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1.
Artigo em Inglês | MEDLINE | ID: mdl-32353390

RESUMO

PURPOSE: This study aimed to develop robust normal-tissue complication probability (NTCP) models for patients with hepatocellular carcinoma treated with radiation therapy (RT) using Child-Pugh (CP) score and albumin-bilirubin (ALBI) grade increase as endpoints for hepatic toxicity. METHODS AND MATERIALS: Data from 108 patients with hepatocellular carcinoma treated with RT between 2008 and 2017 were evaluated, of which 47 patients (44%) were treated with proton RT. Of these patients, 29 received stereotactic body RT and 79 moderately hypofractionated RT to median physical tumor doses of 43 Gy in 5 fractions and 59 Gy in 15 fractions, respectively. A generalized Lyman-Kutcher-Berman (LKB) model was used to model the NTCP using 2 clinical endpoints, both evaluated at 3 months after RT: CP score increase of ≥2 and ALBI grade increase of ≥1 from the pre-RT baseline. Confidence intervals on LKB fit parameters were determined using bootstrap resampling. RESULTS: Compared with previous NTCP models, this study found a stronger correlation between normal liver volume receiving low doses of radiation (5-10 Gy) and a CP score or ALBI grade increase. A CP score increase exhibited a stronger correlation to normal liver volumes irradiated than an ALBI grade increase. LKB models for CP increase found values for the volume-effect parameter of a = 0.06 for all patients, and a = 0.02/0.09 when fit to photon/proton patients separately. Subset analyses for patients with superior initial liver functions showed consistent dose-volume effects (a = 0.1) and consistent dose-response relationships. CONCLUSIONS: This study presents an update of liver NTCP models in the era of modern RT techniques using relevant endpoints of hepatic toxicity, CP score and ALBI grade increase. The results show a stronger influence of low-dose bath on hepatic toxicity than those found in previous studies, indicating that RT techniques that minimize the low-dose bath may be beneficial for patients.

3.
Ann Surg Oncol ; 27(4): 1122-1129, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31873931

RESUMO

OBJECTIVE: The aim of this study was to evaluate outcomes for patients with unresectable intrahepatic cholangiocarcinoma (ICC) treated with hypofractionated proton or photon radiation therapy (HF-RT). METHODS: We retrospectively identified 66 patients with ICC who were treated with HF-RT from 2008 to 2018. Median age at RT was 76 years (range 30-92), including 27 patients (41%) aged ≥ 80 years. Median RT dose was 58.05 Gy (range 37.5-67.5), all delivered in 15 daily fractions. Thirty-two patients received proton RT and 34 patients received photon RT. RESULTS: Median follow-up times from diagnosis and RT start were 21 months and 14 months, respectively. In total, five patients (7.6%) developed local failure. The 2-year outcomes were 84% local control (LC) and 58% OS. Among the 51 patients treated with definitive intent, the 2-year LC rate was 93% and the OS rate was 62%. On multivariate analysis for LC, older age was associated with a lower risk of local failure [hazard ratio (HR) 0.91; p = 0.02], while prior surgery (HR 16.5; p = 0.04) and macrovascular invasion (HR 123.93; p = 0.02) were independently associated with an increased risk of local failure. On multivariate analysis for OS, female sex (HR 0.33; p = 0.001) and prior chemotherapy (HR 0.38; p = 0.003) remained significantly associated with OS. On multivariate analysis for OS, compared with photon RT, there was a trend towards improved survival with proton RT (HR 0.50; p = 0.05). The rate of overall grade 3 + toxicity was 11%. One patient developed radiation-induced liver disease and was treated with corticosteroids. CONCLUSIONS: HF-RT yields high rates of local control and is an effective modality to optimize biliary control for unresectable/locally recurrent ICC.

