RESUMO
Radiotherapy is a complex medical speciality involving technology research, biology research and clinical research. All these basic researches are performed in order to optimise the management of cancer treatment patients. The aim of the present review is to present radiotherapy as a moving speciality whatever the concerned section. It will be particularly described the new approaches in terms of technology but also clinical developments.
Assuntos
Neoplasias/radioterapia , Radioterapia/tendências , Humanos , Radioterapia/métodos , Radioterapia Conformacional/métodos , Técnicas EstereotáxicasRESUMO
It is widely believed that ductal breast cancer dissemination involves a succession of clinical and pathological stages starting with carcinoma in situ, progressing into invasive lesion and culminating in metastatic disease. Such changes have frequently been attributed to the sequential acquisition of various alterations in a single cell followed by clonal selection and expansion, thus leading to intra-tumor diversity. According to this multi-step view, extensive genotype and phenotype (marker expression, grade) shift may occur in the same tumor during progression; this may lead to the co-existence of molecularly and/or pathologically different areas within the same lesion. An increasing amount of data of various natures now appear to challenge this concept: only a few distinct 'portraits', in relation to estrogen receptor (ER) status and grade, may be found among tumors. Moreover, although undergoing increasing genetic alteration, most individual lesions largely maintain their phenotype when they evolve from in situ to the metastatic state. While many of the data presented here are related to ductal tumors, lobular cancer is also discussed.
Assuntos
Neoplasias da Mama , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , HumanosRESUMO
NF-kappaB (Nuclear Factor-kappaB) was described for the first time in 1986 as a nuclear protein binding to the kappa immunoglobulin-light chain enhancer. Since then, NF-kappaB has emerged as an ubiquitous factor involved in the regulation of numerous important processes as diverse as immune and inflammatory responses, apoptosis and cell proliferation. These last two properties explain the implication of NF-kappaB in the tumorigenic process as well as the promise of a targeted therapeutic intervention. This review focuses on the current knowledge on NF-kappaB regulation and discusses the therapeutic potential of targeting NF-kappaB in cancer in particular during radiotherapy.
Assuntos
Fatores Imunológicos , NF-kappa B/fisiologia , NF-kappa B/efeitos da radiação , Neoplasias/radioterapia , Antioxidantes/fisiologia , Apoptose/fisiologia , Proliferação de Células , Sobrevivência Celular/efeitos da radiação , Humanos , Neoplasias/etiologia , Fosforilação , Inibidores de Proteassoma , Tolerância a Radiação , Radiação IonizanteRESUMO
The importance of targeted therapies has been emphasized by clinical trials using antiangiogenic or HER2 inhibitors in breast cancer. First with trastuzumab, it was demonstrated that targeted therapies may improve outcome in patients with HER overexpressing breast cancer in metastatic or adjuvant settings. The emerging role for angiogenesis inhibitors has also been demonstrated with bevacizumab. Unfortunately, there is growing clinical and biological evidence that tumour cells may develop unexpected and complex mechanisms of resistance to those targeted therapies. This review outlines the mechanisms by which tumour cells may resist to new targeted agents. Most recent developments are also highlighted.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Receptor ErbB-2/antagonistas & inibidores , Inibidores da Angiogênese/metabolismo , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais Humanizados , Bevacizumab , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/metabolismo , Sinergismo Farmacológico , Feminino , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Receptor ErbB-2/metabolismo , TrastuzumabRESUMO
The Trk family of neurotrophin tyrosine kinase receptors is emerging as an important player in carcinogenic progression in non-neuronal tissues. Here, we show that breast tumors present high levels of TrkA and phospho-TrkA compared to normal breast tissues. To further evaluate the precise functions of TrkA overexpression in breast cancer development, we have performed a series of biological tests using breast cancer cells that stably overexpress TrkA. We show that (1) TrkA overexpression promoted cell growth, migration and invasion in vitro; (2) overexpression of TrkA per se conferred constitutive activation of its tyrosine kinase activity; (3) signal pathways including PI3K-Akt and ERK/p38 MAP kinases were activated by TrkA overexpression and were required for the maintenance of a more aggressive cellular phenotype; and (4) TrkA overexpression enhanced tumor growth, angiogenesis and metastasis of xenografted breast cancer cells in immunodeficient mice. Moreover, recovered metastatic cells from the lungs exhibited enhanced anoikis resistance that was abolished by the pharmacological inhibitor K252a, suggesting that TrkA-promoted breast tumor metastasis could be mediated at least in part by enhancing anoikis resistance. Together, these results provide the first direct evidence that TrkA overexpression enhances the tumorigenic properties of breast cancer cells and point to TrkA as a potential target in breast cancer therapy.
