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1.
Int J Cancer ; 128(3): 715-25, 2011 Feb 01.
Article in English | MEDLINE | ID: mdl-20725999

ABSTRACT

Hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promise in treatment of ovarian carcinosis. Despite its efficiency for the treatment of peritoneal carcinosis from digestive tract neoplasia, it has failed to demonstrate significant benefit in ovarian cancers. It is therefore essential to understand the mechanism underlying resistance to HIPEC in ovarian cancers. Mesenchymal stem cells (MSC) play an important role in the development of ovarian cancer metastasis and resistance to treatments. A recent study suggests that MSCs may be cytotoxic for cancer cells upon heat shock. In contrast, we describe the protective role of MSC against hyperthermia. Using cytokine arrays we determined that the tumor associated MSC (TAMC) secrete pro-tumoral cytokines. We studied the effect of hyperthermia in co-culture setting of TAMC or BM-MCS associated with ovarian cancer cell lines (SKOV3 and CaOV3) with polyvariate flow cytometry. We demonstrate that hyperthermia does not challenge survival of TAMC or bone marrow derived MSC (BM-MSC). Both TAMC and BM-MSC displayed strong protective effect inducing thermotolerance in ovarian cancer cells (OCC). Transwell experiments demonstrated the role of secreted factors. We showed that CXCL12 was inducing thermotolerance and that inhibition of CXCL12/CXCR4 interaction restored cytotoxicity of hyperthermia in co-culture experiments. Contrary to the previous published study we demonstrated that TAMC and BM-MSC co-cultured with OCC induced thermotolerance in a CXCL12 dependant manner. Targeting the interaction between stromal and cancer cells through CXCL12 inhibition might restore hyperthermia sensitivity in ovarian cancers, and thus improve HIPEC efficiency.


Subject(s)
Mesenchymal Stem Cells/physiology , Ovarian Neoplasms/pathology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Survival , Chemokine CXCL12/antagonists & inhibitors , Coculture Techniques , Female , Flow Cytometry , Genes, Reporter , Green Fluorescent Proteins/genetics , Hot Temperature , Humans , Hyperthermia, Induced , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/pathology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/mortality , Receptors, CXCR4/antagonists & inhibitors , Survival Rate
2.
Arch Pediatr Adolesc Med ; 160(6): 596-601, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16754821

ABSTRACT

OBJECTIVE: To assess the clinical and genetic characteristics of symptomatic children with hereditary hemorrhagic telangiectasia (HHT). DESIGN: Cross-sectional study. SETTING: The HHT clinics in Toronto. PARTICIPANTS: All children with symptomatic HHT treated from April 1, 1996, through December 31, 2002. INTERVENTIONS: Participants were screened for visceral arteriovenous malformations (AVMs). Molecular testing was performed in the children or their affected family members. MAIN OUTCOME MEASURES: Prevalence of epistaxis, telangiectases, pulmonary and cerebral AVMs, and genetic characteristics. RESULTS: Fourteen children presented with manifestations of HHT. Seven had cardiorespiratory symptoms related to pulmonary AVMs. Three had neurological symptoms secondary to bleeding from spinal or cerebral AVMs. Two were referred because of skin telangiectases and 2, because of multiple episodes of epistaxis. Screening results revealed a cerebral AVM in 1 of 11 neurologically asymptomatic children. Of the children without respiratory symptoms, 1 was diagnosed as having definite and 1, suspected pulmonary AVMs. Four children with pulmonary AVMs carried an endoglin gene mutation (HHT type 1), and 1 carried an activin receptor-like kinase 1 gene mutation (HHT type 2). The 2 children with spinal AVMs belong to the same HHT type 2 family. No mutation was found in 1 child with pulmonary and 1 with cerebral AVMs. CONCLUSIONS: Visceral AVMs and mucosal telangiectases are present in children with HHT and can lead to life-threatening events. Failure to identify a disease-associated mutation for each child suggests complex mutations or novel HHT genes.


