RESUMEN
BACKGROUND: Treatment with immune checkpoint inhibitors (ICIs) targeting CTLA-4 and the PD-1/PD-L1 axis is effective against many cancer types. However, due in part to unresponsiveness or acquired resistance, not all patients experience a durable response to ICIs. HBI-8000 is a novel, orally bioavailable class I selective histone deacetylase inhibitor that directly modifies antitumor activity by inducing apoptosis, cell cycle arrest, and resensitization to apoptotic stimuli in adult T cell lymphoma patients. We hypothesized that HBI-8000 functions as an epigenetic immunomodulator to reprogram the tumor microenvironment from immunologically cold (nonresponsive) to hot (responsive). METHOD: Mice bearing syngeneic tumors (MC38 and CT26 murine colon carcinoma and A20 B-cell lymphoma were treated daily with HBI-8000 (orally), alone or in combination with PD-1, PD-1 L, or CTLA-4 antibodies. MC38 tumors were also analyzed in nanoString gene expression analysis. RESULTS: HBI-8000 augmented the activity of ICI antibodies targeting either PD-1, PD-L1 or CTLA-4, and significantly increased tumor regression (p < 0.05) in the above models. Gene expression analysis of the treated MC38 tumors revealed significant changes in mRNA expression of immune checkpoints, with enhanced dendritic cell and antigen-presenting cell functions, and modulation of MHC class I and II molecules. CONCLUSIONS: These findings suggest that HBI-8000 mediates epigenetic modifications in the tumor microenvironment, leading to improved efficacy of ICIs, and provide strong rationale for combination therapies with ICIs and HBI-8000 in the clinical setting. PRECIS: As an HDACi, HBI-8000 plays an important role in priming the immune system in the tumor microenvironment. The current preclinical data further justifies testing combination of HBI-8000 and ICIs in the clinic.
Asunto(s)
Benzamidas/farmacología , Neoplasias del Colon/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/farmacología , Factores Inmunológicos/farmacología , Piridinas/farmacología , Animales , Apoptosis , Proliferación Celular , Neoplasias del Colon/inmunología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Epigénesis Genética , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
HBI-8000 is a small molecule inhibitor of class I HDACs and has been approved for the treatment of PTCL, ATL and, in combination with exemestane, in a subpopulation of breast cancer. Given the roles of HDACs in normal and cancerous cells, there are currently multiple clinical trials, by HUYABIO International, to test the efficacy of HBI-8000 in monotherapy or in combination settings in leukemias and in solid tumors. The current review is focused on the applications of HDACi HBI-8000 in cancer therapy and its potential in combination with DDR agents.
RESUMEN
The identification and quantitative evaluation of lung tumors in mouse models is challenging and an unmet need in preclinical arena. In this study, we developed a noninvasive contrast-enhanced microCT (µCT) method to longitudinally evaluate and quantitate lung tumors in mice. Commercially available µCT contrast agents were compared to determine the optimal agent for visualization of thoracic blood vessels and lung tumors in naïve mice and in non-small-cell lung cancer models. Compared with the saline control, iopamidol and iodinated lipid agents provided only marginal increases in contrast resolution. The inorganic nanoparticulate agent provided the best contrast and visualization of thoracic vascular structures; the density contrast was highest at 15 min after injection and was stable for more than 4 h. Differential contrast of the tumors, vascular structures, and thoracic air space by the nanoparticulate agent enabled identification of tumor margins and accurate quantification. µCT data correlated closely with traditional histologic measurements (Pearson correlation coefficient, 0.995). Treatment of ELM4-ALK mice with crizotinib yielded 65% reduction in tumor size and thus demonstrated the utility of quantitative µCT in longitudinal preclinical trials. Overall and among the 3 agents we tested, the inorganic nanoparticulate product was the best commercially available contrast agent for visualization of thoracic blood vessels and lung tumors. Contrast-enhanced µCT imaging is an excellent noninvasive method for longitudinal evaluation during preclinical lung tumor studies.
