17 research outputs found
PO-485 Low abundance circulating proteins in giant cell tumours of bone
Introduction Circulating low-abundance proteins/fragments generating from tumour cells and tissues, represent the most important source of cancer biomarkers useful for early diagnosis and prognosis. Giant cell tumour of bone (GCT) is a benign neoplasm occurring in the long bone and in the axial skeleton of young adults. Approximately 5% of GCT develop pulmonary metastases. Although many biomarkers have been proposed, identification of circulating low abundance molecules may be useful to predict metastasis with a non invasive method. Material and methods The hydrogel nanoparticles technique followed by mass spectrometry was used to detect low molecular weight serum proteins or protein fragments in serum of 20 GCT patients with different clinical course and in 10 healthy sera used as control. The most representative low-abundant de novo or differentially abundant proteins were submitted to String database in order to define protein-protein interaction network. Cluster analysis was performed to identify prognostic groups of patients with similar abundance of proteins that significantly discriminate between the groups. Results and discussions For the 25 low-abundant de novo or differentially abundant proteins identified, we recognised that the top interconnected pathways included protein activation cascade, wound healing, blood coagulation, cell-substrate adhesion. Proteoma cluster analysis separated metastasis-free from metastatic GCT patients in two well-defined groups where serum levels of signalling transduction mediators and regulators of kinase activity presented a high discriminatory power. Increased expression of proteins STAT5B, GRB2 and OXSR1 was related to a higher probability of metastasis. Conclusion In conclusion, using a no invasive technique, we identified differentially abundant serum biomarkers, also providing prognostic information in patients with GCT of bone. Future studies are ongoing to establish the interplay between these biomarkers in order to fully understand the mechanism involved in tumour development and to focus on the planning of tailored therapies that should be more effective and less toxic
Correction to: ABCA6 affects the malignancy of Ewing sarcoma cells via cholesterol-guided inhibition of the IGF1R/AKT/MDM2 axis
In this article an incorrect affiliation had inadvertently been added. The original article has been updated
Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma
Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor of children and young adults in which the principal driver is a fusion gene, EWSR1-FLI1. Although the essential role of EWSR1-FLI1 protein in the regulation of oncogenesis, survival, and tumor progression processes has been described in-depth, little is known about the regulation of chimeric fusion-gene expression. Here, we demonstrate that the active nuclear HDAC6 in EWS modulates the acetylation status of specificity protein 1 (SP1), consequently regulating the SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters. Selective inhibition of HDAC6 impairs binding of the activator complex SP1/P300, thereby inducing EWSR1-FLI1 downregulation and significantly reducing its oncogenic functions. In addition, sensitivity of EWS cell lines to HDAC6 inhibition is higher than other tumor or non-tumor cell lines. High expression of HDAC6 in primary EWS tumor samples from patients correlates with a poor prognosis in two independent series accounting 279 patients. Notably, a combination treatment of a selective HDAC6 and doxorubicin (a DNA damage agent used as a standard therapy of EWS patients) dramatically inhibits tumor growth in two EWS murine xenograft models. These results could
lead to suitable and promising therapeutic alternatives for patients with EWS.Research in the E.D.A. lab is supported by Asociación Española Contra el Cáncer (AECC), the Ministry of Science of Spain-FEDER (CIBERONC, PI1700464, PI2000003, RD06/0020/0059)S. D.G.D. and L.H.P. are supported by CIBERONC (CB16/12/00361). D.G.D., M.J.R. and L.H.P. are PhD researchers funded by the Consejería de Salud, Junta de Andalucía (PI-0197-2016, ECAI F2-0012-2018 and PI-0013-2018, respectively).Peer reviewe
Giant Cell Tumor of Bone in Patients under 16 Years Old: A Single-Institution Case Series
none9noGiant cell tumor of the bone is a locally aggressive, rarely metastasizing tumor
that accounts for about 5% of bone tumors; it generally occurs in patients between 20 and 45 years
old. Sporadic cases (less than 140) have been described as occurring in the first two decades of life. A
histone 3.3 (H3.3) gene, H3F3A, has been recently identified in as many as 96% of giant cell tumors
of bone. These mutations are useful in the differential diagnosis of giant cell tumor of bone with
its mimickers. The immunohistochemical expression of H3F3A resulted comparable to molecular
analysis as reported in a recent investigation. In the present study, we describe our series of giant cell