Subject(s)
Arteriovenous Malformations/complications , Intracranial Arteriovenous Malformations/complications , Telangiectasia, Hereditary Hemorrhagic/complications , Telangiectasia, Hereditary Hemorrhagic/genetics , Adolescent , Child , Child, Preschool , Cross-Sectional Studies , Epistaxis/complications , Female , Humans , Infant , Infant, Newborn , Male , Mutation , Pulmonary Circulation , Telangiectasia, Hereditary Hemorrhagic/diagnosis
3.
Hum Mutat ; 25(3): 320-1, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15712271

ABSTRACT

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder caused by mutations in Endoglin (ENG) or activin receptor-like kinase-1 (ALK1, ACVRL1) genes. We performed molecular characterization in clinically affected probands of 31 HHT families and detected a total of 28 different mutations in the two genes, including four shared by more than one family. Twelve mutations were identified in the ENG gene, six of which were novel and comprised two nonsense mutations in exons 6 and 8, deletions in exons 5 and 11, and splice site mutations in exon 12 and intron 8. Eleven of sixteen mutations identified in the ALK1 gene were novel single base pair substitutions in exons 4, 7, 8, and 9. We also describe the first de novo ALK1 mutation that causes a previously unreported c.1133C>A substitution of a highly conserved residue (p.P378H). The proband and his two daughters, who also carried the familial mutation, all suffered from gastrointestinal (GI) bleeding. In addition, we report seven newly identified polymorphisms and summarize all known ones in both genes.


Subject(s)
Antigens, CD/genetics , Membrane Proteins/genetics , Mutation, Missense , Point Mutation , Polymorphism, Single Nucleotide , Receptors, Cell Surface/genetics , Telangiectasia, Hereditary Hemorrhagic/genetics , Activin Receptors, Type II , Adolescent , Adult , Amino Acid Substitution , DNA Mutational Analysis , Endoglin , Exons/genetics , Female , Gastrointestinal Hemorrhage/etiology , Humans , Intracranial Arteriovenous Malformations/etiology , Introns/genetics , Liver/pathology , Lung/pathology , Male , Membrane Proteins/deficiency , Middle Aged , RNA Splice Sites/genetics , Telangiectasia, Hereditary Hemorrhagic/complications , Telangiectasia, Hereditary Hemorrhagic/pathology
4.
Eur J Hum Genet ; 11(4): 279-87, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12700602

ABSTRACT

Activin receptor-like kinase-1 (ALK-1), the gene mutated in HHT type 2 (HHT2), is a serine/threonine kinase receptor type I of the TGF-beta superfamily, specifically expressed on endothelial cells. We established an HHT2 genotype in 16 families and report nine novel mutations. These include insertions and deletions of single base pairs in exons 3, 8 and 9, as well as nonsense mutations in exons 4 and 8 of ALK-1, which would lead to premature truncation and unstable mRNA or protein. Three novel missense mutations were identified in exons 7 and 8 of the kinase domain. Five previously reported substitutions were also observed in the families analyzed. Our results bring to 36, the number of mutations associated with HHT2, and are mostly found in exons 8 and 3 followed by exons 4 and 7. To ascertain the potential functional implications of the missense mutations in the ALK-1 kinase domain, we generated a model based on the three-dimensional structure of the homologous ALK-5 kinase domain. Our data reveal that the 11 missense mutations modify residues conserved among type I receptors and alter the polarity, charge, hydrophobicity and/or size of the substituted amino-acid and likely lead to misfolded and nonfunctional proteins.


Subject(s)
Activin Receptors, Type I/genetics , Mutation, Missense/genetics , Telangiectasia, Hereditary Hemorrhagic/genetics , Activin Receptors, Type II , Adult , Aged , Amino Acid Sequence , DNA Mutational Analysis , Endothelium, Vascular/chemistry , Humans , Infant, Newborn , Middle Aged , Molecular Sequence Data , Protein Conformation , Sequence Alignment
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