12 research outputs found
Resistance to antiangiogenic therapies by metabolic symbiosis in renal cell carcinoma PDX models and patients
Antiangiogenic drugs are used clinically for treatment of renal cell carcinoma (RCC) as a standard first-line treatment. Nevertheless, these agents primarily serve to stabilize disease, and resistance eventually develops concomitant with progression. Here, we implicate metabolic symbiosis between tumor cells distal and proximal to remaining vessels as a mechanism of resistance to antiangiogenic therapies in patient-derived RCC orthoxenograft (PDX) models and in clinical samples. This metabolic patterning is regulated by the mTOR pathway, and its inhibition effectively blocks metabolic symbiosis in PDX models. Clinically, patients treated with antiangiogenics consistently present with histologic signatures of metabolic symbiosis that are exacerbated in resistant tumors. Furthermore, the mTOR pathway is also associated in clinical samples, and its inhibition eliminates symbiotic patterning in patient samples. Overall, these data support a mechanism of resistance to antiangiogenics involving metabolic compartmentalization of tumor cells that can be inhibited by mTOR-targeted drugs
New targets in tumor angiogenesis to block tumor re-growth and therapeutic resistance
[eng] Antiangiogenic drugs are used clinically for treatment of different types of cancers and in the case of renal cell carcinoma (RCC) are now standard first-line treatments (Rini, 2009). Nevertheless, these agents mainly serve to stabilize the disease but are not able to eliminate all tumor cells and resistance eventually develops concomitant with progression (Kerber and Folkman, 2002).
Using different orthoxenograft mouse models of RCC we confirmed that inhibitors of the VEGF pathway have a therapeutic window of effectiveness but unfortunately adaptation and tumor relapse always occur.
Several different mechanisms of resistance to antiangiogenics have been already described, many concerning the activation of compensatory signals that produce re-vascularization and tumor re-growth. (Bergers and Hanahan, 2008). In our study we determined that even if resistance is characterized by the up-regulation of the pro-angiogenic enzyme ECGF1 (previous data from the lab); re-vascularization does not occur, the vascular trimming is maintained by the treatment pointing to an alternative mode of adaptation.
Using two different approaches, we demonstrated that PD-ECGF1 is responsible of the acquisition of resistance to anti-anigiogenics. In fact, its enzymatic inhibition as second-line treatment post resistance resulted in the arrest and stabilization of tumor growth. PD-ECGF1 inhibition did not increase the anti-vascular effect of DC101, confirming that resistance was vessel independent, but dramatically affected tumor cell proliferation and apoptosis. Considering the numerous proprieties ascribed to its final metabolite 2-deoxy-D-ribose (Ikeda et al., 2006; Bjinsdorp et al., 2008), we evaluated its role, finding that recombinant 2-deoxy-D-ribose nullified the effect of AEAC on 786O- and Ren28 tumor growth rescuing tumor cell proliferation and apoptosis, without promoting re-vascularization. Overall these findings, confirmed also in an in vitro setting, demonstrate that tumor stroma plays a minor role in this model of anti-angiogenics resistance, and that PD-ECGF1 acts mainly intracellularly supporting tumor cell proliferation and protecting from apoptosis by its enzymatic activity and final metabolite 2-deoxy-D-ribose.
Using a genetic approach in which PD-ECGF1 protein expression was silence as a second line of treatment post DC101-resistance, mimicking what done pharmacologically, we confirmed and improved the anti-tumoral response described, without perceiving any doxycycline toxic effect. In fact, PD-ECGF1 genetic knock down resulted in a complete arrest of tumor progression enhancing the merely partial stabilization produce by AEAC treatment in 786O- tumor bearing mice.
Unfortunately VEGFR-blockers can’t be used in vitro on cancer cells, and to verify this hypothesis we decided to mimic the final effects of anti-angiogenic treatments, finding that under nutrient deprivation conditions cancer cells significantly up-regulate PD-ECGF1 expression, and metabolizing thymidine acquired considerable growth advantages.
Finally, the analysis of plasma and tissue samples of ccRCC patients from the Bellvitge Hospital confirm in a clinical set that PD-ECGF1 is exclusively found in pathologic conditions, where if highly expressed correlates with poor prognosis, suggesting that might represent a good therapeutic predictor factor. Moreover, the analysis of tissues biopsies before and after anti-angiogenic treatment revealed that whilst PD-ECGF1 treatment-induce up-regulation was a common feature, the patients that unfortunately didn’t respond showed the sharp difference, confirming PD-ECGF1 as a possible therapeutic target.[spa] Los fármacos antiangiogénicos se usan clínicamente para el tratamiento de diferentes tipos de cáncer y en el caso del carcinoma de células renales (CCR) representan la primera diana terapéutica (Rini, 2009). Sin embargo, no son capaces de eliminar todas las células tumorales y muchos pacientes desarrollan resistencia al tratamiento y recrecimiento tumoral (Kerber y Folkman, 2002).
Mediante el uso de diferentes modelos de ratón hemos confirmado que los inhibidores de la vía VEGF tienen una limitada ventana terapéutica de efectividad, seguida desafortunadamente de adaptación y recaída tumoral que en nuestro estudio esta` caracterizada por la regulación positiva de la enzima PD-ECGF1.
