RESUMO
Antiangiogenic therapy with antibodies against VEGF (bevacizumab) or VEGFR2 (ramucirumab) has been proven efficacious in colorectal cancer (CRC) patients. However, the improvement in overall survival is modest and only in combination with chemotherapy. Thus, there is an urgent need to identify potential underlying mechanisms of resistance specific to antiangiogenic therapy and develop strategies to overcome them. Here we found that anti-VEGFR2 therapy up-regulates both C-X-C chemokine ligand 12 (CXCL12) and C-X-C chemokine receptor 4 (CXCR4) in orthotopic murine CRC models, including SL4 and CT26. Blockade of CXCR4 signaling significantly enhanced treatment efficacy of anti-VEGFR2 treatment in both CRC models. CXCR4 was predominantly expressed in immunosuppressive innate immune cells, which are recruited to CRCs upon anti-VEGFR2 treatment. Blockade of CXCR4 abrogated the recruitment of these innate immune cells. Importantly, these myeloid cells were mostly Ly6Clow monocytes and not Ly6Chigh monocytes. To selectively deplete individual innate immune cell populations, we targeted key pathways in Ly6Clow monocytes (Cx3cr1-/- mice), Ly6Chigh monocytes (CCR2-/- mice), and neutrophils (anti-Ly6G antibody) in combination with CXCR4 blockade in SL4 CRCs. Depletion of Ly6Clow monocytes or neutrophils improved anti-VEGFR2-induced SL4 tumor growth delay similar to the CXCR4 blockade. In CT26 CRCs, highly resistant to anti-VEGFR2 therapy, CXCR4 blockade enhanced anti-VEGFR2-induced tumor growth delay but specific depletion of Ly6G+ neutrophils did not. The discovery of CXCR4-dependent recruitment of Ly6Clow monocytes in tumors unveiled a heretofore unknown mechanism of resistance to anti-VEGF therapies. Our findings also provide a rapidly translatable strategy to enhance the outcome of anti-VEGF cancer therapies.
Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias Colorretais/terapia , Monócitos/imunologia , Neutrófilos/imunologia , Receptores CXCR4/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Antígenos Ly/metabolismo , Benzilaminas , Bevacizumab/farmacologia , Proliferação de Células , Quimiocina CXCL12/biossíntese , Ciclamos , Compostos Heterocíclicos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/biossíntese , Células Tumorais Cultivadas , RamucirumabRESUMO
With the current epidemic of obesity, a large number of patients diagnosed with cancer are overweight or obese. Importantly, this excess body weight is associated with tumor progression and poor prognosis. The mechanisms for this worse outcome, however, remain poorly understood. We review here the epidemiological evidence for the association between obesity and cancer, and discuss potential mechanisms focusing on angiogenesis and inflammation. In particular, we will discuss how the dysfunctional angiogenesis and inflammation occurring in adipose tissue in obesity may promote tumor progression, resistance to chemotherapy, and targeted therapies such as anti-angiogenic and immune therapies. Better understanding of how obesity fuels tumor progression and therapy resistance is essential to improve the current standard of care and the clinical outcome of cancer patients. To this end, we will discuss how an anti-diabetic drug such as metformin can overcome these adverse effects of obesity on the progression and treatment resistance of tumors.
Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Metformina/uso terapêutico , Neoplasias , Neovascularização Patológica , Obesidade , Animais , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologiaRESUMO
Brain metastases are a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer. Although extracranial disease is controlled with HER2 inhibitors in the majority of patients, brain metastases often develop. Because these brain metastases do not respond to therapy, they are frequently the reason for treatment failure. We developed a mouse model of HER2-amplified breast cancer brain metastasis using an orthotopic xenograft of BT474 cells. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib controlled tumor progression in the breast but failed to contain tumor growth in the brain. We observed that the combination of a HER2 inhibitor with an anti-VEGF receptor-2 (VEGFR2) antibody significantly slows tumor growth in the brain, resulting in a striking survival benefit. This benefit appears largely due to an enhanced antiangiogenic effect: Combination therapy reduced both the total and functional microvascular density in the brain xenografts. In addition, the combination therapy led to a marked increase in necrosis of the brain lesions. Moreover, we observed even better antitumor activity after combining both trastuzumab and lapatinib with the anti-VEGFR2 antibody. This triple-drug combination prolonged the median overall survival fivefold compared with the control-treated group and twofold compared with either two-drug regimen. These findings support the clinical development of this three-drug regimen for the treatment of HER2-amplified breast cancer brain metastases.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/tratamento farmacológico , Amplificação de Genes , Terapia de Alvo Molecular , Receptor ErbB-2/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/patologia , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/patologia , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diagnóstico por Imagem , Modelos Animais de Doenças , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/patologia , Lapatinib , Camundongos , Necrose , Neovascularização Patológica/tratamento farmacológico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Análise de Sobrevida , Trastuzumab , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Anti-vascular endothelial growth factor (VEGF) therapy has failed to improve survival in patients with breast cancer (BC). Potential mechanisms of resistance to anti-VEGF therapy include the up-regulation of alternative angiogenic and proinflammatory factors. Obesity is associated with hypoxic adipose tissues, including those in the breast, resulting in increased production of some of the aforementioned factors. Hence, we hypothesized that obesity could contribute to anti-VEGF therapy's lack of efficacy. We found that BC patients with obesity harbored increased systemic concentrations of interleukin-6 (IL-6) and/or fibroblast growth factor 2 (FGF-2), and their tumor vasculature was less sensitive to anti-VEGF treatment. Mouse models revealed that obesity impairs the effects of anti-VEGF on angiogenesis, tumor growth, and metastasis. In one murine BC model, obesity was associated with increased IL-6 production from adipocytes and myeloid cells within tumors. IL-6 blockade abrogated the obesity-induced resistance to anti-VEGF therapy in primary and metastatic sites by directly affecting tumor cell proliferation, normalizing tumor vasculature, alleviating hypoxia, and reducing immunosuppression. Similarly, in a second mouse model, where obesity was associated with increased FGF-2, normalization of FGF-2 expression by metformin or specific FGF receptor inhibition decreased vessel density and restored tumor sensitivity to anti-VEGF therapy in obese mice. Collectively, our data indicate that obesity fuels BC resistance to anti-VEGF therapy via the production of inflammatory and angiogenic factors.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Fator 2 de Crescimento de Fibroblastos/metabolismo , Interleucina-6/metabolismo , Obesidade/complicações , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Antineoplásicos/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Metformina/uso terapêutico , Camundongos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Current anti-VEGF therapies for colorectal cancer (CRC) provide limited survival benefit, as tumors rapidly develop resistance to these agents. Here, we have uncovered an immunosuppressive role for nonclassical Ly6Clo monocytes that mediates resistance to anti-VEGFR2 treatment. We found that the chemokine CX3CL1 was upregulated in both human and murine tumors following VEGF signaling blockade, resulting in recruitment of CX3CR1+Ly6Clo monocytes into the tumor. We also found that treatment with VEGFA reduced expression of CX3CL1 in endothelial cells in vitro. Intravital microscopy revealed that CX3CR1 is critical for Ly6Clo monocyte transmigration across the endothelium in murine CRC tumors. Moreover, Ly6Clo monocytes recruit Ly6G+ neutrophils via CXCL5 and produce IL-10, which inhibits adaptive immunity. Preventing Ly6Clo monocyte or Ly6G+ neutrophil infiltration into tumors enhanced inhibition of tumor growth with anti-VEGFR2 therapy. Furthermore, a gene therapy using a nanoparticle formulated with an siRNA against CX3CL1 reduced Ly6Clo monocyte recruitment and improved outcome of anti-VEGFR2 therapy in mouse CRCs. Our study unveils an immunosuppressive function of Ly6Clo monocytes that, to our knowledge, has yet to be reported in any context. We also reveal molecular mechanisms underlying antiangiogenic treatment resistance, suggesting potential immunomodulatory strategies to enhance the long-term clinical outcome of anti-VEGF therapies.