Assuntos
Neoplasias da Mama/genética , Proliferação de Células , Receptor trkA/genética , Animais , Anoikis/fisiologia , Biópsia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Linhagem Celular Tumoral , Movimento Celular , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Feminino , Proteínas de Fluorescência Verde/metabolismo , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos SCID , Invasividade Neoplásica , Metástase Neoplásica , Neovascularização Patológica , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , RNA Mensageiro/metabolismo , Transdução de Sinais/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologiaRESUMO
Tamoxifen (TAM), is widely used as a single agent in adjuvant treatment of breast cancer. Here, we investigated the effects of TAM in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in estrogen receptor-alpha (ER-alpha)-positive and -negative breast cancer cells. We showed that cotreatment with TAM and TRAIL synergistically induced apoptosis regardless of ER-alpha status. By contrast, cotreatment did not affect the viability of normal breast epithelial cells. Cotreatment with TAM and TRAIL in breast cancer cells decreased the levels of antiapoptotic proteins including FLIPs and Bcl-2, and enhanced the levels of proapoptotic proteins such as FADD, caspase 8, tBid, Bax and caspase 9. Furthermore, cotreatment-induced apoptosis was efficiently reduced by FADD- or Bid-siRNA, indicating the implication of both extrinsic and intrinsic pathways in synergistic apoptosis induction. Importantly, cotreatment totally arrested tumor growth in an ER-alpha-negative MDA-MB-231 tumor xenograft model. The abrogation of tumor growth correlated with enhanced apoptosis in tumor tissues. Our findings raise the possibility to use TAM in combination with TRAIL for breast cancers, regardless of ER-alpha status.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Proteínas Reguladoras de Apoptose/fisiologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Ligante Indutor de Apoptose Relacionado a TNF/fisiologia , Tamoxifeno/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Inibidores do Crescimento/uso terapêutico , Humanos , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêuticoRESUMO
The knowledge of estrogen receptor (ER) status is important in the management of breast cancer patients. More precisely, analytical methods for ER determination have changed over the last two decades from ligand binding assay (LBA) dextran-coated charcoal (DCC) to enzyme immuno-assay (EIA) and more recently immunohistochemistry (IHC). We examined the respective clinical impact of ER determination according to these 3 methods over the period 1983-1999 within a group of 1940 patients, all operated and followed in the single institution Centre Antoine Lacassagne. Validated cut off values were 10 and 15 fmol/mg protein for both LBA-DCC and EIA, respectively and 10% of stained cells for IHC. During the years it was noted that the initial size of the tumor decreased and that the proportion of positive axillary nodes and negative ER tumors was different according to the ER method. ER negativity was 20, 13 and 10% in LBA-DCC, EIA, IHC, respectively. ER was a strong predictor of overall survival in the whole population (Mantel-Cox, p < 0.00001); however when stratifying the analysis on ER method groups, ER was still a prognostic indicator in the EIA, LBA-DCC group but not in the IHC group (the follow-up was too short). It is important to keep these data in mind when conducting large retrospective studies evaluating prognostic markers in breast cancer patients.