4.
NPJ Precis Oncol ; 2: 22, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30374460

RESUMO

Radiotherapy shows excellent local control in liver cancers but carries the risk of radiation-induced liver dysfunction and liver failure. We conducted a study of plasma hepatocyte growth factor (HGF) in a clinical trial of proton radiotherapy in patients with unresectable liver cancers (NCT00976898), and in an observational study for liver cancer patients undergoing surgical treatments. Liver dysfunction within 3 months after radiotherapy-a Childs-Turcotte-Pugh (CTP) score increase of 1 point or more-occurred in 9/34 (26%) of patients. Patients with no increase in CTP score had lower pretreatment plasma HGF level (p = 0.015). Both the increase in CTP score (p = 0.034) and the pretreatment plasma HGF (p = 0.017) were associated with OS. Plasma HGF was significantly associated with presence of cirrhosis (p = 0.0027) and with Model for End-stage Liver Disease (MELD) score (p < 0.0001), but not with OS in surgical liver cancer patients. Pretreatment plasma HGF is a candidate biomarker for patient selection for radiotherapy.

5.
Pract Radiat Oncol ; 8(6): 414-421, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29937235

RESUMO

PURPOSE: This study aimed to assess the safety and efficacy of administering liver reirradiation to patients with primary liver tumors or liver metastasis. METHODS AND MATERIALS: A total of 49 patients (with 64 individual tumors) who received liver reirradiation at our institution between June 2008 and December 2016 were identified for retrospective review. Patients were treated to the same, different, or a combination of previously treated liver tumors for recurrent primary (53%) or metastatic (47%) disease using photons or protons. Clinical and treatment-related factors were compiled and patients were monitored for toxicity and evidence of classic or nonclassic radiation-induced liver disease. Survival was estimated with the Kaplan-Meier method and cumulative incidence of local failure (LF) was used to estimate LF using the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: The median age at the time of reirradiation was 72 years and the median interval between radiation courses was 9 months. At a median follow-up of 10.5 months, 36 patients (73%) had died, 9 patients (18%) were alive, and 4 patients (8%) were lost to follow-up. The median survival for the cohort was 14 months. The overall 1-year estimate of LF was 46.4%. The 1-year estimates of LF for liver metastases and hepatocellular carcinoma were 61.0% and 32.5%, respectively. The average prescription dose was similar between the reirradiation and initial courses (equivalent dose in 2 Gy fractions EQD2: 65.0 vs 64.3 Gyα/ß = 10, respectively) but the average dose to the untreated liver was lower at the time of reirradiation (EQD2: 10.5 vs 13.9 Gyα/ß = 3, respectively, P = .01). Among patients with hepatocellular carcinoma, the average normal liver dose was significantly larger for patients who exhibited a worsening of Child-Pugh score after reirradiation compared with those who did not (1210 cGy vs 759 cGy, P = .04). With regard to toxicity, 85.7% of patients experienced grade 1 to 2 toxicity, 4.1% developed grade 3, and only 2 patients (4.1%) met the criteria for radiation-induced liver disease after reirradiation. CONCLUSIONS: Liver reirradiation may be an effective and safe option for select patients; however, further prospective study is necessary to establish treatment guidelines and recommended dosing.


Assuntos
Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/radioterapia , Recidiva Local de Neoplasia/radioterapia , Planejamento da Radioterapia Assistida por Computador/métodos , Reirradiação , Idoso , Carcinoma Hepatocelular/patologia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/métodos , Estudos Retrospectivos , Taxa de Sobrevida
6.
Int J Radiat Oncol Biol Phys ; 101(5): 1222-1225, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29859792