Assuntos
Antígenos Ly/metabolismo , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Terapia de Imunossupressão , Monócitos/citologia , Neoplasias/tratamento farmacológico , Receptores de Quimiocinas/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Anticorpos Monoclonais/farmacologia , Receptor 1 de Quimiocina CX3C , Linhagem Celular Tumoral , Quimiocina CX3CL1/metabolismo , Humanos , Microscopia Intravital , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas/química , Neutrófilos/metabolismo , RNA Interferente Pequeno/metabolismo , Regulação para CimaRESUMO
Purpose: Angiotensin system inhibitors (ASI) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients.Experimental Design: We performed an analysis of the records of ASI users and nonuser patients with PDAC seen at Massachusetts General Hospital (Boston, MA) between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA sequencing (RNA-Seq) of resected primary lesions.Results: A total of 794 consecutive patients were included. In 299 resected patients, ASI users experienced longer overall survival (OS) in both univariate (median OS, 36.3 vs. 19.3 months, P = 0.011) and adjusted multivariate [HR, 0.505; 95% confidence interval (CI), 0.339-0.750; P = 0.001] analyses. Propensity score-adjusted analysis also showed a longer median OS for chronic ASI users. In unresected patients, the beneficial effect of ASIs was significant in patients with locally advanced disease, but not in metastatic patients. RNA-Seq analysis revealed in tumors of ASI users (lisinopril) a normalized extracellular matrix, a reduced expression of genes involved in PDAC progression (e.g., WNT and Notch signaling), and an increased expression of genes linked with the activity of T cells and antigen-presenting cells. Finally, chronic use of ASI was associated with a gene expression signature that is predictive of survival in independent validation cohorts.Conclusions: In patients with nonmetastatic PDAC, chronic ASI use is associated with longer OS independently of chemotherapy. Our RNA-Seq analysis suggests that ASIs reduce the malignant potential of cancer cells and stimulate the immune microenvironment in primary PDAC. Clin Cancer Res; 23(19); 5959-69. ©2017 AACR.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/imunologia , Angiotensinas/antagonistas & inibidores , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/imunologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Angiotensinas/imunologia , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , PrognósticoRESUMO
Solid stress and tissue stiffness affect tumour growth, invasion, metastasis and treatment. Unlike stiffness, which can be precisely mapped in tumours, the measurement of solid stresses is challenging. Here, we show that two-dimensional spatial mappings of solid stress and the resulting elastic energy in excised or in situ tumours with arbitrary shapes and wide size ranges can be obtained via three distinct and quantitative techniques that rely on the measurement of tissue displacement after disruption of the confining structures. Application of these methods in models of primary tumours and metastasis revealed that: (i) solid stress depends on both cancer cells and their microenvironment; (ii) solid stress increases with tumour size; and (iii) mechanical confinement by the surrounding tissue significantly contributes to intratumoural solid stress. Further study of the genesis and consequences of solid stress, facilitated by the engineering principles presented here, may lead to significant discoveries and new therapies.
RESUMO
UNLABELLED: It remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacologic inhibition of angiotensin-II type-1 receptor reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSC) in obesity is induced by tumor-associated neutrophils (TAN) recruited by adipocyte-secreted IL1ß. PSCs further secrete IL1ß, and inactivation of PSCs reduces IL1ß expression and TAN recruitment. Furthermore, depletion of TANs, IL1ß inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In patients with pancreatic cancer, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that cross-talk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity. SIGNIFICANCE: Considering the current obesity pandemic, unraveling the mechanisms underlying obesity-induced cancer progression is an urgent need. We found that the aggravation of desmoplasia is a key mechanism of obesity-promoted PDAC progression. Importantly, we discovered that clinically available antifibrotic/inflammatory agents can improve the treatment response of PDAC in obese hosts. Cancer Discov; 6(8); 852-69. ©2016 AACR.See related commentary by Bronte and Tortora, p. 821This article is highlighted in the In This Issue feature, p. 803.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Inflamação/etiologia , Inflamação/patologia , Obesidade/complicações , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Receptor Tipo 1 de Angiotensina/metabolismo , Tecido Adiposo/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Índice de Massa Corporal , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Terapia Combinada , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fibrose , Predisposição Genética para Doença , Humanos , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Knockout , Modelos Biológicos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Obesidade/etiologia , Neoplasias Pancreáticas/etiologia , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral , Microambiente TumoralRESUMO
PURPOSE: Obesity promotes pancreatic and breast cancer progression via mechanisms that are poorly understood. Although obesity is associated with increased systemic levels of placental growth factor (PlGF), the role of PlGF in obesity-induced tumor progression is not known. PlGF and its receptor VEGFR-1 have been shown to modulate tumor angiogenesis and promote tumor-associated macrophage (TAM) recruitment and activity. Here, we hypothesized that increased activity of PlGF/VEGFR-1 signaling mediates obesity-induced tumor progression by augmenting tumor angiogenesis and TAM recruitment/activity. EXPERIMENTAL DESIGN: We established diet-induced obese mouse models of wild-type C57BL/6, VEGFR-1 tyrosine kinase (TK)-null, or PlGF-null mice, and evaluated the role of PlGF/VEGFR-1 signaling in pancreatic and breast cancer mouse models and in human samples. RESULTS: We found that obesity increased TAM infiltration, tumor growth, and metastasis in pancreatic cancers, without affecting vessel density. Ablation of VEGFR-1 signaling prevented obesity-induced tumor progression and shifted the tumor immune environment toward an antitumor phenotype. Similar findings were observed in a breast cancer model. Obesity was associated with increased systemic PlGF, but not VEGF-A or VEGF-B, in pancreatic and breast cancer patients and in various mouse models of these cancers. Ablation of PlGF phenocopied the effects of VEGFR-1-TK deletion on tumors in obese mice. PlGF/VEGFR-1-TK deletion prevented weight gain in mice fed a high-fat diet, but exacerbated hyperinsulinemia. Addition of metformin not only normalized insulin levels but also enhanced antitumor immunity. CONCLUSIONS: Targeting PlGF/VEGFR-1 signaling reprograms the tumor immune microenvironment and inhibits obesity-induced acceleration of tumor progression. Clin Cancer Res; 22(12); 2993-3004. ©2016 AACR.
