miRNA-7 and miRNA-324-5p regulate alpha9-Integrin expression and exert anti-oncogenic effects in rhabdomyosarcoma.

The prognosis of patients with metastatic rhabdomyosarcoma (RMS), the most common type of soft tissue sarcoma in children, is poor and no strategies have been identified to improve their dismal prognosis. Alpha-9 integrin (ITGA9) plays a particularly crucial role in cancer progression and invasiveness. Despite the consensus on the remarkable pro-oncogenic potential of this protein, the miRNA-mediated regulation of ITGA9 has barely been studied to date. In the present study, miR-7 and miR-324-5p were selected as the best candidates after a screening to find ITGA9 regulators, and their effects on cell proliferation and invasion in RMS are described and characterized for the first time. Interestingly, the overexpression of both miRNA produced a clear impairment of cell proliferation, while miR-7 also induced a remarkable drop in cell invasion. Furthermore, the stable overexpression of both miRNA was found to reduce tumor growth in orthotopic RMS models and miR-7 was able to impair metastatic lung colonization. Consequently, we conclude that miR-7 and miR-324-5p show anti-oncogenic and anti-metastatic potential, thereby opening up the possibility of being used as novel therapeutic tools to avoid RMS progression.

Ligand-dependent Hedgehog pathway activation in Rhabdomyosarcoma: the oncogenic role of the ligands.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children. The Hedgehog (HH) pathway is known to develop an oncogenic role in RMS. However, the molecular mechanism that drives activation of the pathway in RMS is not well understood. METHODS: The expression of HH ligands was studied by qPCR, western blot and immunohistochemistry. Functional and animal model studies were carried out with cells transduced with shRNAs against HH ligands or treated with HH-specific inhibitors (Vismodegib and MEDI-5304). Finally, the molecular characterisation of an off-target effect of Vismodegib was also made. RESULTS: The results showed a prominent expression of HH ligands supporting an autocrine ligand-dependent activation of the pathway. A comparison of pharmacologic Smoothened inhibition (Vismodegib) and HH ligand blocking (MEDI-5304) is also provided. Interestingly, a first description of pernicious off-target effect of Vismodegib is also reported. CONCLUSIONS: The clarification of the HH pathway activation mechanism in RMS opens a door for targeted therapies against HH ligands as a possible alternative in the future development of better treatment protocols. Moreover, the description of a pernicious off-target effect of Vismodegib, via unfolded protein response activation, may mechanistically explain its previously reported inefficiency in several ligand-dependent cancers.

Patient-derived xenografts for childhood solid tumors: a valuable tool to test new drugs and personalize treatments

The use of preclinical models is essential in translational cancer research and especially important in pediatric cancer given the low incidence of each particular type of cancer. Cell line cultures have led to significant advances in cancer biology. However, cell lines have adapted to growth in artificial culture conditions, thereby undergoing genetic and phenotypic changes which may hinder the translational application. Tumor grafts developed in mice from patient tumor tissues, generally known as patient-derived xenografts (PDXs), are interesting alternative approaches to reproducing the biology of the original tumor. This review is focused on highlighting the interest of PDX models in pediatric cancer research and supporting strategies of personalized medicine. This review provides: (1) a description of the background of PDX in cancer, (2) the particular case of PDX in pediatric cancer, (3) how PDX can improve personalized medicine strategies, (4) new methods to increase engraftment, and, finally, (5) concluding remarks (AU)

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Patient-derived xenografts for childhood solid tumors: a valuable tool to test new drugs and personalize treatments.

The use of preclinical models is essential in translational cancer research and especially important in pediatric cancer given the low incidence of each particular type of cancer. Cell line cultures have led to significant advances in cancer biology. However, cell lines have adapted to growth in artificial culture conditions, thereby undergoing genetic and phenotypic changes which may hinder the translational application. Tumor grafts developed in mice from patient tumor tissues, generally known as patient-derived xenografts (PDXs), are interesting alternative approaches to reproducing the biology of the original tumor. This review is focused on highlighting the interest of PDX models in pediatric cancer research and supporting strategies of personalized medicine. This review provides: (1) a description of the background of PDX in cancer, (2) the particular case of PDX in pediatric cancer, (3) how PDX can improve personalized medicine strategies, (4) new methods to increase engraftment, and, finally, (5) concluding remarks.

[Genotypes of hepatitis C virus: their relationship with risk factors, the severity of liver disease, and the serologic response]. / Genotipos del virus de la hepatitis C: relación con los factores de riesgo, con la gravedad de la enfermedad hepática y con la respuesta serológica.

BACKGROUND: The objective of our study was to ascertain the prevalence of different HCV genotypes between the hepatitis C patients in the health area of Monforte de Lemos, Spain, as well as the possible influence of risk factors on their distribution and their relation with hepatic disease and with the serologic response. PATIENTS AND METHODS: We have studied 128 patients with hepatitis C. Of these, 41 were intravenous drug users (IVDU), 19 had received transfusions, 7 were hemodialyzed and in 61 the risk factors were unknown. Antibodies against HCV were detected by second-generation enzyme immunoassay (EIA) and confirmed by immunoblot. RNA-HCV presence was studied by reverse transcription-PCR (RT-PCR), and a reverse hybridization test of the amplifications was used for the genotyping. RESULTS: Hepatitis C genotypes 1b (46.1 [8.6%]), 1a (23.4 [7.3%]) and 3a (13.3 [5.9%]) were the most frequently encountered genotype. Genotype 1a (48.8 [15.3%]) was the most prevalent genotypes in IVDU patients, while 1b was the most frequent in patients of unknown risk factors (62.3 [12.1%]). Alanine-aminotransferase (ALT) was elevated in 66.6 (17.7%) of patients with genotype 1a, in 87.5 (8.6%) of patients with genotype 1b (p = 0.0367) and in 94.1 (11.2%) of patients with genotype 3a (p = 0.0347). Subtype 1b was present in 6 of 7 cases of cirrhosis (85.7%) and in 7 of 12 cases of active chronic hepatitis (58.3%). No significant statistical differences were observed between the genotypes and the specific IgM response against core antigen of HCV, neither we observed differences in the serologic response against C1, C2, NS3 and NS4 peptides. CONCLUSIONS: Hepatitis C genotypes 1a and 3a were the most prevalent genotypes between IVDU patients while genotype 1b was the most frequent between non-IVDU patients. Genotype 1b was associated to severe liver disease. Percentage of positivity or the reactivity against HCV peptides was independent of the genotype encountered in the patient.