RESUMO
Barriers presented by the tumor microenvironment including the abnormal tumor vasculature and interstitial matrix invariably lead to heterogeneous distribution of nanotherapeutics. Inspired by the close association between cyclooxygenase-2 (COX-2) and tumor-associated angiogenesis, as well as tumor matrix formation, we proposed that tumor microenvironment normalization by COX-2 inhibitors might improve the distribution and efficacy of nanotherapeutics for solid tumors. The present study represents the first time that celecoxib, a special COX-2 inhibitor widely used in clinics, was explored to normalize the tumor microenvironment and to improve tumor nanotherapeutics delivery using a human-derived A549 tumor xenograft as the solid tumor model. Immunofluorescence staining of tumor slices demonstrated that oral celecoxib treatment at a dose of 200 mg/kg for two weeks successfully normalized the tumor microenvironment, including tumor-associated fibroblast reduction, fibronectin bundle disruption, tumor vessel normalization, and tumor perfusion improvement. Furthermore, it also significantly enhanced the in vivo accumulation and deep penetration of 22-nm micelles rather than 100-nm nanoparticles in tumor tissues by in vivo imaging and distribution experiments and improved the therapeutic efficacy of paclitaxel-loaded micelles in tumor xenograft-bearing mouse models in the pharmacodynamics experiment. As celecoxib is widely and safely used in clinics, our findings may have great potential in clinics to improve solid tumor treatment.
Assuntos
Adenocarcinoma Bronquioloalveolar/tratamento farmacológico , Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/genética , Neoplasias Pulmonares/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Células A549 , Adenocarcinoma Bronquioloalveolar/irrigação sanguínea , Adenocarcinoma Bronquioloalveolar/genética , Adenocarcinoma Bronquioloalveolar/patologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Ciclo-Oxigenase 2/metabolismo , Esquema de Medicação , Sistemas de Liberação de Medicamentos/métodos , Sinergismo Farmacológico , Quimioterapia Combinada , Expressão Gênica , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , Micelas , Nanopartículas/química , Nanopartículas/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Poliésteres/química , Polietilenoglicóis/química , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We propose a computational simulation framework for describing cancer-therapeutic transport in the lung. A discrete vascular graph model (VGM) is coupled to a double-continuum model (DCM) to determine the amount of administered therapeutic agent that will reach the cancer cells. An alveolar cell carcinoma is considered. The processes in the bigger blood vessels (arteries, arterioles, venules and veins) are described by the VGM. The processes in the alveolar capillaries and the surrounding tissue are represented by a continuum approach for porous media. The system of equations of the coupled discrete/continuum model contains terms that account for degradation processes of the therapeutic agent, the reduction of the number of drug molecules by the lymphatic system and the interaction of the drug with the tissue cells. The functionality of the coupled discrete/continuum model is demonstrated in example simulations using simplified pulmonary vascular networks, which are designed to show-off the capabilities of the model rather than being physiologically accurate.
Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Modelos Biológicos , Adenocarcinoma Bronquioloalveolar/irrigação sanguínea , Adenocarcinoma Bronquioloalveolar/tratamento farmacológico , Adenocarcinoma Bronquioloalveolar/fisiopatologia , Transporte Biológico Ativo , Simulação por Computador , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/fisiopatologia , Sistema Linfático/metabolismo , Alvéolos Pulmonares/irrigação sanguínea , Alvéolos Pulmonares/metabolismo , Circulação PulmonarRESUMO
PURPOSE: Treatment of lung cancer patients with antiangiogenesis agents is a new promising paradigm. Tumor cavitation is frequently noted in these patients, but the clinical significance of this finding has not been fully determined. Our purposes were to evaluate the frequency, imaging characteristics, and clinical outcome of patients receiving antiangiogenesis agents who develop tumor cavitation, and correlate these findings with therapy related adverse events, especially hemoptysis. METHODS: Retrospective analysis of lung cancer patients treated with antiangiogenesis agents in MD Anderson Cancer Center between June 1998 and June 2005. Clinical data were retrieved from medical records, and chest imaging findings were documented. RESULTS: One hundred and twenty-four patients were treated in 10 different trials. All patients had advanced lung cancer and failed previous chemotherapy. Seventeen patients developed tumor cavitation during the trial (14%; median time to event, 1.8 months; range, 0.7-6.2 months), 16 patients (13%) had preexisting cavitary tumors, and 91 (73%) did not develop cavitation. Cavity formation was more common with squamous cell histology (p = 0.04) but was not associated with hemoptysis (p = 0.12), tumor location (central versus peripheral), imaging characteristics, progression-free survival (p = 0.56), or overall survival (p = 0.33). Hemoptysis was noted in five patients (median time to event, 1.3 months; range, 0.8-2.9 months). One of five patients with hemoptysis was fatal in a cavitary squamous cell tumor. Additional adverse events were hypertension, rash, and proteinuria, none associated with cavitation. CONCLUSION: Development of tumor cavitation is not rare in lung cancer patients treated with antiangiogenesis agents, but the clinical implications are minimal in most cases.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma Bronquioloalveolar/irrigação sanguínea , Adenocarcinoma Bronquioloalveolar/tratamento farmacológico , Adenocarcinoma Bronquioloalveolar/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Grandes/irrigação sanguínea , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/secundário , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/secundário , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Phosphatase and tensin homologue deleted from chromosome 10 (Pten) is expressed aberrantly in non-small cell lung cancer cells, but the role of Pten in lung neoplasia has not been fully elucidated. In this study, we used a genetic approach to inactivate Pten in the bronchial epithelium of mice. Although, by itself, Pten inactivation had no discernible effect on bronchial epithelial histology, it accelerated lung tumorigenesis initiated by oncogenic K-ras, causing more rapid lethality than that induced by oncogenic K-ras alone (8 weeks versus 24 weeks of median duration of survival, respectively). Lung tumors arose in K-ras mutant, Pten-deficient mice that rapidly obstructed bronchial lumina and replaced alveolar spaces. Relative to K-ras mutant tumors, the K-ras mutant, Pten-deficient tumors exhibited more advanced histologic severity and more prominent inflammation and vascularity. Thus, Pten inactivation cooperated with oncogenic K-ras in promoting lung tumorigenesis.
Assuntos
Transformação Celular Neoplásica/genética , Genes ras , Neoplasias Pulmonares/genética , PTEN Fosfo-Hidrolase/genética , Adenocarcinoma Bronquioloalveolar/irrigação sanguínea , Adenocarcinoma Bronquioloalveolar/genética , Adenocarcinoma Bronquioloalveolar/metabolismo , Adenocarcinoma Bronquioloalveolar/patologia , Alelos , Animais , Transformação Celular Neoplásica/metabolismo , Quimiocinas/biossíntese , Quimiocinas/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/genética , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , PTEN Fosfo-Hidrolase/biossíntese , PTEN Fosfo-Hidrolase/deficiência , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de SinaisRESUMO
Angiogenesis is required for lung cancer growth, which is mediated by various growth factors such as vascular endothelial growth factor (VEGF). Increases in VEGF and angiogenesis have been correlated with poor prognosis and survival in patients with lung cancer. In addition, recent reports show that estradiol and nicotine play important roles in lung tumor initiation and progression. In this report, we demonstrate that estradiol and nicotine exposure enhances the growth of A549 bronchioloalveolar carcinoma xenografts in mice through the stimulation of cell proliferation, VEGF secretion and angiogenesis. We detect a four-fold increase in microvascular density in tumors from mice exposed to estradiol and nicotine compared to control tumors resulting in an increase in tumor growth. Intriguingly, the effects on angiogenesis and tumor growth by the combination of agents were additive when compared to either agent alone. Furthermore, estradiol promotes VEGF secretion from various non-small cell lung carcinoma (NSCLC) cells and this effect is augmented by nicotine in a tumor xenograft model. These results indicate that aside from their roles in promoting cell proliferation, estradiol and nicotine appear to have additive effects on the induction of angiogenesis through the stimulation of VEGF secretion during NSCLC progression.