RESUMO

PURPOSE: Irradiation may have significant immunomodulatory effects that impact tumor response and could potentiate immunotherapeutic approaches. The purposes of this study were to prospectively investigate circulating lymphoid cell population fractions during hypofractionated proton therapy (HPT) in blood samples of liver cancer patients and to explore their association with survival. METHODS AND MATERIALS: We collected serial blood samples before treatment and at days 8 and 15 of HPT from 43 patients with liver cancer-22 with hepatocellular carcinoma (HCC) and 21 with intrahepatic cholangiocarcinoma (ICC)-enrolled in a phase 2 clinical trial. All patients received 15 fractions of proton therapy to a median dose of 58 Gy (relative biological effectiveness). We used flow cytometry to measure the changes in the fractions of total CD3+, CD4+, and CD8+ T cells; CD4+ CD25+ T cells; CD4+ CD127+ T cells; CD3+ CD8+ CD25+ activated cytotoxic T lymphocytes (CTLs); and CD3- CD56+ natural killer cells. RESULTS: With a median follow-up period of 42 months, median overall survival (OS) in the study cohort was 30.6 months for HCC and 14.5 months for ICC patients. Longer OS was significantly correlated with greater CD4+ CD25+ T-cell (P = .003) and CD4+ CD127+ T-cell (P = .01) fractions at baseline only in ICC patients. In HCC patients, the fraction of activated CTLs mid treatment (at day 8) was significantly associated with OS (P = .007). These findings suggest a differential relevance of immunomodulation by HPT in these liver cancers. CONCLUSIONS: Antitumor immunity may depend on maintenance of a sufficiently high number of activated CTLs during HPT in HCC patients and CD4+ CD25+ T cells and CD4+ CD127+ T cells prior to treatment in ICC patients. These results could guide the design of future studies to determine the optimal treatment schedules when combining irradiation with specific immunotherapy approaches.


Assuntos
Carcinoma Hepatocelular/radioterapia , Colangiocarcinoma/radioterapia , Imunoterapia/métodos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/radioterapia , Linfócitos T/citologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Complexo CD3/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Carcinoma Hepatocelular/sangue , Colangiocarcinoma/sangue , Feminino , Seguimentos , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Células Matadoras Naturais/citologia , Subpopulações de Linfócitos , Masculino , Pessoa de Meia-Idade , Terapia com Prótons , Linfócitos T/metabolismo , Fatores de Tempo , Resultado do Tratamento
8.
J Clin Invest ; 122(10): 3473-5, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23006324

RESUMO

The explosive growth in our understanding of the molecular underpinnings of glioblastomas has served as an instructive paradigm for other cancers. However, the exact nature by which many of the pathogenic drivers connect is less well known, and elucidation of relationships between critical genetic and signaling alterations may inform the development of therapeutic approaches to the disease. In this issue, Song et al. identify miR-182 induction as a mechanism by which TGF-ß stimulation aberrantly activates NF-κB signaling in glioblastoma cells, clarifying a critical point of cross-talk between molecular signaling pathways. Their findings provide a greater understanding of the complex interplay between signaling pathways in cancer that may ultimately prove useful in the development of synergistic targeting approaches.

9.
Cell ; 146(1): 53-66, 2011 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-21729780

RESUMO

Malignant gliomas are aggressive brain tumors with limited therapeutic options, and improvements in treatment require a deeper molecular understanding of this disease. As in other cancers, recent studies have identified highly tumorigenic subpopulations within malignant gliomas, known generally as cancer stem cells. Here, we demonstrate that glioma stem cells (GSCs) produce nitric oxide via elevated nitric oxide synthase-2 (NOS2) expression. GSCs depend on NOS2 activity for growth and tumorigenicity, distinguishing them from non-GSCs and normal neural progenitors. Gene expression profiling identified many NOS2-regulated genes, including the cell-cycle inhibitor cell division autoantigen-1 (CDA1). Further, high NOS2 expression correlates with decreased survival in human glioma patients, and NOS2 inhibition slows glioma growth in a murine intracranial model. These data provide insight into how GSCs are mechanistically distinct from their less tumorigenic counterparts and suggest that NOS2 inhibition may be an efficacious approach to treating this devastating disease.