Asunto(s)
Medios de Contraste , Modelos Animales de Enfermedad , Neoplasias Pulmonares/diagnóstico por imagen , Microtomografía por Rayos X/métodos , Animales , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: VEGF is one of the key drivers of physiological or pathological angiogenesis hence several VEGF inhibitors are in different stages of clinical development. To further dissect the role of VEGF in different stages of tumor progression in lung tumors, we utilized KrasG12D-LSL GEMMs (genetically engineered mouse models). METHODS: Intranasal delivery of adenoviruses expressing cre recombinase in KrasG12D-LSL mice results in the expression of mutant Kras that leads to development of tumor lesions ranging from adenomatous hyperplasia to large adenoma and adenocarcinoma over time in lung. In the current study, we treated KrasG12D-LSL mice at 14 weeks post inhalation with three different angiogenic inhibitors including axitinib and PF-00337210 both of which are selective inhibitors of VEGFR and sunitinib which targets VEGFR, C-SF1-R, PDGFR and KIT. RESULTS: Pathology findings showed no significant difference in percentage of adenomatous hyperplastic lesions between the vehicle vs. any of the treatments suggesting that angiogenesis may not play a major role at early stages of tumorigenesis. However, each inhibitor suppressed percentage of benign adenoma lesions and almost fully inhibited growth of adenocarcinoma lesions in the recipients which was consistent with a reduction in tumor vasculature. Treatment with sunitinib which is a multi-targeted RTKI did not provide any advantage compared to selective VEGFR inhibitor further emphasizing role of VEGF in tumor angiogenesis in this model. CONCLUSION: Overall, our studies indicate significance of VEGF and angiogenesis in a spontaneous model of lung tumorigenesis and provide a proof of mechanism for anti-cancer activity of VEGF inhibitors in this model.
Asunto(s)
Adenocarcinoma/irrigación sanguínea , Adenoma/irrigación sanguínea , Modelos Animales de Enfermedad , Hiperplasia/patología , Neoplasias Pulmonares/irrigación sanguínea , Neovascularización Patológica/patología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenoma/tratamiento farmacológico , Adenoma/metabolismo , Adenoma/patología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Hiperplasia/tratamiento farmacológico , Hiperplasia/metabolismo , Técnicas para Inmunoenzimas , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Mutación/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genética , Células Tumorales Cultivadas , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The role of PI3K and MAPK pathways in tumor initiation and progression is well established; hence, several inhibitors of these pathways are currently in different stages of clinical trials. Recent studies identified a PI3K/mTOR (PF-04691502) and a MEK inhibitor (PD-0325901) with strong potency and efficacy in different cell lines and tumor models. PD-0325901, however, showed adverse effects when administered at or above MTD (maximum tolerated dose) in the clinic. Here, we show in preclinical models that PD-0325901 at doses well below MTD (sub-MTD 1.5 mg/kg SID) is still a potent compound as single agent or in combination with PF-04691502. We first observed that PD-0325901 at 1.5 mg/kg SID and in combination with PF-04691502 (7.5 mg/kg; SID) significantly inhibited growth of H460 (carry Kras and PIK3CA mutations) orthotopic lung tumors. Additionally, we tested efficacy of PD-0325901 in Kras(G12D-LSL) conditional GEMMs (genetically engineered mouse models) which are a valuable tool in translational research to study tumor progression. Intranasal delivery of adenoviruses expressing Cre recombinase (Adeno-Cre) resulted in expression of mutant Kras leading to development of tumor lesions in lungs including adenomatous hyperplasia, large adenoma, and adenocarcinoma. Similar to H460 tumors, PD-0325901 as single agent or in combination with PF-04691502 significantly inhibited growth of tumor lesions in lungs in Kras(G12D-LSL) mice when treatment started at adenocarcinoma stage (at 14 weeks post-Adeno-Cre inhalation). In addition, immunohistochemistry showed inhibition of pS6 (phosphorylated ribosomal S6) in the treated animals particularly in the combination group providing a proof of mechanism for tumor growth inhibition. Finally, m-CT imaging in live Kras(G12D-LSL) mice showed reduction of tumor burdens in PD-0325901-treated animals at sub-MTD dose. In conclusion, our data suggest that PD-0325901 at doses below MTD is still a potent compound capable of tumor growth inhibition where Kras and/or PI3K are drivers of tumor growth and progression.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas p21(ras)/genética , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adenocarcinoma/enzimología , Adenocarcinoma del Pulmón , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Benzamidas/administración & dosificación , Línea Celular Tumoral , Difenilamina/administración & dosificación , Difenilamina/análogos & derivados , Relación Dosis-Respuesta a Droga , Heterocigoto , Humanos , Neoplasias Pulmonares/enzimología , Dosis Máxima Tolerada , Ratones , Ratones Mutantes , Trasplante de Neoplasias , Piridonas/administración & dosificación , Pirimidinas/administración & dosificaciónRESUMEN