Assuntos
Adenocarcinoma Bronquioloalveolar/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Estradiol/farmacologia , Neoplasias Pulmonares/metabolismo , Neovascularização Patológica/etiologia , Nicotina/farmacologia , Adenocarcinoma Bronquioloalveolar/irrigação sanguínea , Adenocarcinoma Bronquioloalveolar/patologia , Animais , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Estradiol/administração & dosagem , Feminino , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Transplante de Neoplasias , Nicotina/administração & dosagem , Transplante Heterólogo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
AIM: Bronchioloalveolar carcinomas (BACs) are rare primitive lung adenocarcinomas growing along the alveolar septum without stromal, vascular or pleural invasion. We report an immunohistochemical study of their vascular microenvironment. METHODS AND RESULTS: In three mucinous BACs (M-BAC) and three non-mucinous BACs (NM-BAC) we examined the following parameters in comparison with the normal lung: (i) constituents of the alveolar extracellular matrix; (ii) qualitative and quantitative changes of alveolar capillaries; and (iii) expression of vascular endothelial growth factor (VEGF) by tumour cells. In M-BAC, the alveolar matrix was unchanged compared with the normal parenchyma. Capillaries expressed normal alveolar endothelial markers and their average surface was calculated, as in normal lung, as 8%. VEGF was negative in tumour cells. In NM-BAC, the alveolar wall was thickened by deposits of fibronectin and type III collagen containing myofibroblasts and the basement membrane was disrupted. Capillaries did not retain alveolar endothelial markers and their surface was calculated as 19%. Tumour cells expressed high levels of VEGF. CONCLUSIONS: In contrast to NM-BAC, M-BAC do not modify the alveolar structure and seem to exploit the normal alveolar vascular bed to grow, without inducing neoangiogenesis. A better understanding of the mechanisms of growth of lung cancers may have implications for future anti-angiogenic therapeutic strategies.
Assuntos
Adenocarcinoma Bronquioloalveolar/patologia , Adenocarcinoma Mucinoso/patologia , Matriz Extracelular/metabolismo , Neoplasias Pulmonares/patologia , Adenocarcinoma Bronquioloalveolar/irrigação sanguínea , Adenocarcinoma Bronquioloalveolar/metabolismo , Adenocarcinoma Mucinoso/irrigação sanguínea , Adenocarcinoma Mucinoso/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/metabolismo , Neovascularização Patológica , Fator A de Crescimento do Endotélio Vascular/biossínteseRESUMO
The three-dimensional architecture of blood vessels within lung adenocarcinomas has not been well studied. In 19 cases with bronchioloalveolar carcinoma with central fibrosis, we three-dimensionally examined blood vessel architecture in 150 microm thick sections stained with elastin staining and anti-CD34 antibody. We examined four regions: normal alveoli and three regions within the tumor including an area adjacent to the normal alveoli (external area), an area in which tumor cells were replacing epithelial cells (replacement area), and a central fibrotic area (fibrotic area). Elastin staining showed that elastic fibers formed the framework of the alveoli, and the alveolar structure shrank more strongly to the center of the tumor due to folding of alveolar walls invaded by adenocarcinoma cells. We also measured three vessel parameters in these four regions. The vessel diameters were 4.08+/-1.10 microm, 3.95+/-1.02 microm, 5.04+/-1.56 microm, and 6.11+/-2.23 microm, the circumferences of those vessels seen as complete circles were 43.11+/-12.78 microm, 43.71+/-12.87 microm, 95.21+/-39.32 microm, and 126.77+/-54.65 microm; the lengths between vessel bifurcations were 13.28+/-3.08 microm, 13.47+/-4.58 microm, 24.91+/-9.66 microm, and 41.82+/-28.08 microm in the normal alveoli, and the external, replacement, and fibrotic areas, respectively. Blood vessel architecture changed such that the vessels became larger and coarser towards the center of the tumor. Our three-dimensional analysis suggests continuous remodeling of alveolar capillaries rather than angiogenesis within bronchioloalveolar carcinoma.
