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1.
EMBO J ; 41(9): e110466, 2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35307861

RESUMO

Pancreatic ductal adenocarcinoma (PDA) tumor cells are deprived of oxygen and nutrients and therefore must adapt their metabolism to ensure proliferation. In some physiological states, cells rely on ketone bodies to satisfy their metabolic needs, especially during nutrient stress. Here, we show that PDA cells can activate ketone body metabolism and that ß-hydroxybutyrate (ßOHB) is an alternative cell-intrinsic or systemic fuel that can promote PDA growth and progression. PDA cells activate enzymes required for ketogenesis, utilizing various nutrients as carbon sources for ketone body formation. By assessing metabolic gene expression from spontaneously arising PDA tumors in mice, we find HMG-CoA lyase (HMGCL), involved in ketogenesis, to be among the most deregulated metabolic enzymes in PDA compared to normal pancreas. In vitro depletion of HMGCL impedes migration, tumor cell invasiveness, and anchorage-independent tumor sphere compaction. Moreover, disrupting HMGCL drastically decreases PDA tumor growth in vivo, while ßOHB stimulates metastatic dissemination to the liver. These findings suggest that ßOHB increases PDA aggressiveness and identify HMGCL and ketogenesis as metabolic targets for limiting PDA progression.


Assuntos
Corpos Cetônicos , Neoplasias Pancreáticas , Ácido 3-Hidroxibutírico/metabolismo , Animais , Corpos Cetônicos/metabolismo , Camundongos , Oxo-Ácido-Liases , Pâncreas/metabolismo
2.
Arch Biochem Biophys ; 689: 108438, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32497547

RESUMO

Cancer cells display increased oxidative stress from reactive oxygen species (ROS) and constantly have to counteract them below a tolerable threshold to avoid any toxicity due to overload of ROS. The involvement of ROS in cancer progression from precursor lesions to aggressive tumor and metastasis formation is still debated, but it is recognized that cancer cells succeed to use ROS for their own benefit in circumstances that are tumor cell-type specific. In this review, we focus on amino acids' metabolic pathways that tumor cells activate as antioxidants including cysteine, methionine metabolisms and their connection with the folate, transulfuration pathways and ferroptosis. We discuss how the tumor context definitively dictates the impact of ROS on tumor progression towards a metastatic disease as well as the therapeutic approaches that target ROS to abrogate tumors or limit their aggressiveness.


Assuntos
Aminoácidos/metabolismo , Neoplasias/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Animais , Ferroptose , Ácido Fólico/metabolismo , Humanos , Redes e Vias Metabólicas
3.
Proc Natl Acad Sci U S A ; 112(8): 2473-8, 2015 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-25675507

RESUMO

The malignant progression of pancreatic ductal adenocarcinoma (PDAC) is accompanied by a profound desmoplasia, which forces proliferating tumor cells to metabolically adapt to this new microenvironment. We established the PDAC metabolic signature to highlight the main activated tumor metabolic pathways. Comparative transcriptomic analysis identified lipid-related metabolic pathways as being the most highly enriched in PDAC, compared with a normal pancreas. Our study revealed that lipoprotein metabolic processes, in particular cholesterol uptake, are drastically activated in the tumor. This process results in an increase in the amount of cholesterol and an overexpression of the low-density lipoprotein receptor (LDLR) in pancreatic tumor cells. These findings identify LDLR as a novel metabolic target to limit PDAC progression. Here, we demonstrate that shRNA silencing of LDLR, in pancreatic tumor cells, profoundly reduces uptake of cholesterol and alters its distribution, decreases tumor cell proliferation, and limits activation of ERK1/2 survival pathway. Moreover, blocking cholesterol uptake sensitizes cells to chemotherapeutic drugs and potentiates the effect of chemotherapy on PDAC regression. Clinically, high PDAC Ldlr expression is not restricted to a specific tumor stage but is correlated to a higher risk of disease recurrence. This study provides a precise overview of lipid metabolic pathways that are disturbed in PDAC. We also highlight the high dependence of pancreatic cancer cells upon cholesterol uptake, and identify LDLR as a promising metabolic target for combined therapy, to limit PDAC progression and disease patient relapse.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Colesterol/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/patologia , Animais , Compartimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Clonais , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Humanos , Lipoproteínas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Camundongos , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/patologia , Fenótipo , Prognóstico , Receptores de LDL/genética , Receptores de LDL/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Gencitabina , Neoplasias Pancreáticas
4.
Semin Cancer Biol ; 33: 34-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25931390