Assuntos
Proliferação de Células , Glioma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Animais , Autoantígenos/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Células-Tronco Neurais/metabolismo , Óxido Nítrico/metabolismo , Células Tumorais Cultivadas
10.
Cancer Cell ; 19(4): 498-511, 2011 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-21481791

RESUMO

Glioblastomas display cellular hierarchies containing tumor-propagating glioblastoma stem cells (GSCs). STAT3 is a critical signaling node in GSC maintenance but molecular mechanisms underlying STAT3 activation in GSCs are poorly defined. Here we demonstrate that the bone marrow X-linked (BMX) nonreceptor tyrosine kinase activates STAT3 signaling to maintain self-renewal and tumorigenic potential of GSCs. BMX is differentially expressed in GSCs relative to nonstem cancer cells and neural progenitors. BMX knockdown potently inhibited STAT3 activation, expression of GSC transcription factors, and growth of GSC-derived intracranial tumors. Constitutively active STAT3 rescued the effects of BMX downregulation, supporting that BMX signals through STAT3 in GSCs. These data demonstrate that BMX represents a GSC therapeutic target and reinforces the importance of STAT3 signaling in stem-like cancer phenotypes.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Células-Tronco Neoplásicas/patologia , Proteínas Tirosina Quinases/fisiologia , Fator de Transcrição STAT3/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/análise , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/análise , Fator de Transcrição 2 de Oligodendrócitos , Receptores de Interleucina-6/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia
11.
Biotechniques ; 50(1): 41-5, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21231921

RESUMO

A wide range of mammalian signaling and stress pathways are mediated by nitric oxide (NO), which is synthesized in vivo by the nitric oxide synthase (NOS) family of enzymes. Experimental manipulations of NO are frequently achieved by either inhibition or activation of endogenous NOS or via providing exogenous NO sources. On the contrary, many microbes consume NO via flavohemoglobin (FlavoHb), a highly efficient NO-dioxygenase that protects from nitrosative stress. Here we report a novel resource for studying NO in mammalian cells by heterologously expressing Escherichia coli FlavoHb within a lentiviral delivery system. This technique boosts endogenous cellular consumption of NO, thus providing a simple and efficacious approach to studying mammalian NO biology that can be employed as both a primary experimental and confirmatory tool.


Assuntos
Di-Hidropteridina Redutase/química , Proteínas de Escherichia coli/química , Hemeproteínas/química , NADH NADPH Oxirredutases/química , Óxido Nítrico/metabolismo , Di-Hidropteridina Redutase/análise , Di-Hidropteridina Redutase/genética , Escherichia coli/genética , Proteínas de Escherichia coli/análise , Proteínas de Escherichia coli/genética , Flavina-Adenina Dinucleotídeo/química , Células HEK293 , Hemeproteínas/análise , Hemeproteínas/genética , Humanos , Lentivirus/genética , NADH NADPH Oxirredutases/análise , NADH NADPH Oxirredutases/genética , Óxido Nítrico/química , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Oxirredução , Transdução de Sinais , Transfecção/métodos
12.
Genes Cancer ; 1(1): 50-61, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-20657792

RESUMO

Recombinant erythropoietin (EPO) is a growth factor used in the treatment of chemotherapy-induced anemia, but recent studies suggest that EPO may accelerate cancer growth. Although several cancers express EPO receptors (EPORs), the mechanism by which EPOR promotes tumor growth remains poorly understood. Glioblastomas display a cellular hierarchy of self-renewal and tumor propagation restricted to glioma stem cells (GSCs). We find that GSCs express higher levels of EPOR than matched non-stem glioma cells. Prospective enrichment for EPOR on GSCs increased neurosphere formation, suggesting that EPOR can select for a subset of GSCs with increased self-renewal capacity. Targeting EPOR expression with lentiviral mediated short hairpin RNA (shRNA) reduced GSC growth, survival, and neurosphere formation capacity, defining a crucial role for EPOR in GSC maintenance. We further find that STAT3 is an important mediator of EPOR signals in GSCs. EPOR knockdown attenuated the basal activation of STAT3 present in GSCs, and a small molecule inhibitor of STAT3 reduced GSC growth and survival. EPOR signaling was critical for survival in vivo, as targeting EPOR expression decreased GSC tumorigenic potential. Elevated EPOR expression also associated with poor patient outcome. Thus, EPOR on GSCs promotes tumor growth and may explain the poor survival of cancer patients treated with EPO.