Assuntos
Adenocarcinoma Bronquioloalveolar/irrigação sanguínea , Vasos Sanguíneos/patologia , Imageamento Tridimensional , Neoplasias Pulmonares/irrigação sanguínea , Alvéolos Pulmonares/irrigação sanguínea , Humanos , Neovascularização Patológica/patologia , Fibrose Pulmonar/patologiaRESUMO
OBJECTIVE: Bronchioloalveolar lung carcinoma (BAC) is characterized by bronchial and lymphatic dissemination explaining multifocal and bilateral spreading. Bilateral BAC is usually considered as a contraindication to surgery. Regarding poor efficacy of symptomatic and oncological treatments, we hypothesized that surgery might play a role to palliate hypoxemia associated with serious intrapulmonary shunting, as well as continuous bronchorrhea. METHODS: We retrospectively studied here four consecutive patients, who underwent palliative pneumonectomy. RESULTS: The shunt was confirmed again at the time of the surgery by a pulmonary artery occlusion demonstrating immediate improvement in arterial oxygen saturation from 89% at baseline to 98% after occlusion. Lung resections consisted of a left pneumonectomy in three cases and a right pneumonectomy in one. PaO(2) levels under 5l/min oxygen therapy improved dramatically when comparing preoperative data (mean 50.5 mmHg) to post-operative results (mean 150 mmHg). One patient died postoperatively. Three patients, who experienced an uneventful immediate post-operative course, received chemotherapy after surgery. Improvement of quality of life is testified by the absence of both symptoms and any need for oxygen therapy for few months. Disabling symptoms reappeared at 1, 8 and 10 months. Survival of these patients was 3, 12 and 18 months. CONCLUSIONS: These results support the interest of consideration of a surgical resection for highly selected patients presenting with bilateral BAC and severe intrapulmonary shunting.
Assuntos
Adenocarcinoma Bronquioloalveolar/cirurgia , Neoplasias Pulmonares/cirurgia , Pneumonectomia , Adenocarcinoma Bronquioloalveolar/irrigação sanguínea , Idoso , Feminino , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The antitumor efficiency of secondary lymphoid organ chemokine (SLC), a CC chemokine that chemoattracts both dendritic cells (DCs) and T lymphocytes,was evaluated in SV40 large T-antigen transgenic mice that develop bilateral multifocal pulmonary adenocarcinomas. Injection of recombinant SLC in the axillary lymph node region led to a marked reduction in tumor burden with extensive lymphocytic and DC infiltration of the tumors and enhanced survival. SLC injection led to significant increases in CD4 and CD8 lymphocytes as well as DC at the tumor sites, lymph nodes, and spleen. The cellular infiltrates were accompanied by the enhanced elaboration of Type 1 cytokines and the antiangiogenic chemokines IFN-gamma inducible protein 10, and monokine induced by IFN-gamma (MIG). In contrast, lymph node and tumor site production of the immunosuppressive cytokine transforming growth factor beta was decreased in response to SLC treatment. In vitro, after stimulation with irradiated autologous tumor, splenocytes from SLC-treated mice secreted significantly more IFN-gamma and granulocyte macrophage colony-stimulating factor, but reduced levels of interleukin 10. Significant reduction in tumor burden in a model in which tumors develop in an organ-specific manner provides a strong rationale for additional evaluation of SLC in regulation of tumor immunity and its use in lung cancer immunotherapy.