tumors of bone in pediatric patients <16 years old.openAmbrosi, Francesca; Righi, Alberto; Benini, Stefania; Magagnoli, Giovanna; Chiaramonte, Ilaria; Manfrini, Marco; Gasbarrini, Alessandro; Frisoni, Tommaso; Gambarotti, MarcoAmbrosi, Francesca; Righi, Alberto; Benini, Stefania; Magagnoli, Giovanna; Chiaramonte, Ilaria; Manfrini, Marco; Gasbarrini, Alessandro; Frisoni, Tommaso; Gambarotti, Marc
Detection of H3F3A p.G35W and p.G35R in giant cell tumor of bone by Allele Specific Locked Nucleic Acid quantitative PCR (ASLNAqPCR)
Giant Cell Tumor (GCT) represents about 20% of benign bone tumors, is locally aggressive although malignant transformation is extremely rare, <1% of cases but 2-3% give pulmonary metastasis. Age at onset is between 20 and 40 years with a slight predominance for the female gender.GCT is characterized by specific mutations in H3F3A gene encoding the protein histone 3.3. The study of these mutations is important for the differential diagnosis with giant cell rich sarcomas, chondroblastoma and aneurysmal bone cyst.To identify the most frequent H3F3A mutations we developed a novel allele specific Real Time Polymerase Chain Reaction method, based on Allele Specific Locked Nucleic Acid (ASLNAqPCR) that is here described. Molecular analyses were performed on 20 GCT and 2 osteosarcoma arising on a previous GCT. All cases were verified by Sanger sequencing. We demonstrated that ASLNAqPCR is a quick, sensitive and reliable method to identify mutations of the H3F3A gene, in giant cell tumor of bone, to support diagnosis in morphologically ambiguous cases
Tissue and serum loss of metalloproteinase inhibitors in high grade soft tissue sarcomas
The activity of matrix metalloproteinases
(MMPs) in degrading extracellular matrix is controlled
by activation of pro-enzymes and inhibition of MMP
tissue inhibitors (TIMPs).
To assess proteolytic cascade imbalance in
malignancy progression, the enzymatic activity of
MMP2 and MMP9 and the expression and serum level
of their inhibitors, TIMP2 and TIMP1 respectively, was
evaluated in selected patients with high-risk soft tissue
sarcoma (STS). Gelatinase activity and inhibitor
expression was evaluated on 69 biopsies by zymography
and immunohistochemistry. TIMP1 and TIMP2 serum
concentration was tested in 53 STS patients and in 56
controls using a sandwich enzyme immunoassay.
Clinical and biological variables were related to
clinical outcome of the patients.
A significant gelatinolytic activity was seen in a high
percentage of STS. TIMP expression was weak or
negative in the majority of samples. The difference
between disease-free (p=0.001) and overall survival
(p=0.007) curves based on TIMP2 immunoreactivity
was statistically significant. TIMP plasma concentration
of 53 STS revealed significantly lower levels compared
to those of 56 controls (p=0.0001).
In conclusion, low levels of negative regulators of
proteolysis may be related to tumor biological
aggressiveness and used to select patients with poor
prognosis to improve cure
Genetic and molecular alterations in rhabdomyosarcoma: mRNA overexpression of MCL1 and MAP2K4 genes
Rhabdomyosarcoma, the most common soft
tissue sarcoma in childhood, belongs to the small round
cell tumor family and is classified according to its
histopathological features as embryonal, alveolar and
pleomorphic. In this study we propose to explore
genetic alterations involved in rhabdomyosarcoma
tumorigenesis and assess the level of mRNA gene
expression of controlling survival signalling pathways.
For genetic and molecular analysis, array-based
comparative genomic hybridization, combined with Real
Time PCR using the comparative method, was
performed on 14 primary well-characterized human
primary rhabdomyosarcomas. Multiple changes affecting
chromosome arms were detected in all cases, including
gain or loss of specific regions harbouring cancer
progression-associated genes. Evaluation of mRNA
levels showed in the majority of cases overexpression of MCL1 and MAP2K4 genes, both involved in cell
viability regulation. Our findings on rhabdomyosarcoma
samples showed multiple copy number alterations in
chromosome regions implicated in malignancy
progression and indicated a strong expression of
MAP2K4 and MCL1 genes, both involved in different
biological functions of complicated signalling pathways
Primary Malignant Peripheral Nerve Sheath Tumors of Bone: A Clinicopathologic Reappraisal of 8 Cases
: Primary spindle cell and pleomorphic sarcomas of bone represent an exceedingly rare group of mesenchymal malignancies that include "soft tissue" histotypes, as malignant peripheral nerve sheath tumour. Outside the head and neck region, only 36 cases of primary malignant peripheral nerve sheath tumour of bone have been described. We retrieved from our archives eight cases of primary malignant peripheral nerve sheath tumour of bone arising outside the head and neck region, describing their clinical, radiological, and morphologic features. Our series, in which all but one patient died of diseases after a median of seven months, confirms that primary malignant peripheral nerve sheath tumours of bone are aggressive tumours. Pathologists should be aware of this rare histotype. More aggressive and active adjuvant treatments should be investigated