Assuntos
Neoplasias da Mama/química , Receptores de Estrogênio/análise , Idoso , Anticorpos Monoclonais , Carvão Vegetal , Dextranos , Feminino , Humanos , Técnicas Imunoenzimáticas , Ligantes , Pessoa de Meia-IdadeRESUMO
PURPOSE: Estrogen receptor alpha (ERalpha) plays a major role in breast cancer development. It acts as ligand-inducible transcription factor which determines growth, survival and differentiation of breast cancer cells. The aim of this study is to evaluate the potential interference between radiotherapy and estrogen receptor responsiveness. Materials and methods. The effect of ionizing radiation was assessed on the estrogen receptor alpha status, growth (proliferation and apoptosis) and sensitivity of MCF-7 breast cancer cells to estrogenic (17beta-estradiol (E2)), selective estrogen receptor modulator (SERM) and anti-estrogenic compounds. Results. We have observed a ligand-independent decrease in ERalpha expression after radiation, resulting from a specific reduction in mRNA level and protein synthesis. This ERalpha disappearance occurred 72 h post-irradiation at 8 Gy and decreased the transcriptional activity in ERalpha of these cells. On the other hand, E2 impedes the growth inhibitory effects (essentially on proliferation) of ionizing radiation in MCF-7 cells, which potentially decreases radiosensitivity of these cells. This effect was totally blocked by SERM and anti-estrogenic treatments. Moreover, this growth effect of concurrent anti-estrogenic drugs and ionizing radiation appeared to be strongly synergistic. CONCLUSIONS: This study may increase general comprehension of ERalpha modulation by radiotherapy and improve adjuvant therapeutic approaches based on co-administration of radiation and endocrine therapy.
Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Receptor alfa de Estrogênio/efeitos dos fármacos , Receptor alfa de Estrogênio/efeitos da radiação , Análise de Variância , Apoptose/efeitos da radiação , Ciclo Celular/efeitos da radiação , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Interações Medicamentosas , Estradiol/farmacologia , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/biossíntese , Humanos , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Células Tumorais CultivadasRESUMO
Breast epithelial cells produce both mitogens and growth inhibitors which are involved in the control of mammary gland development through autocrine and paracrine pathways. While the mechanisms of action of several growth factors have been well established and related strategies proposed for breast cancer therapy, little is known concerning growth inhibitors. In this review, we present an overview of current information about major autocrine and paracrine growth inhibitors of breast epithelial cells, and we discuss their potential functions in the control of breast cancer development.
Assuntos
Comunicação Autócrina/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Substâncias de Crescimento/farmacologia , Comunicação Parácrina/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Células Epiteliais/efeitos dos fármacos , Feminino , Humanos , Proteoglicanas/metabolismoRESUMO
Heparan sulfate proteoglycans (HSPG) are involved in the regulation of cellular proliferation, differentiation, and migration. We have studied the effect of three inhibitors of proliferation on 35S incorporation into HSPG of the breast cancer cell lines MCF-7 and MDA-MB-231 and the normal breast epithelial cells (NBEC). Transforming growth factor beta-1 (TGFbeta-1), which inhibits the proliferation of NBEC, but not of MCF-7 and MDA-MB-231, cells induced an increase in 35S incorporation of HSPG in NBEC, but had no effect on cancer cells. Sodium butyrate (NaB), which inhibits NBEC as well as cancer cell proliferation, induced an increase in 35S incorporation into HSPG in all cell types studied. In contrast, retinoic acid had no effect on HSPG of breast epithelial cells. Modification of HSPG induced by TGFbeta-1 or NaB treatments in normal and breast cancer epithelial cells resulted in an increase in 125I-fibroblast growth factor-2 (FGF-2) binding on HSPG. More importantly, NaB pretreatment resulted in an inhibition of the MCF-7 cell responsiveness to FGF-2, even though these cells remained sensitive to growth stimulation induced by serum or epidermal growth factor. These results indicate that changes in HSPG production are a key process involved in the mechanism of breast epithelial cell growth regulation.