Assuntos
Neoplasias da Mama/patologia , Macrófagos/metabolismo , Obesidade/patologia , Neoplasias Pancreáticas/patologia , Fator de Crescimento Placentário/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Neoplasias da Mama/imunologia , Dieta Hiperlipídica , Feminino , Glucose/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Macrófagos/imunologia , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Neovascularização Patológica/genética , Obesidade/imunologia , Neoplasias Pancreáticas/imunologia , Fator de Crescimento Placentário/genética , Prognóstico , Transdução de Sinais , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
The survival benefit of anti-vascular endothelial growth factor (VEGF) therapy in metastatic colorectal cancer (mCRC) patients is limited to a few months because of acquired resistance. We show that anti-VEGF therapy induced remodeling of the extracellular matrix with subsequent alteration of the physical properties of colorectal liver metastases. Preoperative treatment with bevacizumab in patients with colorectal liver metastases increased hyaluronic acid (HA) deposition within the tumors. Moreover, in two syngeneic mouse models of CRC metastasis in the liver, we show that anti-VEGF therapy markedly increased the expression of HA and sulfated glycosaminoglycans (sGAGs), without significantly changing collagen deposition. The density of these matrix components correlated with increased tumor stiffness after anti-VEGF therapy. Treatment-induced tumor hypoxia appeared to be the driving force for the remodeling of the extracellular matrix. In preclinical models, we show that enzymatic depletion of HA partially rescued the compromised perfusion in liver mCRCs after anti-VEGF therapy and prolonged survival in combination with anti-VEGF therapy and chemotherapy. These findings suggest that extracellular matrix components such as HA could be a potential therapeutic target for reducing physical barriers to systemic treatments in patients with mCRC who receive anti-VEGF therapy.
Assuntos
Bevacizumab/uso terapêutico , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/efeitos adversos , Fenômenos Biomecânicos , Linhagem Celular Tumoral , Neoplasias Colorretais/terapia , Resistencia a Medicamentos Antineoplásicos , Matriz Extracelular/patologia , Matriz Extracelular/fisiologia , Glicosaminoglicanos/metabolismo , Humanos , Ácido Hialurônico/metabolismo , Hipóxia/etiologia , Hipóxia/fisiopatologia , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pesquisa Translacional BiomédicaRESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor with a dismal prognosis for most patients. Fibrosis and inflammation are hallmarks of tumor desmoplasia. We have previously demonstrated that preventing the activation of pancreatic stellate cells (PSCs) and alleviating desmoplasia are beneficial strategies in treating PDAC. Metformin is a widely used glucose-lowering drug. It is also frequently prescribed to diabetic pancreatic cancer patients and has been shown to associate with a better outcome. However, the underlying mechanisms of this benefit remain unclear. Metformin has been found to modulate the activity of stellate cells in other disease settings. In this study, we examine the effect of metformin on PSC activity, fibrosis and inflammation in PDACs. METHODS/RESULTS: In overweight, diabetic PDAC patients and pre-clinical mouse models, treatment with metformin reduced levels of tumor extracellular matrix (ECM) components, in particular hyaluronan (HA). In vitro, we found that metformin reduced TGF-ß signaling and the production of HA and collagen-I in cultured PSCs. Furthermore, we found that metformin alleviates tumor inflammation by reducing the expression of inflammatory cytokines including IL-1ß as well as infiltration and M2 polarization of tumor-associated macrophages (TAMs) in vitro and in vivo. These effects on macrophages in vitro appear to be associated with a modulation of the AMPK/STAT3 pathway by metformin. Finally, we found in our preclinical models that the alleviation of desmoplasia by metformin was associated with a reduction in ECM remodeling, epithelial-to-mesenchymal transition (EMT) and ultimately systemic metastasis. CONCLUSION: Metformin alleviates the fibro-inflammatory microenvironment in obese/diabetic individuals with pancreatic cancer by reprogramming PSCs and TAMs, which correlates with reduced disease progression. Metformin should be tested/explored as part of the treatment strategy in overweight diabetic PDAC patients.
