Glioblastomas (GBM) are some bad prognosis brain tumors despite a conventional treatment associating surgical resection and subsequent radio-chemotherapy. Among these heterogeneous tumors, a ...subpopulation of chemo- and radioresistant GBM stem-like cells appears to be involved in the systematic GBM recurrence. Moreover, recent studies showed that differentiated tumor cells may have the ability to dedifferentiate and acquire a stem-like phenotype, a phenomenon also called plasticity, in response to microenvironment stresses such as hypoxia. We hypothesized that GBM cells could be subjected to a similar dedifferentiation process after ionizing radiations (IRs), then supporting the GBM rapid recurrence after radiotherapy. In the present study we demonstrated that subtoxic IR exposure of differentiated GBM cells isolated from patient resections potentiated the long-term reacquisition of stem-associated properties such as the ability to generate primary and secondary neurospheres, the expression of stemness markers and an increased tumorigenicity. We also identified during this process an upregulation of the anti-apoptotic protein survivin and we showed that its specific downregulation led to the blockade of the IR-induced plasticity. Altogether, these results demonstrated that irradiation could regulate GBM cell dedifferentiation via a survivin-dependent pathway. Targeting the mechanisms associated with IR-induced plasticity will likely contribute to the development of some innovating pharmacological strategies for an improved radiosensitization of these aggressive brain cancers.
Despite the growing evidence that dihydropyrimidine dehydrogenase deficiency (DPD, encoded by the DPYD gene) confers a higher risk of developing severe toxicity, most patients are not screened for ...DPD deficiency before fluoropyrimidine treatment. We report here the genetic and phenotypic analyses of DPD in a family related to a patient who died after a first cycle of 5‐fluorouracil and in 15 additional retrospective patients having a partial DPD deficiency (as measured by plasma dihydrouracil/uracil ratio). The patient with lethal toxicity was found to be a compound heterozygote for two DPYD mutations: a novel 8‐bp duplication (c.168_175dupGAATAATT, p.Phe59Ter) and c.1679T>G (Ile560Ser). The patient's dihydrouracil/uracil ratio indicates complete DPD deficiency. The novel mutation was found in two members of the patient's family. Deleterious DPYD mutations were identified in 9 out of the 15 patients. The relationship between genotype and dihydrouracil/uracil values in the 22 patients of the present study was significant (P = 0.01).
Germline mutations of the
POLE
gene are responsible for polymerase proofreading-associated polyposis syndrome (PPAP). These mutations were hypothesised to predispose to extra-gastrointestinal tumours ...(ovary, endometrium, brain), but this association has not been confirmed so far. We report a family with an autosomal dominant inheritance of PPAP due to a c.1089C>A; p.Asn363Lys mutation in the proofreading exonuclease domain of
POLE
. Ten patients presenting a history of colorectal tumours and three patients with polyposis are indexed in this family. Three carriers (including siblings and a distant cousin at 30, 45 and 52 respectively) and another member (at 37 not tested) presented glioblastoma. This is the second family reported to carry this mutation. Among the four glioblastomas in the family that we report, both show similar pathology: giant cell glioblastoma. These cases suggest that the c.1089C>A germline
POLE
mutation may confer an increased risk of brain cancer incidence 17.4% (4/23) in mutation carriers combining the two families. More observations are needed to support this hypothesis. It seems that not all mutations of
POLE
are equally associated with extra-gastrointestinal tumours. Although carriers of a mutation responsible for PPAP should benefit from screening for colorectal and uterine cancer, due to the rapid evolution of glioblastoma the value of neurological follow-up and brain imaging screening remains questionable. Nevertheless, considering the limitations of standard therapy for glioblastoma, mutation status could be useful for targeting therapy. The biological mechanism linking
POLE
mutation to glioblastoma remains to be determined.