Osteopontin (OPN), also known as SPP1 (secreted phosphoprotein), is an integrin binding glyco-phosphoprotein produced by a variety of tissues. In cancer patients expression of OPN has been associated with poor prognosis in several tumor types including breast, lung, and colorectal cancers. Despite wide expression in tumor cells and stroma, there is limited evidence supporting role of OPN in tumor progression and metastasis. Using phage display technology we identified a high affinity anti-OPN monoclonal antibody (hereafter AOM1). The binding site for AOM1 was identified as SVVYGLRSKS sequence which is immediately adjacent to the RGD motif and also spans the thrombin cleavage site of the human OPN. AOM1 efficiently inhibited OPNa binding to recombinant integrin αvß3 with an IC50 of 65 nM. Due to its unique binding site, AOM1 is capable of inhibiting OPN cleavage by thrombin which has been shown to produce an OPN fragment that is biologically more active than the full length OPN. Screening of human cell lines identified tumor cells with increased expression of OPN receptors (αvß3 and CD44v6) such as mesothelioma, hepatocellular carcinoma, breast, and non-small cell lung adenocarcinoma (NSCLC). CD44v6 and αvß3 were also found to be highly enriched in the monocyte, but not lymphocyte, subset of human peripheral blood mononuclear cells (hPBMCs). In vitro, OPNa induced migration of both tumor and hPBMCs in a transwell migration assay. AOM1 significantly blocked cell migration further validating its specificity for the ligand. OPN was found to be enriched in mouse plasma in a number of pre-clinical tumor model of non-small cell lung cancers. To assess the role of OPN in tumor growth and metastasis and to evaluate a potential therapeutic indication for AOM1, we employed a Kras(G12D-LSL)p53(fl/fl) subcutaneously implanted in vivo model of NSCLC which possesses a high capacity to metastasize into the lung. Our data indicated that treatment of tumor bearing mice with AOM1 as a single agent or in combination with Carboplatin significantly inhibited growth of large metastatic tumors in the lung further supporting a role for OPN in tumor metastasis and progression.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/secundario , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Osteopontina/metabolismo , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/metabolismo , Factores Quimiotácticos/química , Factores Quimiotácticos/inmunología , Factores Quimiotácticos/metabolismo , Modelos Animales de Enfermedad , Humanos , Fragmentos Fab de Inmunoglobulinas/inmunología , Fragmentos Fab de Inmunoglobulinas/metabolismo , Integrinas/metabolismo , Ratones , Ratones SCID , Datos de Secuencia Molecular , Osteopontina/química , Osteopontina/inmunología , Unión Proteica , Estabilidad Proteica , Trombina/metabolismoRESUMEN
It has been nearly 9years since the FDA (Food and Drug Administration) approved the first anti-angiogenic drug (bevacizumab) for treatment of metastatic colorectal cancer. Other angiogenic inhibitors have since been approved or are in different stages of clinical trials. However, continued clinical and preclinical investigations have identified major drawbacks associated with the application of this class of agents, including inherent/acquired resistance and induction of tumor invasiveness. In addition, lack of thoroughly validated predictive biomarkers has been one of the major hurdles to stratify cancer patients and to monitor tumor progression and response to the therapy. Investigations in clinic and preclinical models have provided some molecular and cellular mechanisms for the above challenges. This review aims to provide a concise update from recent findings.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de la Angiogénesis/efectos adversos , Biomarcadores de Tumor/metabolismo , Resistencia a Antineoplásicos , Humanos , Metástasis de la Neoplasia , Neoplasias/patología , Polimorfismo de Nucleótido Simple , Células del Estroma/fisiología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Recent studies in several tumor models indicated that treatment with angiogenic inhibitors may trigger induction of metastasis to other organs. Here we investigated modes of resistance and invasion in several tumor cell lines including 4T1 (breast), H460 (lung) and Colo205 (colorectal) using sunitinib at doses comparable to clinically utilized regimen. In comparison with vehicle-treated tumors, sunitinib increased metastasis to lung in 4T1 tumors and to peritoneal lymph node in Colo205 tumors. However, the same treatment did not induce invasiveness in H460 tumors, further suggesting that accelerating metastasis during treatment with angiogenic inhibitors is tumor cell-type dependent. Interestingly, Crizotinib (a dual inhibitor of c-Met and ALK pathways) as single agent or in combination with sunitinib reduced metastasis in all models tested suggesting a role for c-Met/HGF pathway in intrinsic- or sunitinib-induced-metastasis. Moreover, ELISA data showed that while c-Met is highly enriched in tumor cells, HGF is secreted mainly by the stroma (mouse HGF) suggesting a paracrine fashion for c-Met pathway activation in the tumors. In conclusion, our findings indicate that sunitinib-induced metastasis is tumor cell-type dependent and further supports a rationale for combination of anti-angiogenics and c-Met inhibition in the clinic.