Assuntos
Adenocarcinoma Bronquioloalveolar/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Quimiocinas CC/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma Bronquioloalveolar/irrigação sanguínea , Adenocarcinoma Bronquioloalveolar/genética , Adenocarcinoma Bronquioloalveolar/imunologia , Inibidores da Angiogênese/metabolismo , Animais , Antígenos Transformantes de Poliomavirus/genética , Antígenos Transformantes de Poliomavirus/imunologia , Quimiocina CCL21 , Quimiocinas/metabolismo , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Fatores de Crescimento Endotelial/metabolismo , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Linfonodos/citologia , Linfonodos/imunologia , Linfocinas/metabolismo , Camundongos , Camundongos Transgênicos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Proteínas Recombinantes/farmacologia , Baço/citologia , Baço/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Fator de Crescimento Transformador beta/metabolismo , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularAssuntos
Adenocarcinoma Bronquioloalveolar/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adenocarcinoma Bronquioloalveolar/irrigação sanguínea , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Sensibilidade e EspecificidadeAssuntos
Adenocarcinoma Bronquioloalveolar/diagnóstico por imagem , Fístula Arteriovenosa/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Artéria Pulmonar/diagnóstico por imagem , Veias Pulmonares/diagnóstico por imagem , Adenocarcinoma Bronquioloalveolar/irrigação sanguínea , Idoso , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Masculino , RadiografiaRESUMO
Bronchioloalveolar carcinoma caused severe refractory hypoxemia due to intrapulmonary shunting in a patient. Preoperative evaluation by occlusion of the pulmonary lobar artery supplying the tumor showed normalization of the arterial oxygen saturation. Resection of the involved lobe corrected the intrapulmonary shunting, and the patient required no further supplemental oxygen. However, with recurrence of the tumor over the next 6 months the patient became progressively more hypoxemic and died.
Assuntos
Adenocarcinoma Bronquioloalveolar/complicações , Hipóxia/etiologia , Neoplasias Pulmonares/complicações , Circulação Pulmonar , Adenocarcinoma Bronquioloalveolar/irrigação sanguínea , Idoso , Humanos , Neoplasias Pulmonares/irrigação sanguínea , MasculinoRESUMO
The authors reviewed computed tomographic (CT) scans of 12 patients with lobar bronchioloalveolar carcinoma. Seven patients had consolidation of the entire lobe, and five patients had segmental consolidation. After contrast material was administered intravenously, the consolidated lung typically appeared on the scan as an area of homogeneous low attenuation, within which were enhanced branching pulmonary vessels (the CT angiogram sign). To evaluate the specificity of this sign in the discrimination of bronchioloalveolar carcinoma, CT scans of 26 patients who had lobar consolidation from other diseases were randomly mixed with the CT scans of 11 patients with bronchioloalveolar carcinoma. Two independent observers who were unfamiliar with the cases classified 10 and nine of the 11 patients with bronchioloalveolar carcinoma, respectively, as positive for bronchioloalveolar carcinoma by applying the CT angiogram sign, and classified as negative 25 and 23 of the 26 patients without bronchioloalveolar carcinoma, respectively, for an overall specificity of 92.3%. The angiogram sign appeared on the CT scan because of the low-attenuating consolidation, which was caused by the production of mucin or other fluid and the intact bronchovascular framework within the tumor.
Assuntos
Adenocarcinoma Bronquioloalveolar/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adenocarcinoma Bronquioloalveolar/irrigação sanguínea , Meios de Contraste , Feminino , Humanos , Ácido Iotalâmico , Neoplasias Pulmonares/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/diagnóstico por imagem , Veias Pulmonares/diagnóstico por imagemRESUMO
A patient with bronchiolo-alveolar cell carcinoma presented with a veno-arterial shunt localized to the area of tumor involvement by differential position shunt testing. Perfusion lung scan revealed increased radionucleotide uptake in the area of the tumor, confirmed by pulmonary angiography, and suggested that the primary blood supply to the tumor was originating from the pulmonary circulation. Surgical resection of the tumor resulted in marked reduction of the intrapulmonary shunt.