Assuntos
Macrófagos/efeitos dos fármacos , Metformina/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Células Estreladas do Pâncreas/efeitos dos fármacos , Células Estreladas do Pâncreas/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/metabolismo , Células Estreladas do Pâncreas/metabolismo , Prognóstico , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Cancers with specific genetic mutations are susceptible to selective kinase inhibitors. However, there is a wide spectrum of benefit among cancers harboring the same sensitizing genetic mutations. Herein, we measured apoptotic rates among cell lines sharing the same driver oncogene following treatment with the corresponding kinase inhibitor. There was a wide range of kinase inhibitor-induced apoptosis despite comparable inhibition of the target and associated downstream signaling pathways. Surprisingly, pretreatment RNA levels of the BH3-only pro-apoptotic BIM strongly predicted the capacity of EGFR, HER2, and PI3K inhibitors to induce apoptosis in EGFR-mutant, HER2-amplified, and PIK3CA-mutant cancers, respectively, but BIM levels did not predict responsiveness to standard chemotherapies. Furthermore, BIM RNA levels in EGFR-mutant lung cancer specimens predicted response and duration of clinical benefit from EGFR inhibitors. These findings suggest assessment of BIM levels in treatment-naïve tumor biopsies may indicate the degree of benefit from single-agent kinase inhibitors in multiple oncogene-addiction paradigms.
Assuntos
Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/genética , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Proteína 11 Semelhante a Bcl-2 , Linhagem Celular Tumoral , Estudos de Coortes , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Oncogenes , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Transdução de Sinais/efeitos dos fármacosRESUMO
Evidence has been gathered regarding the association between angiogenesis and inflammation in pathological situations. These two phenomena have long been coupled together in many chronic inflammatory disorders with distinct etiopathogenic origin, including psoriasis, rheumatoid arthritis, Crohn's disease, diabetes, and cancer. Lately, this concept has further been substantiated by the finding that several previously established non-inflammatory disorders, such as osteoarthritis and obesity, display both inflammation and angiogenesis in an exacerbated manner. In addition, the interplay between inflammatory cells, endothelial cells and fibroblasts in chronic inflammation sites, together with the fact that inflammation and angiogenesis can actually be triggered by the same molecular events, further strengthen this association. Therefore, elucidating the underlying cellular and molecular mechanisms that gather together the two processes is mandatory in order to understand their synergistic effect, and to develop new therapeutic approaches for the management of these disorders that cause a great deal of discomfort, disability, and in some cases death.
Assuntos
Inflamação/tratamento farmacológico , Neovascularização Patológica , Animais , Doença Crônica , Citocinas/fisiologia , Modelos Animais de Doenças , Humanos , Inflamação/etiologia , Inflamação/fisiopatologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Modelos Biológicos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/etiologia , Neovascularização Patológica/fisiopatologiaRESUMO
Angiogenesis is a complex multistep process that comprises proliferation, migration, and anastomosis of endothelial cells, followed by stabilization of the newly formed vessel through the attachment of support cells. This process is imbalanced in a large number of disorders, including cardiovascular disease, diabetes and cancer. Evidence indicates that xanthohumol (XN), a prenylated chalcone present in beer, exerts anti-angiogenic properties. However, its precise effect within the angiogenic steps is not accurately established. The purpose of the present study was to examine which features of the angiogenic process can be disturbed by XN. Human umbilical vein endothelial cells (HUVEC) and human fetal aortic smooth muscle cells (SMC) were incubated with xanthohumol at 5 and 10 µM, and cell viability, apoptosis, invasion and capillary-like structures formation were examined. Treatment with 10 µM XN significantly decreased viability and invasion capacity and increased apoptosis in both cell types as assessed by MTT, double-chamber assay and TUNEL assay respectively. The two concentrations of XN further led to a significant reduction in the number of capillary-like structures, when HUVEC were cultured on growth factor reduced-Matrigel-coated plates. Interestingly, XN exhibited the opposite effect when HUVEC were co-cultured with SMC, leading to an increase in the number of cord structures. In addition, incubation of both types of cells with XN resulted in reduced activity of NFκB, a transcription factor implicated in these cell fates. Given the absence of adverse effects in mature vasculature by XN, these findings emphasize the potential use of XN against pathological situations where angiogenesis is stimulated.