Asunto(s)
Inhibidores de la Angiogénesis/efectos adversos , Neoplasias de la Mama/patología , Neoplasias Colorrectales/patología , Factor de Crecimiento de Hepatocito/metabolismo , Indoles/efectos adversos , Neoplasias Pulmonares/secundario , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirroles/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/irrigación sanguínea , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Ensayo de Inmunoadsorción Enzimática , Humanos , Indoles/uso terapéutico , Neoplasias Pulmonares/metabolismo , Metástasis Linfática , Ratones , Ratones Desnudos , Metástasis de la Neoplasia , Neovascularización Patológica/tratamiento farmacológico , Pirroles/uso terapéutico , Transducción de Señal/efectos de los fármacos , SunitinibRESUMEN
Molecular and cellular mechanisms underlying resistance/low responsiveness to antiangiogenic compounds are under extensive investigations. Both populations of tumor and stroma (nontumor compartment) seem to contribute in inherent/acquired resistance to antiangiogenic therapy. Here, investigating in vivo efficacy of sunitinib in experimental models resulted in the identification of tumors that were resistant/sensitive to the therapy. Analysis of tumor protein lysates indicated a greater concentration of hepatocyte growth factor (HGF) in resistant tumors than in sensitive ones. In addition, using flow cytometry, c-Met expression was found to be significantly higher in endothelial cells than in tumor cells, suggesting that HGF might target the vascular endothelial cells in resistant tumors. Combination of sunitinib and a selective c-Met inhibitor significantly inhibited tumor growth compared with sunitinib or c-Met inhibitor alone in resistant tumors. Histology and in vitro analyses suggested that combination treatment mainly targeted the vasculature in the resistant tumors. Conversely, systemic injection of HGF in the sensitive tumor models conferred resistance to sunitinib through maintenance of tumor angiogenesis. In conclusion, our study indicates a role for HGF/c-Met pathway in development of resistance to antiangiogenic therapy and suggests a potential strategy to circumvent resistance to vascular endothelial growth factor receptor tyrosine kinase inhibitor in the clinic.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Factor de Crecimiento de Hepatocito/metabolismo , Indoles/farmacología , Neoplasias Experimentales/irrigación sanguínea , Neoplasias Experimentales/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirroles/farmacología , Animales , Resistencia a Antineoplásicos , Factor de Crecimiento de Hepatocito/biosíntesis , Factor de Crecimiento de Hepatocito/genética , Humanos , Ratones , Ratones Desnudos , Células 3T3 NIH , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/biosíntesis , Proteínas Proto-Oncogénicas c-met/genética , Transducción de Señal , Sunitinib , TransfecciónRESUMEN
Recent studies suggest that tumor-associated CD11b(+)Gr1(+) myeloid cells contribute to refractoriness to antiangiogenic therapy with an anti-VEGF-A antibody. However, the mechanisms of peripheral mobilization and tumor-homing of CD11b(+)Gr1(+) cells are unclear. Here, we show that, compared with other cytokines [granulocyte-macrophage colony stimulating factor (GM-CSF), stromal derived factor 1alpha, and placenta growth factor], G-CSF and the G-CSF-induced Bv8 protein have preferential expression in refractory tumors. Treatment of refractory tumors with the combination of anti-VEGF and anti-G-CSF (or anti-Bv8) reduced tumor growth compared with anti-VEGF-A monotherapy. Anti-G-CSF treatment dramatically suppressed circulating or tumor-associated CD11b(+)Gr1(+) cells, reduced Bv8 levels, and affected the tumor vasculature. Conversely, G-CSF delivery to animals bearing anti-VEGF sensitive tumors resulted in reduced responsiveness to anti-VEGF-A treatment through induction of Bv8-dependent angiogenesis. We conclude that, at least in the models examined, G-CSF expression by tumor or stromal cells is a determinant of refractoriness to anti-VEGF-A treatment.