13.
Cell Stem Cell ; 6(5): 421-32, 2010 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-20452317

RESUMO

Cancer stem cells (CSCs) are a subpopulation of tumor cells suggested to be critical for tumor maintenance, metastasis, and therapeutic resistance. Prospective identification and targeting of CSCs are therefore priorities for the development of novel therapeutic paradigms. Although CSC enrichment has been achieved with cell surface proteins including CD133 (Prominin-1), the roles of current CSC markers in tumor maintenance remain unclear. We examined the glioblastoma stem cell (GSC) perivascular microenvironment in patient specimens to identify enrichment markers with a functional significance and identified integrin alpha6 as a candidate. Integrin alpha6 is coexpressed with conventional GSC markers and enriches for GSCs. Targeting integrin alpha6 in GSCs inhibits self-renewal, proliferation, and tumor formation capacity. Our results provide evidence that GSCs express high levels of integrin alpha6, which can serve not only as an enrichment marker but also as a promising antiglioblastoma therapy.


Assuntos
Glioblastoma/metabolismo , Glioblastoma/patologia , Integrina alfa6/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Antígeno AC133 , Animais , Anticorpos Bloqueadores/farmacologia , Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Proliferação de Células/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Glioblastoma/irrigação sanguínea , Glicoproteínas/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Células-Tronco Neoplásicas/efeitos dos fármacos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Peptídeos/metabolismo , Fenótipo
14.
J Biol Chem ; 284(52): 36160-6, 2009 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-19847012

RESUMO

Nitric oxide exerts a plethora of biological effects via protein S-nitrosylation, a redox-based reaction that converts a protein Cys thiol to a S-nitrosothiol. However, although the regulation of protein S-nitrosylation has been the subject of extensive study, much less is known about the systems governing protein denitrosylation. Most recently, thioredoxin/thioredoxin reductases were shown to mediate both basal and stimulus-coupled protein denitrosylation. We now demonstrate that protein denitrosylation by thioredoxin is regulated dynamically by thioredoxin-interacting protein (Txnip), a thioredoxin inhibitor. Endogenously synthesized nitric oxide represses Txnip, thereby facilitating thioredoxin-mediated denitrosylation. Autoregulation of denitrosylation thus allows cells to survive nitrosative stress. Our findings reveal that denitrosylation of proteins is dynamically regulated, establish a physiological role for thioredoxin in protection from nitrosative stress, and suggest new approaches to manipulate cellular S-nitrosylation.


Assuntos
Proteínas de Transporte/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/fisiologia , Proteínas de Transporte/genética , Linhagem Celular , Sobrevivência Celular/fisiologia , Humanos , Óxido Nítrico/genética , Oxirredução , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/genética , Tiorredoxina Dissulfeto Redutase/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
15.
Stem Cells ; 27(10): 2393-404, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19658188

RESUMO

Glioblastomas are the most common and most lethal primary brain tumor. Recent studies implicate an important role for a restricted population of neoplastic cells (glioma stem cells (GSCs)) in glioma maintenance and recurrence. We now demonstrate that GSCs preferentially express two interleukin 6 (IL6) receptors: IL6 receptor alpha (IL6R alpha) and glycoprotein 130 (gp130). Targeting IL6R alpha or IL6 ligand expression in GSCs with the use of short hairpin RNAs (shRNAs) significantly reduces growth and neurosphere formation capacity while increasing apoptosis. Perturbation of IL6 signaling in GSCs attenuates signal transducers and activators of transcription three (STAT3) activation, and small molecule inhibitors of STAT3 potently induce GSC apoptosis. These data indicate that STAT3 is a downstream mediator of prosurvival IL6 signals in GSCs. Targeting of IL6R alpha or IL6 expression in GSCs increases the survival of mice bearing intracranial human glioma xenografts. IL6 is clinically significant because elevated IL6 ligand and receptor expression are associated with poor glioma patient survival. The potential utility of anti-IL6 therapies is demonstrated by decreased growth of subcutaneous human GSC-derived xenografts treated with IL6 antibody. Together, our data indicate that IL6 signaling contributes to glioma malignancy through the promotion of GSC growth and survival, and that targeting IL6 may offer benefit for glioma patients.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Apoptose/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Receptor gp130 de Citocina/efeitos dos fármacos , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/metabolismo , Glioma/genética , Glioma/imunologia , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/fisiologia , Inibidores do Crescimento/farmacologia , Humanos , Interleucina-6/metabolismo , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Interferência de RNA/fisiologia , RNA Interferente Pequeno/farmacologia , Receptores de Interleucina-6/efeitos dos fármacos , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Transplante Heterólogo , Células Tumorais Cultivadas
16.
J Biol Chem ; 284(25): 16705-9, 2009 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-19286664