Despite post-operative radio-chemotherapy, the prognosis of the patients with a glioblastoma (GBM) remains poor because of a local recurrence, mainly due to resistance of the GBM cells to ...radiotherapy. We have previously demonstrated that FGF-2 controls cell radioresistance and that expression of FGFR1 in the tumor of patients with GBM was an independent prognostic factor of overall survival and of time to progression after radio-chemotherapy. These results led to the hypothesis that FGFR1 could be involved in the radioresistance of GBM and that inhibiting FGFR1 in tumor cells may increase the efficiency of radiotherapy. To investigate this, we used in vitro and in vivo silencing strategies in GBM radioresistant U87 cells mainly expressing FGFR1. We first showed that the surviving fraction after a 5Gy irradiation (SF5) of U87 cells was significantly reduced when FGFR-1 has been silenced compared to U87 control cells (SF5=0.58% plus or minus 0.06 to 0.33% plus or minus 0.03; p < 0.001). Moreover, inhibition of FGFR1 led to a significant increase of the mitotic cell death after irradiation. We then showed that inhibiting FGFR1 led to an inhibition of PLC gamma phosphorylation which radiosensitizes U87 cells in vitro. We then performed an in vivo approach by generating subcutaneous limb xenografts with two different FGFR-1 silenced U87 clones, locally or sham irradiated with two 3 Gy fractions when tumor size reached 300 mm3. We showed a significant growth delay in the two silenced FGFR1 xenografts compared to control cell xenografts. In addition, a dramatic decrease in expression of hypoxia inducible factor, HIF-1 alpha has been found by immunohistochemistry in silenced FGFR-1 xenografts compared to control cell xenografts and confirmed in vitro by western blot. Our data establishes the proof-of-concept of FGFR1 inhibition as a new treatment for radiosensitizing these aggressive tumors. Considering that we showed that FGFR-1 expression in GBM patients is an independent prognostic factor of survival and time to progression after radio-chemotherapy, our present study highly suggests the interest to associating a FGFR1 inhibitor with radiotherapy in clinical trials for patients with glioblastoma.
L’objectif était d’évaluer l’impact des radiations ionisantes sur l’expression d’intégrines de choix dans différentes lignées tumorales colorectales humaines, et de corréler ces variations avec le ...profil invasif de ces lignées.
Trois lignées d’adénocarcinome colorectal ont été étudiées : SW480, SW620 et HCT116. Les intégrines d’intérêt, définies après analyse préliminaire par PCR (polymerase chain reaction) sur plaques microfluidiques, étaient les suivantes : α1, α2, α5, α6, αv, β1, et β2. Les cellules ont été irradiées à 10Gy et l’expression des ARNm des intégrines a été quantifiée pour chaque lignée à 72heures de l’irradiation par reverse transcription quantitative PCR (RT-qPCR) et comparée à la condition non irradiée. Les profils d’expression des intégrines ont ensuite été corrélés avec le niveau d’expression de la vimentine, reflet du profil invasif, par RT-qPCR.
L’expression des ARNm des intégrines suivantes était significativement augmentée après irradiation : α1 pour les lignées SW480 (expression multipliée par 4,04, p=7 · 10−6) et SW620 (4,51 fois, p=0,0003) ; α2 pour les trois lignées (SW480 3,31 fois, p=0,0002, SW620 2,74 fois, p=0,001 et HCT116 2,43 fois, p=0,02) ; α5 pour la lignée SW620 (1,75 fois, p=0,0006) ; et αv pour la lignée SW480 (2,05 fois, p=0,03). Il n’y avait pas de modification significative de l’expression des ARNm des intégrines α6, β1 et β2. Par ailleurs, SW480 et SW620 avaient un niveau d’expression basal de la vimentine plus élevé que HCT116 (respectivement 17,51 fois plus et 588,13 fois plus que HCT116). Pour la lignée SW620, l’expression de la vimentine était augmentée après irradiation (1,84 fois, p=0,004).
L’irradiation de lignées colorectales entraîne une majoration de l’expression de l’ARNm des intégrines α1, α2, α5 et αv. Cette augmentation est plus marquée dans les lignées présentant un niveau d’expression basal de la vimentine élevé et donc probablement un phénotype basal plus invasif. L’analyse de ces résultats suggère un lien étroit entre le pouvoir invasif des cellules d’adénocarcinome rectal et la stimulation radio-induite des voies des intégrines, dont l’inhibition pharmacologique pourrait être étudiée pour contourner la radiorésistance de ces tumeurs.
The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the ...origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population.
To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).
The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85; 95% CI, 0.76-0.97; P(trend) = 0.011) and ovarian cancer (per-allele HR, 0.69; 95% CI, 0.53-0.89; P(trend) = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers.
CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers.
The combined application of these and other recently identified genetic risk modifiers could in the future allow better individual risk calculation and could aid in the individualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers.
PDF