Asunto(s)
Anticuerpos Antineoplásicos/uso terapéutico , Movimiento Celular/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos/farmacología , Células Mieloides/citología , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/inmunología , Factor A de Crecimiento Endotelial Vascular/inmunología , Animales , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Hormonas Gastrointestinales/inmunología , Humanos , Ratones , Ratones Desnudos , Células Mieloides/efectos de los fármacos , Neoplasias/irrigación sanguínea , Neoplasias/inmunología , Neuropéptidos/inmunologíaRESUMEN
Angiogenesis is critical for growth of many tumor types and the development of anti-angiogenic agents opened a new era in cancer therapy. However, similar to other anti-cancer therapies, inherent/acquired resistance to anti-angiogenic drugs may occur in cancer patients leading to disease recurrence. Recent studies in several experimental models suggest that both tumor and non-tumor (stromal) cell types may be involved in the reduced responsiveness to the treatments. The current review focuses on the role of stromal cells in tumor growth and in refractoriness to anti-VEGF treatment.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Resistencia a Antineoplásicos , Neoplasias/irrigación sanguínea , Neovascularización Patológica/tratamiento farmacológico , Inhibidores de la Angiogénesis/farmacología , Animales , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patología , Neovascularización Patológica/inmunología , Neovascularización Patológica/metabolismo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
OBJECTIVE: Human embryonic stem cells (hESCs) have been differentiated into CD45(+) hematopoietic cells in vitro. A subset of hESC-derived CD45(+) cells coexpresses CD34 and show progenitor function in colony-forming units assays. These hESC-derived hematopoietic stem (HSC), or progenitor cells, display, however, distinct functional properties, including poor repopulation ability; impaired differentiation; and lack of homing when compared to HSCs from fetal blood (FB) or cord blood. Whether these differences are cell-autonomous or driven by their microenvironment remains to be elucidated. MATERIALS AND METHODS: Here, to gain insight into the molecular determinants accounting for these functional differences, a gene-expression profiling comparing candidate hESC-HSCs vs FB-derived HSCs (FB-HSCs) was conducted. RESULTS: Only 2.4% of differentially expressed transcripts were common for FB-HSCs and candidate hESC-HSCs, suggesting a completely different molecular signature for HSCs isolated from two different in utero ontogeny stages. Several key hematopoietic transcription factors, apoptosis and cycle regulators, and cell aggregation and homing genes may contribute to explain the functional differences between hESC-HSCs and FB-HSCs. Importantly, components of Notch and Wnt signaling pathways involved in HSC self-renewal and hematopoietic specification were significantly underexpressed in candidate hESC-HSCs. CONCLUSION: Our study provides a platform to understand the molecular basis underlying hESC-HSCs functional properties. Future studies are needed to address the functional role of the transcripts identified here, eventually leading to identification of intrinsic determinants and cytokines driving physiological specification of hESCs into definitive HSCs.
Asunto(s)
Células Madre Embrionarias/citología , Perfilación de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Humanos , Familia de Multigenes , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologíaRESUMEN
CD11b+Gr1+ cells, which include neutrophils, macrophages, and myeloid-derived suppressor cells, have been shown to contribute to tumor angiogenesis. Recently, we found that accumulation of CD11b+Gr1+ in tumors renders them refractory to angiogenic blockade by vascular endothelial growth factor (VEGF) antibodies. This effect was traced to a pathway of CD11b+Gr1+-mediated angiogenesis that is, at least in part, driven by the secreted protein Bv8, which is up-regulated by the important myeloid growth factor granulocyte colony-stimulating factor (G-CSF). Thus, G-CSF may promote tumor angiogenesis through a Bv8-dependent pathway that bypasses VEGF and renders tumors refractory to anti-VEGF therapy.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Células Mieloides/citología , Neovascularización Patológica , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismo , Inhibidores de la Angiogénesis/farmacología , Animales , Antígenos de Neoplasias/química , Antígeno CD11b/biosíntesis , Hormonas Gastrointestinales/biosíntesis , Factor Estimulante de Colonias de Granulocitos/metabolismo , Humanos , Modelos Biológicos , Células Mieloides/metabolismo , Neuropéptidos/biosíntesisRESUMEN
Cells of the innate immune system have a key role in maintaining homeostasis by providing the first line of defense against many pathogens. Innate immunity can also modulate the activity of acquired immunity by several mechanisms. However, subsets of myeloid cells can facilitate tumor growth, because these cells produce angiogenic factors and can also prevent the immune system from attacking tumor cells. Recent studies also emphasize the role of myeloid cells in mediating refractoriness to anti-VEGF treatments. This function of myeloid cells occurs through a proangiogenic pathway that is, at least in part, driven by the secreted protein Bv8. This review summarizes recent findings on the complex role of bone marrow-derived cells in tumor growth.
