32 research outputs found
Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing's sarcoma via inhibition of cell migration
Background: Ewingâs sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents
with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15%
at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our
previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary
tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis.
Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties.
Methods: Invasion assays were performed in vitro in Boydenâs chambers covered with Matrigel. Matrix
Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant
model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic
injection of 106 human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 ÎŒg/kg, 3x/week)
was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed
by histology.
Results: ZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2
and â9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung
metastases from a primary ES tumor but had no effect on the growth of established lung metastases.
Conclusion: These results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor
growth but also to prevent the early metastatic events to the lungs
Drugs targeting the bone microenvironment: new therapeutic tools in Ewing's sarcoma?
Introduction: Ewing's sarcoma (ES) is the second most frequent malignant primary bone tumour in children, adolescents and young adults. The overall survival is 60 â 70% at 5 years but still very poor for patients with metastases, disease relapse or for those not responding to chemotherapy. For these high risk patients, new therapeutic approaches are needed beyond conventional therapies (chemotherapy, surgery and radiation) such as targeted therapies.
Areas covered: Transcriptomic and genomic analyses in ES have revealed alterations in genes that control signalling pathways involved in many other cancer types. To set up more specific approaches, it is reasonable to think that the particular microenvironment of these bone tumours is essential for their initiation and progression, including in ES. To support this hypothesis, preclinical studies using drugs targeting bone cells (bisphosphonate zoledronate, anti-receptor activator of NF-ÎșB ligand strategies) showed promising results in animal models. This review will discuss the new targeted therapeutic options in ES, focusing more particularly on the ones modulating the bone microenvironment.
Expert opinion: Targeting the microenvironment represents a new option for patients with ES. The proof-of-concept has been demonstrated in preclinical studies using relevant animal models, especially for zoledronate, which induced a strong inhibition of tumour progression in an orthotopic bone model
Zoledronic acid in metastatic osteosarcoma: encouraging progression free survival in four consecutive patients
Analysis of apoptosis methods recently used in Cancer Research and Cell Death & Disease publications
Three-dimensional Frankfort horizontal plane for 3D cephalometry: a comparative assessment of conventional versus novel landmarks and horizontal planes
Shape and volume of craniofacial cavities in intentional skull deformations
Intentional cranial deformations (ICD) have been observed worldwide but are especially prevalent in preColombian cultures. The purpose of this study was to assess the consequences of ICD on three cranial cavities (intracranial cavity, orbits, and maxillary sinuses) and on cranial vault thickness, in order to screen for morphological changes due to the external constraints exerted by the deformation device. We acquired CT-scans for 39 deformed and 19 control skulls. We studied the thickness of the skull vault using qualitative and quantitative methods. We computed the volumes of the orbits, of the maxillary sinuses, and of the intracranial cavity using haptic-aided semi-automatic segmentation. We finally defined 3D distances and angles within orbits and maxillary sinuses based on 27 anatomical landmarks and measured these features on the 58 skulls. Our results show specific bone thickness patterns in some types of ICD, with localized thinning in regions subjected to increased pressure and thickening in other regions. Our findings confirm that volumes of the cranial cavities are not affected by ICDs but that the shapes of the orbits and of the maxillary sinuses are modified in circumferential deformations. We conclude that ICDs can modify the shape of the cranial cavities and the thickness of their walls but conserve their volumes. These results provide new insights into the morphological effects associated with ICDs and call for similar investigations in subjects with deformational plagiocephalies and craniosynostoses. Am J Phys Anthropol 151:110-119, 2013. © 2013 Wiley Periodicals, Inc