RESUMO

Tumors are complex collections of heterogeneous cells with recruited vasculature, inflammatory cells, and stromal elements. Neoplastic cells frequently display a hierarchy in differentiation status. Recent studies suggest that brain tumors have a limited population of neoplastic cells called cancer stem cells with the capacity for sustained self-renewal and tumor propagation. Brain tumor stem cells contribute to therapeutic resistance and tumor angiogenesis. In this minireview, we summarize recent data regarding critical signaling pathways involved in brain tumor stem cell biology and discuss how targeting these molecules may contribute to the development of novel anti-glioma therapies.


Assuntos
Neoplasias Encefálicas/fisiopatologia , Glioma/fisiopatologia , Células-Tronco Neoplásicas/fisiologia , Transdução de Sinais/fisiologia , Animais , Proteínas Morfogenéticas Ósseas/fisiologia , Neoplasias Encefálicas/genética , Glioma/genética , Proteínas Hedgehog/fisiologia , Humanos , MicroRNAs/genética , Modelos Biológicos , RNA Neoplásico/genética , Receptores Proteína Tirosina Quinases/fisiologia , Receptores Notch/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia
17.
Stem Cells ; 26(12): 3027-36, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18802038

RESUMO

Malignant brain tumors are among the most lethal cancers, and conventional therapies are largely limited to palliation. Novel therapies targeted against specific molecular pathways may offer superior efficacy and less toxicity than conventional therapies, but initial clinical trials of molecular targeted agents in brain cancer therapy have been frequently disappointing. In brain tumors and other cancers, subpopulations of tumor cells have recently been characterized by their ability to self-renew and initiate tumors. Although these cancer stem cells, or tumor initiating cells, are often only present in small numbers in human tumors, mounting evidence suggests that cancer stem cells contribute to tumor maintenance and therapeutic resistance. Thus, the development of therapies that target cancer stem cell signal transduction and biology may improve brain tumor patient survival. We now demonstrate that populations enriched for cancer stem cells are preferentially sensitive to an inhibitor of Akt, a prominent cell survival and invasion signaling node. Treatment with an Akt inhibitor more potently reduced the numbers of viable brain cancer stem cells relative to matched nonstem cancer cells associated with a preferential induction of apoptosis and a suppression of neurosphere formation. Akt inhibition also reduced the motility and invasiveness of all tumor cells but had a greater impact on cancer stem cell behaviors. Furthermore, inhibition of Akt activity in cancer stem cells increased the survival of immunocompromised mice bearing human glioma xenografts in vivo. Together, these results suggest that Akt inhibitors may function as effective anticancer stem cell therapies.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Antígeno AC133 , Animais , Antígenos CD/biossíntese , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Inibidores Enzimáticos/farmacologia , Glicoproteínas/biossíntese , Humanos , Camundongos , Camundongos SCID , Transplante de Neoplasias , Peptídeos
18.
J Clin Oncol ; 26(17): 2839-45, 2008 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-18539962