Asunto(s)
Células Mieloides/patología , Neoplasias/patología , Neovascularización Patológica/patología , Células de la Médula Ósea/patología , Humanos , Escape del TumorRESUMEN
The secreted Bv8 protein has been recently characterized as a regulator of myeloid cell mobilization and a neutrophil-derived mediator of tumor angiogenesis in several xenografts, but its role in tumor progression in an endogenous setting was unknown. The rat insulin promoter (RIP)-T-antigen (Tag) is a well characterized transgenic mouse model of multistage pancreatic beta-cell tumorigenesis. Also, the role of neutrophils in RIP-Tag angiogenic switching, as assessed by systemic ablation using anti-Gr1 antibodies at different stages of tumor progression, has been recently described. Here, we show that early treatment of RIP-Tag mice with anti-Bv8 antibodies resulted in a significant reduction in the number of angiogenic islets relative to control antibody-treated mice, implicating Bv8 in the angiogenic switch during neoplasia. Histological analysis showed a significant reduction in vascular surface areas in hyperplastic and angiogenic lesions in pancreatic islets from anti-Bv8-treated mice. Anti-Bv8 treatment also inhibited the mobilization and homing of CD11b+Gr1+ cells to the peripheral blood and the emerging neoplastic lesions. However, anti-Bv8 treatment had no effect on tumor vascularization or burden when initiated at later stages of tumor progression. The stage-dependent efficacy of anti-Bv8 treatment appears remarkably similar to that reported after neutrophil ablation, suggesting that Bv8 is an important mediator of neutrophil-dependent angiogenesis in this transgenic model. In summary, our studies verify a role for Bv8 in the mobilization and recruitment of myeloid cells and in the induction of tumor angiogenesis in the early stages of neoplastic progression.
Asunto(s)
Hormonas Gastrointestinales/metabolismo , Neoplasias/irrigación sanguínea , Neoplasias/metabolismo , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neuropéptidos/metabolismo , Neutrófilos/metabolismo , Animales , Médula Ósea/metabolismo , Antígeno CD11b/metabolismo , Progresión de la Enfermedad , Hormonas Gastrointestinales/genética , Hormonas Gastrointestinales/inmunología , Regulación Neoplásica de la Expresión Génica , Insulina/genética , Ratones , Ratones Transgénicos , Estadificación de Neoplasias , Neoplasias/genética , Neoplasias/patología , Neovascularización Patológica/genética , Neuropéptidos/genética , Neuropéptidos/inmunología , Infiltración Neutrófila , Páncreas/metabolismo , Regiones Promotoras Genéticas/genética , RatasRESUMEN
Bone-marrow-derived cells facilitate tumour angiogenesis, but the molecular mechanisms of this facilitation are incompletely understood. We have previously shown that the related EG-VEGF and Bv8 proteins, also known as prokineticin 1 (Prok1) and prokineticin 2 (Prok2), promote both tissue-specific angiogenesis and haematopoietic cell mobilization. Unlike EG-VEGF, Bv8 is expressed in the bone marrow. Here we show that implantation of tumour cells in mice resulted in upregulation of Bv8 in CD11b+Gr1+ myeloid cells. We identified granulocyte colony-stimulating factor as a major positive regulator of Bv8 expression. Anti-Bv8 antibodies reduced CD11b+Gr1+ cell mobilization elicited by granulocyte colony-stimulating factor. Adenoviral delivery of Bv8 into tumours was shown to promote angiogenesis. Anti-Bv8 antibodies inhibited growth of several tumours in mice and suppressed angiogenesis. Anti-Bv8 treatment also reduced CD11b+Gr1+ cells, both in peripheral blood and in tumours. The effects of anti-Bv8 antibodies were additive to those of anti-Vegf antibodies or cytotoxic chemotherapy. Thus, Bv8 modulates mobilization of CD11b+Gr1+ cells from the bone marrow during tumour development and also promotes angiogenesis locally.