Assuntos
Divisão Celular/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/metabolismo , Inibidores do Crescimento/farmacologia , Proteoglicanas de Heparan Sulfato/metabolismo , Sítios de Ligação/efeitos dos fármacos , Neoplasias da Mama , Butiratos/farmacologia , Membrana Celular/metabolismo , Células Cultivadas , Fator de Crescimento Epidérmico/farmacologia , Células Epiteliais , Feminino , Humanos , Mitógenos , Sódio/farmacologia , Fator de Crescimento Transformador beta/farmacologia , Tretinoína/farmacologia , Células Tumorais CultivadasRESUMO
MCF-7 cells express voltage-activated K+ channels. In the present study, we used the patch-clamp and RT-PCR techniques to investigate the involvement of these channels during the cell cycle progression. The outward rectifier current (IK) recorded during depolarization was almost completely suppressed by the classical K+ channel blocker tetraethylammonium (TEA) in MCF-7 cells. TEA also inhibited cell proliferation, as measured with 3H-thymidine incorporation. Moreover, profound changes were observed in both the resting membrane potential (RMP) and IK during the release from the G0/G1 phase of the cell cycle. MCF-7 cells arrested in G0/G1 were depolarized (-26.3 +/- 10 mV, n = 30) and IK-density was small (9.4 +/- 5.6 pA/pF, n = 60) compared to cells progressing in the G1 phase (RMP = -60 +/- 7.9 mV; n = 35 and IK-density = 30.2 +/- 8.5 pA/pF; n = 76). IK was highly sensitive to Mg2+, astemizole and TEA (10 mM). Extracellular perfusion of 5 mM Mg2+ dramatically slowed the activation and perfusion of 2 microM astemizole inhibited both IK (20 +/- 3%) and cell proliferation (23%). Moreover, the h-EAG mRNA expression was modulated during the cell cycle. Thus, these data suggested that h-EAG K+ channels play a role in controlling the proliferation and/or cell cycle.
Assuntos
Neoplasias da Mama/metabolismo , Canais de Potássio/metabolismo , Potássio/metabolismo , Astemizol/farmacologia , Transporte Biológico , Ciclo Celular/efeitos dos fármacos , Condutividade Elétrica , Canais de Potássio Éter-A-Go-Go , Feminino , Fase G1/efeitos dos fármacos , Inibidores do Crescimento/farmacologia , Humanos , Potenciais da Membrana , Bloqueadores dos Canais de Potássio/farmacologia , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Tetraetilamônio/farmacologia , Células Tumorais CultivadasRESUMO
Cancer development depends not only on the nature of the tumor cells themselves but also on the regulatory effects of various normal cells. The present study was performed to better understand the mechanism by which normal breast epithelial cells (NBEC) can control the growth of MCF-7 breast cancer cells. When MCF-7 cells were treated with NBEC conditioned medium, cell growth was inhibited in a concentration-dependent manner. This inhibition was due to an induction of apoptosis without any change in cell cycle progression. The induction of apoptosis was correlated with increased levels of p53, p21(waf1) and decreased levels of bcl-2. Transient transfections of MCF-7 cells with two p53 cDNA constructs demonstrated the induction of apoptosis was mediated by endogenous p53. Taken together, our results indicate that NBEC inhibit the growth of MCF-7 breast cancer cells by inducing apoptosis in them via endogenous p53.
Assuntos
Apoptose , Neoplasias da Mama/patologia , Mama/metabolismo , Células Epiteliais/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adulto , Apoptose/efeitos dos fármacos , Western Blotting , Mama/citologia , Neoplasias da Mama/metabolismo , Divisão Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Feminino , Citometria de Fluxo , Humanos , Mutação , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transfecção , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Proteína X Associada a bcl-2RESUMO
We show here that the neurotrophin nerve growth factor (NGF), which has been shown to be a mitogen for breast cancer cells, also stimulates cell survival through a distinct signaling pathway. Breast cancer cell lines (MCF-7, T47-D, BT-20, and MDA-MB-231) were found to express both types of NGF receptors: p140(trkA) and p75(NTR). The two other tyrosine kinase receptors for neurotrophins, TrkB and TrkC, were not expressed. The mitogenic effect of NGF on breast cancer cells required the tyrosine kinase activity of p140(trkA) as well as the mitogen-activated protein kinase (MAPK) cascade, but was independent of p75(NTR). In contrast, the anti-apoptotic effect of NGF (studied using the ceramide analogue C2) required p75(NTR) as well as the activation of the transcription factor NF-kB, but neither p140(trkA) nor MAPK was necessary. Other neurotrophins (BDNF, NT-3, NT-4/5) also induced cell survival, although not proliferation, emphasizing the importance of p75(NTR) in NGF-mediated survival. Both the pharmacological NF-kappaB inhibitor SN50, and cell transfection with IkBm, resulted in a diminution of NGF anti-apoptotic effect. These data show that two distinct signaling pathways are required for NGF activity and confirm the roles played by p75(NTR) and NF-kappaB in the activation of the survival pathway in breast cancer cells.