RESUMO

In an increasing number of cancers, tumor populations called cancer stem cells (CSCs), or tumor-initiating cells, have been defined in functional assays of self-renewal and tumor initiation. Moreover, recent work in several different cancers has suggested the CSC population as a source of chemotherapy and radiation-therapy resistance within tumors. Work in glioblastoma and breast cancers supports the idea that CSCs may possess innate resistance mechanisms against radiation- and chemotherapy-induced cancer cell death, allowing them to survive and initiate tumor recurrence. Several resistance mechanisms have been proposed, including amplified checkpoint activation and DNA damage repair as well as increased Wnt/beta-catenin and Notch signaling. Novel targeted therapies against the DNA damage checkpoint or stem-cell maintenance pathways may sensitize CSCs to radiation or other therapies. Another important category of cancer therapies are antiangiogenic and vascular targeting agents, which are also becoming integrated in the treatment paradigm of an increasing number of cancers. Recent results from our laboratory and others support a role for CSCs in the angiogenic drive as well as the mechanism of antiangiogenic agents. Identifying and targeting the molecular mechanisms responsible for CSC therapeutic resistance may improve the efficacy of current cancer therapies.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias/terapia , Células-Tronco Neoplásicas , Neovascularização Patológica/terapia , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Humanos , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/efeitos da radiação , Neovascularização Patológica/patologia , Radioterapia , Falha de Tratamento
19.
Br J Haematol ; 141(1): 105-8, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18324973

RESUMO

Sickle red cell (SS RBC) adhesion is thought to contribute to sickle cell disease (SCD) pathophysiology. SS RBC adhesion to laminin increases in response to adrenaline stimulation of beta(2)-adrenergic receptors (beta(2)ARs) and adenylate cyclase (ADCY6), and previous evidence suggests such activation occurs in vivo. We explored whether polymorphisms of the beta(2)AR and ADCY6 genes (ADRB2 and ADCY6, respectively) affect RBC adhesion to laminin. We found that the beta(2)AR arg(16)-->gly substitution and two non-coding ADCY6 polymorphisms were associated with elevated adhesion. We postulate that ADRB2 and ADCY6 polymorphisms may influence SCD severity through the mechanism of RBC adhesion.


Assuntos
Adenilil Ciclases/genética , Anemia Falciforme/genética , Polimorfismo de Nucleotídeo Único , Receptores Adrenérgicos beta 2/genética , Anemia Falciforme/sangue , Adesão Celular/genética , Eritrócitos/metabolismo , Genótipo , Humanos , Laminina/metabolismo
20.
Transfusion ; 46(4): 668-77, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16584446

RESUMO

The Lutheran blood group system, which comprises one of the largest families of human red blood cell (RBC) antigens, resides on two immunoglobulin superfamily (IgSF) proteins: Lutheran and basal cell adhesion molecule (B-CAM). These two glycoproteins arise via alternative splicing of mRNA from a single gene and differ in structure only in the lengths of their cytoplasmic tails. Both are expressed on RBCs as well as a variety of other cell types, and they are overexpressed on sickle RBCs (SS RBC). B-CAM/Lu is the critical receptor for SS RBC adhesion to the extracellular matrix protein laminin, an interaction thought to contribute to the pathogenesis of sickle cell-related vasoocclusive events. Recent work has also shown that B-CAM/Lu on RBCs can undergo activation as a result of adrenergic signaling pathways. The high affinity of B-CAM/Lu for laminin is also thought to contribute to various developmental processes, including organogenesis, vascular development, erythropoiesis, and smooth muscle development and organization. Interestingly, the B-CAM spliceoform seems to be overexpressed by a variety of different malignant tumors and may be involved, along with other adhesion receptor proteins, in malignant transformation and tumor metastasis. Studies of B-CAM/Lu have thus expanded from defining antigen-specific polymorphisms to investigations of processes involved in sickle cell disease, human development, and cancer biology.


Assuntos
Adesão Celular/fisiologia , Sistema do Grupo Sanguíneo Lutheran/fisiologia , Proteínas de Membrana/fisiologia , Sequência de Aminoácidos , Antígenos CD/genética , Antígenos CD/fisiologia , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/fisiologia , Sequência de Bases , Eritrócitos/citologia , Eritrócitos/fisiologia , Regulação da Expressão Gênica , Frequência do Gene , Humanos , Lectinas Tipo C , Sistema do Grupo Sanguíneo Lutheran/genética , Glicoproteínas de Membrana , Dados de Sequência Molecular , Complexo Glicoproteico GPIb-IX de Plaquetas
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