Asunto(s)
Hormonas Gastrointestinales/metabolismo , Células Mieloides/metabolismo , Neoplasias/irrigación sanguínea , Neovascularización Patológica , Neuropéptidos/metabolismo , Animales , Anticuerpos/inmunología , Anticuerpos/farmacología , Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Línea Celular Tumoral , Hormonas Gastrointestinales/antagonistas & inhibidores , Hormonas Gastrointestinales/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos/farmacología , Humanos , Ratones , Ratones Desnudos , Células Mieloides/efectos de los fármacos , Trasplante de Neoplasias , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Neovascularización Patológica/tratamiento farmacológico , Neuropéptidos/antagonistas & inhibidores , Neuropéptidos/inmunología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
The identification and characterization of several important regulators of angiogenesis, which led to Food and Drug Administration approval of the first antiangiogenic drugs, has opened a new era in cancer therapy. This article focuses on the clinical progress in targeting one of the major regulators of angiogenesis, vascular endothelial growth factor-A and also discusses some recent advances in the elucidation of potential cellular and molecular mechanisms underlying refractoriness or resistance to antiangiogenic therapies.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias/tratamiento farmacológico , Aprobación de Drogas , Humanos , Neoplasias/irrigación sanguínea , Neovascularización Patológica/prevención & control , Estados Unidos , United States Food and Drug Administration , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Vascular endothelial growth factor (VEGF) is an essential regulator of normal and abnormal blood vessel growth. A monoclonal antibody (mAb) that targets VEGF suppresses tumor growth in murine cancer models and human patients. We investigated cellular and molecular events that mediate refractoriness of tumors to anti-angiogenic therapy. Inherent anti-VEGF refractoriness is associated with infiltration of the tumor tissue by CD11b+Gr1+ myeloid cells. Recruitment of these myeloid cells is also sufficient to confer refractoriness. Combining anti-VEGF treatment with a mAb that targets myeloid cells inhibits growth of refractory tumors more effectively than anti-VEGF alone. Gene expression analysis in CD11b+Gr1+ cells isolated from the bone marrow of mice bearing refractory tumors reveals higher expression of a distinct set of genes known to be implicated in active mobilization and recruitment of myeloid cells. These findings indicate that, in our models, refractoriness to anti-VEGF treatment is determined by the ability of tumors to prime and recruit CD11b+Gr1+ cells.
Asunto(s)
Antineoplásicos/administración & dosificación , Antígeno CD11b/metabolismo , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Receptores de Quimiocina/metabolismo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Resistencia a Antineoplásicos , Ratones , Ratones Endogámicos C57BL , Resultado del TratamientoRESUMEN
The vascular endothelium is best known for its role in oxygen and nutrient delivery to the various tissues. Growing evidence supports a far more complex role in tissue homeostasis. In particular, reciprocal interactions between endothelial cells and the local microenvironment may regulate organ development and pattern formation. Such interactions appear to be important also in the adult, in normal and pathological conditions.
Asunto(s)
Vasos Sanguíneos/embriología , Embrión de Mamíferos/irrigación sanguínea , Embrión de Mamíferos/embriología , Endotelio Vascular/embriología , Endotelio Vascular/metabolismo , Adulto , Animales , Humanos , Neoplasias/irrigación sanguínea , Neoplasias/patología , Especificidad de Órganos , Transducción de SeñalRESUMEN
Identification and characterization of several important regulators of angiogenesis, and FDA approval of the first antiangiogenic drugs, has opened a new era in the therapy of cancer and neovascular age-related macular degeneration. This brief review focuses on the progress in targeting one of the major regulators of angiogenesis, VEGF-A, and also discusses potential cellular and molecular mechanisms underlying resistance to antiangiogenic treatments.