. Here, we use a translucent zebrafish larval model of Ras(G12V)-driven neoplasia to image the interactions between inflammatory cells drawn to a wound, and to adjacent pre-neoplastic cells. We show that neutrophils are rapidly diverted from a wound to pre-neoplastic cells and these interactions lead to increased proliferation of the pre-neoplastic cells. One of the wound-inflammation-induced trophic signals is prostaglandin E2 (PGE2). In an adult model of chronic wounding in zebrafish, we show that repeated wounding with subsequent inflammation leads to a greater incidence of local melanoma formation. Our zebrafish studies led us to investigate the innate immune cell associations in ulcerated melanomas in human patients. We find a strong correlation between neutrophil presence at sites of melanoma ulceration and cell proliferation at these sites, which is associated with poor prognostic outcome.
Assuntos
Melanoma/imunologia , Neoplasias Experimentais/imunologia , Lesões Pré-Cancerosas/imunologia , Ferimentos e Lesões/imunologia , Peixe-Zebra/imunologia , Animais , Proliferação de Células , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Melanoma/genética , Mutação de Sentido Incorreto , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neutrófilos/imunologia , Neutrófilos/patologia , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Ferimentos e Lesões/genética , Ferimentos e Lesões/patologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/imunologia , Proteínas ras/genética , Proteínas ras/imunologiaRESUMO
Specification of digit number and identity is central to digit pattern in vertebrate limbs. The classical talpid(3) chicken mutant has many unpatterned digits together with defects in other regions, depending on hedgehog (Hh) signalling, and exhibits embryonic lethality. The talpid(3) chicken has a mutation in KIAA0586, which encodes a centrosomal protein required for the formation of primary cilia, which are sites of vertebrate Hh signalling. The highly conserved exons 11 and 12 of KIAA0586 are essential to rescue cilia in talpid(3) chicken mutants. We constitutively deleted these two exons to make a talpid3(-/-) mouse. Mutant mouse embryos lack primary cilia and, like talpid(3) chicken embryos, have face and neural tube defects but also defects in left/right asymmetry. Conditional deletion in mouse limb mesenchyme results in polydactyly and in brachydactyly and a failure of subperisoteal bone formation, defects that are attributable to abnormal sonic hedgehog and Indian hedgehog signalling, respectively. Like talpid(3) chicken limbs, the mutant mouse limbs are syndactylous with uneven digit spacing as reflected in altered Raldh2 expression, which is normally associated with interdigital mesenchyme. Both mouse and chicken mutant limb buds are broad and short. talpid3(-/-) mouse cells migrate more slowly than wild-type mouse cells, a change in cell behaviour that possibly contributes to altered limb bud morphogenesis. This genetic mouse model will facilitate further conditional approaches, epistatic experiments and open up investigation into the function of the novel talpid3 gene using the many resources available for mice.
Assuntos
Galinhas/genética , Botões de Extremidades/anatomia & histologia , Botões de Extremidades/embriologia , Morfogênese/genética , Proteínas/genética , Proteínas/metabolismo , Animais , Embrião de Galinha , Cílios/metabolismo , Embrião de Mamíferos/anormalidades , Embrião de Mamíferos/anatomia & histologia , Embrião de Mamíferos/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Botões de Extremidades/anormalidades , Botões de Extremidades/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteogênese/fisiologia , Transdução de Sinais/fisiologiaRESUMO
Dense Acropora cervicornis aggregations, or patches, have been documented within nearshore habitats in Southeast Florida (SE FL) despite close proximity to numerous anthropogenic stressors and subjection to frequent natural disturbance events. Limited information has been published concerning the distribution and abundance of A. cervicornis outside of these known dense patches. The first goal of this study was to conduct a spatially extensive and inclusive survey (9.78 km2) to determine whether A. cervicornis distribution in the nearshore habitat of SE FL was spatially uniform or clustered. The second goal was to investigate potential relationships between broad-scale seafloor topography and A. cervicornis abundance using high resolution bathymetric data. Acropora cervicornis was distributed throughout the study area, and the Getis-Ord Gi* statistic and Anselin Local Moran's I spatial cluster analysis showed significant clustering along topographic features termed ridge crests. Significant clustering was further supported by the inverse distance weighted surface model. Ordinal logistic regression indicated 1) as distance from a ridge increases, odds of reduced A. cervicornis abundance increases; 2) as topographic elevation increases, odds of increased abundance increases; and 3) as mean depth increases, odds of increased abundance increases. This study provides detailed information on A. cervicornis distribution and abundance at a regional scale and supports modeling its distributions in similar habitats elsewhere throughout the western Atlantic and Caribbean. Acropora cervicornis is frequently observed and in areas an abundant species within the nearshore habitat along the SE FL portion of the Florida Reef Tract (FRT). This study provides a better understanding of local habitat associations thus facilitating appropriate management of the nearshore environment and species conservation. The portion of the FRT between Hillsboro and Port Everglades inlets should be considered for increased management and protection to reduce local stressors.