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Clin Cancer Res ; 26(21): 5709-5719, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33097493


PURPOSE: Angiogenesis is thought to be critical for tumor metastasis. However, inhibiting angiogenesis using antibodies such as bevacizumab (Avastin), has had little impact on melanoma patient survival. We have demonstrated that both angiogenesis and metastasis are increased in older individuals, and therefore sought to investigate whether there was an age-related difference in response to bevacizumab, and if so, what the underlying mechanism could be. EXPERIMENTAL DESIGN: We analyzed data from the AVAST-M trial of 1,343 patients with melanoma treated with bevacizumab to determine whether there is an age-dependent response to bevacizumab. We also examined the age-dependent expression of VEGF and its cognate receptors in patients with melanoma, while using syngeneic melanoma animal models to target VEGF in young versus old mice. We also examined the age-related proangiogenic factor secreted frizzled-related protein 2 (sFRP2) and whether it could modulate response to anti-VEGF therapy. RESULTS: We show that older patients respond poorly to bevacizumab, whereas younger patients show improvement in both disease-free survival and overall survival. We find that targeting VEGF does not ablate angiogenesis in an aged mouse model, while sFRP2 promotes angiogenesis in vitro and in young mice. Targeting sFRP2 in aged mice successfully ablates angiogenesis, while the effects of targeting VEGF in young mice can be overcome by increasing sFRP2. CONCLUSIONS: VEGF is decreased during aging, thereby reducing response to bevacizumab. Despite the decrease in VEGF, angiogenesis is increased because of an increase in sFRP2 in the aged tumor microenvironment. These results stress the importance of considering age as a factor for designing targeted therapies.

Mol Cell ; 77(3): 633-644.e5, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-31836388


Metastatic melanoma is an aggressive disease, despite recent improvements in therapy. Eradicating all melanoma cells even in drug-sensitive tumors is unsuccessful in patients because a subset of cells can transition to a slow-cycling state, rendering them resistant to most targeted therapy. It is still unclear what pathways define these subpopulations and promote this resistant phenotype. In the current study, we show that Wnt5A, a non-canonical Wnt ligand that drives a metastatic, therapy-resistant phenotype, stabilizes the half-life of p53 and uses p53 to initiate a slow-cycling state following stress (DNA damage, targeted therapy, and aging). Inhibiting p53 blocks the slow-cycling phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. In vivo, this can be accomplished with a single dose of p53 inhibitor at the commencement of BRAF/MEK inhibitor therapy. These data suggest that taking the paradoxical approach of inhibiting rather than activating wild-type p53 may sensitize previously resistant metastatic melanoma cells to therapy.

Melanoma/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Wnt-5a/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , MAP Quinase Quinase Quinases/metabolismo , Melanoma/genética , Melanoma/patologia , Terapia de Alvo Molecular , Mutação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/fisiologia
Cancer Discov ; 9(1): 82-95, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30279172


Older patients with melanoma have lower rates of sentinel lymph node (LN) metastases yet paradoxically have inferior survival. Patient age correlated with an inability to retain Technetium radiotracer during sentinel LN biopsy in more than 1,000 patients, and high Technetium counts correlated to better survival. We hypothesized that loss of integrity in the lymphatic vasculature due to extracellular matrix (ECM) degradation might play a role. We have implicated HAPLN1 in age-dependent ECM degradation in the dermis. Here, we queried whether HAPLN1 could be altered in the lymphatic ECM. Lymphatic HAPLN1 expression was prognostic of long-term patient survival. Adding recombinant HAPLN1 to aged fibroblast ECMs in vitro reduced endothelial permeability via modulation of VE-cadherin junctions, whereas endothelial permeability was increased following HAPLN1 knockdown in young fibroblasts. In vivo, reconstitution of HAPLN1 in aged mice increased the number of LN metastases, but reduced visceral metastases. These data suggest that age-related changes in ECM can contribute to impaired lymphatics. SIGNIFICANCE: Our studies reveal that changes in the stroma during aging may influence the way tumor cells traffic through the lymphatic vasculature. Aging may dictate the route of metastatic dissemination of tumor cells, and understanding these changes may help to reveal targetable moieties in the aging tumor microenvironment.See related commentary by Marie and Merlino, p. 19.This article is highlighted in the In This Issue feature, p. 1.

