ABSTRACT
The tumor microenvironment has a dynamic and usually cancer-promoting function during all tumorigenic steps. Glioblastoma (GBM) is a fatal tumor of the central nervous system, in which a substantial number of non-tumoral infiltrated cells can be found. Astrocytes neighboring these tumor cells have a particular reactive phenotype and can enhance GBM malignancy by inducing aberrant cell proliferation and invasion. The tumor suppressor p53 has a potential non-cell autonomous function by modulating the expression of secreted proteins that influence neighbor cells. In this work, we investigated the role of p53 on the crosstalk between GBM cells and astrocytes. We show that extracellular matrix (ECM) from p53(+/-) astrocytes is richer in laminin and fibronectin, compared with ECM from p53(+/+) astrocytes. In addition, ECM from p53(+/-) astrocytes increases the survival and the expression of mesenchymal markers in GBM cells, which suggests haploinsufficient phenotype of the p53(+/-) microenvironment. Importantly, conditioned medium from GBM cells blocks the expression of p53 in p53(+/+) astrocytes, even when DNA was damaged. These results suggest that GBM cells create a dysfunctional microenvironment based on the impairment of p53 expression that in turns exacerbates tumor endurance.
ABSTRACT
Oculoleptomeningeal amyloidosis (OA) is a fatal and untreatable hereditary disease characterized by the accumulation of transthyretin (TTR) amyloid within the central nervous system. The mechanisms underlying the pathogenesis of OA, and in particular how amyloid triggers neuronal damage, are still unknown. Here, we show that amyloid fibrils formed by a mutant form of TTR, A25T, activate microglia, leading to the secretion of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and nitric oxide. Further, we found that A25T amyloid fibrils induce the activation of Akt, culminating in the translocation of NFκB to the nucleus of microglia. While A25T fibrils were not directly toxic to neurons, the exposure of neuronal cultures to media conditioned by fibril-activated microglia caused synapse loss that culminated in extensive neuronal death via apoptosis. Finally, intracerebroventricular (i.c.v.) injection of A25T fibrils caused microgliosis, increased brain TNF-α and IL-6 levels and cognitive deficits in mice, which could be prevented by minocycline treatment. These results indicate that A25T fibrils act as pro-inflammatory agents in OA, activating microglia and causing neuronal damage.
Subject(s)
Amyloid Neuropathies, Familial/pathology , Memory Disorders/pathology , Memory, Short-Term , Microglia/pathology , Prealbumin/metabolism , Synapses/metabolism , Amyloid , Amyloid Neuropathies, Familial/complications , Amyloid Neuropathies, Familial/physiopathology , Animals , Brain/metabolism , Cell Death/drug effects , Cell Nucleus/metabolism , Cells, Cultured , Culture Media, Conditioned/pharmacology , Disease Models, Animal , Endocytosis , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Inflammation Mediators/metabolism , Interleukin-6/metabolism , Memory Disorders/complications , Memory Disorders/physiopathology , Memory, Short-Term/drug effects , Mice , Microglia/drug effects , Microglia/metabolism , Minocycline/pharmacology , Mutation/genetics , NF-kappa B/metabolism , Neurons/drug effects , Neurons/metabolism , Phosphorylation , Protein Transport , Proto-Oncogene Proteins c-akt/metabolism , Synapses/drug effects , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Foram analisadas 600 pacientes com leiomioma uterino (LU), atendidas na Escola Paulista de Medicina, que se submeteram a terapêutica cirúrgica entre 1976 e 1987. O exame histopatológico das peças cirúrgicas confirmou a presença de neoplasia benigna e, na maioria das vezes, surpeendeu outras patologias associadas. Estudaram-se também, como grupo controle, 150 úteros (de histerectomias), procurando-se conhecer a freqüência dessas entidades patológicas associadas em näo portadoras de LU. As principais associaçöes encontradas foram: cervicite crônica, adenomiose, cistos foliculars, alteraçöes tubárias - congestäo, edema e processo inflamatório -, pólipos uterinos, hiperplasia endometrial, endometriose, neoplasias do ovário e do endométrio. A coexistência dessas condiçöes patológicas ocorreu em 71,17% dos casos. O leiomioma é a neoplasia mais freqüente do útero e da pelve (18,19). A coexistência do tumor com outras entidades patológicas é pouco citada na literatura, assim como suas possíveis inter-relaçöes. Por causa da alta freqüência do leiomioma na populaçäo, poder-se ia associa-lo, apenas de forma fortuita, a outras entidades nosológicas do trato genital. Interessados em saber se haveria patologias secundárias ao leiomioma ou coexistência meramente casual, e também se as associaçöes teriam o mesmo denominador comum, fizemos o presente estudo
Subject(s)
Humans , Adult , Middle Aged , Female , Uterine Neoplasms/complications , Leiomyoma/complications , Uterine Diseases/complications , Uterine Neoplasms/epidemiology , Brazil/epidemiology , Case-Control Studies , Retrospective Studies , Hysterectomy , Leiomyoma/epidemiologyABSTRACT
The authors analyzed 600 patients with uterine leiomyoma examined at the Escola Paulista de Medicina and submitted to surgical treatment between 1976 and 1987. The uteri were carefully studied and leiomyomas were confirmed. Other diseases were also found in 71.17% of the cases. Uteri from hysterectomies performed for conditions other than leiomyoma were also studied for control purposes. Major conditions found were chronic cervicitis; adenomyosis; follicular cysts; tubal changes (congestion, edema, and salpingitis); uterine polyps; endometrial hyperplasia; endometriosis; ovarian and endometrial neoplasias.