Usando dos enfoques diferentes, demostramos que PD-ECGF1 es responsable de la adquisición de resistencia a anti-anigiogénicos. De hecho, su inhibición enzimática como tratamiento de segunda línea después de la resistencia dio como resultado la detención y la estabilización del crecimiento tumoral. La inhibición de PD-ECGF1 no aumentó el efecto antivascular de DC101, pero afectó de manera dramática la proliferación y apoptosis de las células tumorales. Teniendo en cuenta las numerosas propiedades atribuidas a su metabolito final 2-deoxy-D-ribose (Ikeda et al., 2006; Bjinsdorp et al., 2008), evaluamos su papel, encontrando que la 2-deoxy-D-ribose anuló el efecto de la inhibición de PD-ECGF1 rescatando el crecimiento tumoral.
Experimentos en vitro demostraron como las células tumorales incrementaban la expresión de PD-ECGF1 en condiciones de falta de nutrientes haciéndonos especular que esta proteína tenga un papel en la adaptación metabolica.
Finalmente, el análisis de muestras de plasma y tejido de pacientes con ccRCC del Hospital de Bellvitge confirma en un conjunto clínico que PD-ECGF1 se encuentra exclusivamente en condiciones patológicas, donde se correlaciona con mal pronóstico, sugiriendo que podría representar un buen factor predictor terapéutico
Impeding Macrophage Entry into Hypoxic Tumor Areas by Sema3A/Nrp1 Signaling Blockade Inhibits Angiogenesis and Restores Antitumor Immunity
Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 2013
SUMMARY Recruitment of tumor-associated macrophages (TAMs) into avascular areas sustains tumor progression; however, the underlying guidance mechanisms are unknown. Here, we report that hypoxia-induced Semaphorin 3A (Sema3A) acts as an attractant for TAMs by triggering vascular endothelial growth factor receptor 1 phosphorylation through the associated holoreceptor, composed of Neuropilin-1 (Nrp1) and PlexinA1/PlexinA4. Importantly, whereas Nrp1 levels are downregulated in the hypoxic environment, Sema3A continues to regulate TAMs in an Nrp1-independent manner by eliciting PlexinA1/PlexinA4-mediated stop signals, which retain them inside the hypoxic niche. Consistently, gene deletion of Nrp1 in macrophages favors TAMs' entrapment in normoxic tumor regions, which abates their pro-angiogenic and immunosuppressive functions, hence inhibiting tumor growth and metastasis. This study shows that TAMs' heterogeneity depends on their localization, which is tightly controlled by Sema3A/Nrp1 signaling
Impeding Macrophage Entry into Hypoxic Tumor Areas by Sema3A/Nrp1 Signaling Blockade Inhibits Angiogenesis and Restores Antitumor Immunity
Recruitment of tumor-associated macrophages (TAMs) into avascular areas sustains tumor progression; however, the underlying guidance mechanisms are unknown. Here, we report that hypoxia-induced Semaphorin 3A (Sema3A) acts as an attractant for TAMs by triggering vascular endothelial growth factor receptor 1 phosphorylation through the associated holoreceptor, composed of Neuropilin-1 (Nrp1) and PlexinA1/PlexinA4. Importantly, whereas Nrp1 levels are downregulated in the hypoxic environment, Sema3A continues to regulate TAMs in an Nrp1-independent manner by eliciting PlexinA1/PlexinA4-mediated stop signals, which retain them inside the hypoxic niche. Consistently, gene deletion of Nrp1 in macrophages favors TAMs' entrapment in normoxic tumor regions, which abates their pro-angiogenic and immunosuppressive functions, hence inhibiting tumor growth and metastasis. This study shows that TAMs' heterogeneity depends on their localization, which is tightly controlled by Sema3A/Nrp1 signaling. © 2013 Elsevier Inc
Resistance to Antiangiogenic Therapies by Metabolic Symbiosis in Renal Cell Carcinoma PDX Models and Patients
Antiangiogenic drugs are used clinically for treatment of renal cell carcinoma (RCC) as a standard first-line treatment. Nevertheless, these agents primarily serve to stabilize disease, and resistance eventually develops concomitant with progression. Here, we implicate metabolic symbiosis between tumor cells distal and proximal to remaining vessels as a mechanism of resistance to antiangiogenic therapies in patient-derived RCC orthoxenograft (PDX) models and in clinical samples. This metabolic patterning is regulated by the mTOR pathway, and its inhibition effectively blocks metabolic symbiosis in PDX models. Clinically, patients treated with antiangiogenics consistently present with histologic signatures of metabolic symbiosis that are exacerbated in resistant tumors. Furthermore, the mTOR pathway is also associated in clinical samples, and its inhibition eliminates symbiotic patterning in patient samples. Overall, these data support a mechanism of resistance to antiangiogenics involving metabolic compartmentalization of tumor cells that can be inhibited by mTOR-targeted drugs
Resistance to antiangiogenic therapies by metabolic symbiosis in renal cell carcinoma PDX models and patients
Antiangiogenic drugs are used clinically for treatment of renal cell carcinoma (RCC) as a standard first-line treatment. Nevertheless, these agents primarily serve to stabilize disease, and resistance eventually develops concomitant with progression. Here, we implicate metabolic symbiosis between tumor cells distal and proximal to remaining vessels as a mechanism of resistance to antiangiogenic therapies in patient-derived RCC orthoxenograft (PDX) models and in clinical samples. This metabolic patterning is regulated by the mTOR pathway, and its inhibition effectively blocks metabolic symbiosis in PDX models. Clinically, patients treated with antiangiogenics consistently present with histologic signatures of metabolic symbiosis that are exacerbated in resistant tumors. Furthermore, the mTOR pathway is also associated in clinical samples, and its inhibition eliminates symbiotic patterning in patient samples. Overall, these data support a mechanism of resistance to antiangiogenics involving metabolic compartmentalization of tumor cells that can be inhibited by mTOR-targeted drugs