Envelhecimento , Proteínas da Matriz Extracelular/metabolismo , Melanoma/metabolismo , Proteoglicanas/metabolismo , Pele/metabolismo , Adulto , Animais , Células Cultivadas , Humanos , Sistema Imunitário , Metástase Linfática , Melanoma/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Pele/fisiopatologia , Microambiente Tumoral
Cancer Res ; 78(10): 2705-2720, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29490948


To date, no consistent oncogenic driver mutations have been identified in most adult soft tissue sarcomas; these tumors are thus generally insensitive to existing targeted therapies. Here we investigated alternate mechanisms underlying sarcomagenesis to identify potential therapeutic interventions. Undifferentiated pleomorphic sarcoma (UPS) is an aggressive tumor frequently found in skeletal muscle where deregulation of the Hippo pathway and aberrant stabilization of its transcriptional effector yes-associated protein 1 (YAP1) increases proliferation and tumorigenesis. However, the downstream mechanisms driving this deregulation are incompletely understood. Using autochthonous mouse models and whole genome analyses, we found that YAP1 was constitutively active in some sarcomas due to epigenetic silencing of its inhibitor angiomotin (AMOT). Epigenetic modulators vorinostat and JQ1 restored AMOT expression and wild-type Hippo pathway signaling, which induced a muscle differentiation program and inhibited sarcomagenesis. YAP1 promoted sarcomagenesis by inhibiting expression of ubiquitin-specific peptidase 31 (USP31), a newly identified upstream negative regulator of NFκB signaling. Combined treatment with epigenetic modulators effectively restored USP31 expression, resulting in decreased NFκB activity. Our findings highlight a key underlying molecular mechanism in UPS and demonstrate the potential impact of an epigenetic approach to sarcoma treatment.Significance: A new link between Hippo pathway signaling, NFκB, and epigenetic reprogramming is highlighted and has the potential for therapeutic intervention in soft tissue sarcomas. Cancer Res; 78(10); 2705-20. ©2018 AACR.

Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Transformação Celular Neoplásica/patologia , NF-kappa B/metabolismo , Fosfoproteínas/metabolismo , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Proteases Específicas de Ubiquitina/antagonistas & inibidores , Proteases Específicas de Ubiquitina/biossíntese , Animais , Antineoplásicos/farmacologia , Azepinas/farmacologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Músculo Esquelético/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , Sarcoma/genética , Transdução de Sinais/genética , Neoplasias de Tecidos Moles/genética , Fatores de Transcrição , Triazóis/farmacologia , Vorinostat/farmacologia
Vitae (Medellín) ; 19(1): 60-69, ene.-abr. 2012.
Artigo em Inglês | LILACS | ID: lil-626196


Microalgae are capable of producing biomolecules that have a wide variety of applications in agriculture, food industry, and medicine. In this study, three process variables are evaluated in order to determine its incidence on biomass and exopolysaccharides production. The effect of light intensity, agitation and carbon concentration on Scenedesmus obliquus (UTEX 393) growth and expolysaccaharides production is evaluated using 23 factorial design through the screening methodology. The simultaneous effect of level variation for three different experimental variables is examined in the present study in three levels for each parameter (Light intensity: 80, 130, 180 µE m-2 s-1, Agitation: 0, 600, 1200 rpm, carbon concentration 0, 2, 4% v/v Air-CO2). Specific growth rate and the exopolysaccharides concentration are the selected response variables. Results show that the optimal conditions for the two response variables correspond to the maximum levels of the three experimental variables (180 µE m-2 s-1, 4% air-CO2, and 1200 rpm), obtaining a specific growth rate of 0.64 d-1 and a exopolysaccharides concentration of 24.7 mg L-1. A significant interaction between the variables is observed, which has direct effects on cellular growth and exopolysaccharides production. The EPS production is facilitated by the turbulent flow (agitation maximum level), which is associated with a higher availability and better distribution of energy sources (light) and carbon dioxide. The validation of polynomials models verifies the relevance of the analysis performed.

Microalgas , Scenedesmus