RESUMO

Both the hexosamine biosynthetic pathway (HBP) and the endoplasmic reticulum (ER) are considered sensors for the nutritional state of the cell. The former is a branch of the glucose metabolic pathway that provides donor molecules for glycosylation processes, whereas the second requires co-translational N-glycosylation to ensure proper protein folding. It has become clear that the microenvironment of solid tumours, characterised by poor oxygen and nutrient supply, challenges optimal functions of the ER and the HBP. Here, we review recent advances demonstrating that the ER stress (ERS) response and HBP pathways are interconnected to promote cell viability. We then develop the idea that communication between ER and HBP is a survival feature of neoplastic cells that plays a prominent role during tumourigenesis.


Assuntos
Estresse do Retículo Endoplasmático , Hexosaminas/metabolismo , Neoplasias/metabolismo , Animais , Carcinogênese , Linhagem da Célula , Sobrevivência Celular , Transformação Celular Neoplásica/metabolismo , Retículo Endoplasmático/metabolismo , Glucose/metabolismo , Glicosilação , Humanos , Neoplasias/fisiopatologia , Dobramento de Proteína , Microambiente Tumoral
5.
Int J Cancer ; 138(4): 787-96, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25732227

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a debilitating and almost universally fatal malignancy. Despite advances in understanding of the oncogenetics of the disease, very few clinical benefits have been shown. One of the main characteristics of PDAC is the tumor architecture where tumor cells are surrounded by a firm desmoplasia. By reducing vascularization, thus both oxygen and nutrients delivery to the tumor, this stroma causes the appearance of hypoxic zones driving metabolic adaptation in surviving tumor cells in order to cope with challenging conditions. This metabolic reprogramming promoted by environmental constraints enhances PDAC aggressiveness. In this review, we provide a brief overview of previous works regarding the importance of glucose and glutamine addiction of PDAC cells. In particular we aim to highlight the need for exploring the impact of metabolites other than glucose and glutamine, such as non-essential amino acids and oncometabolites, to find new treatments. We also discuss the need for progress in methodology for metabolites detection. The overall purpose of our review is to emphasize the need to look beyond what is currently known, with a focus on amino acid availability, in order to improve our understanding of PDAC biology.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Humanos
6.
Proc Natl Acad Sci U S A ; 110(10): 3919-24, 2013 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-23407165

RESUMO

Pancreatic ductal adenocarcinoma is one of the most intractable and fatal cancer. The decreased blood vessel density displayed by this tumor not only favors its resistance to chemotherapy but also participates in its aggressiveness due to the consequent high degree of hypoxia. It is indeed clear that hypoxia promotes selective pressure on malignant cells that must develop adaptive metabolic responses to reach their energetic and biosynthetic demands. Here, using a well-defined mouse model of pancreatic cancer, we report that hypoxic areas from pancreatic ductal adenocarcinoma are mainly composed of epithelial cells harboring epithelial-mesenchymal transition features and expressing glycolytic markers, two characteristics associated with tumor aggressiveness. We also show that hypoxia increases the "glycolytic" switch of pancreatic cancer cells from oxydative phosphorylation to lactate production and we demonstrate that increased lactate efflux from hypoxic cancer cells favors the growth of normoxic cancer cells. In addition, we show that glutamine metabolization by hypoxic pancreatic tumor cells is necessary for their survival. Metabolized glucose and glutamine converge toward a common pathway, termed hexosamine biosynthetic pathway, which allows O-linked N-acetylglucosamine modifications of proteins. Here, we report that hypoxia increases transcription of hexosamine biosynthetic pathway genes as well as levels of O-glycosylated proteins and that O-linked N-acetylglucosaminylation of proteins is a process required for hypoxic pancreatic cancer cell survival. Our results demonstrate that hypoxia-driven metabolic adaptive processes, such as high glycolytic rate and hexosamine biosynthetic pathway activation, favor hypoxic and normoxic cancer cell survival and correlate with pancreatic ductal adenocarcinoma aggressiveness.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Glicólise , Hipóxia/metabolismo , Neoplasias Pancreáticas/metabolismo , Animais , Carcinoma Ductal Pancreático/patologia , Hipóxia Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Modelos Animais de Doenças , Glutamina/metabolismo , Hexosaminas/biossíntese , Humanos , Ácido Láctico/metabolismo , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Nus , Camundongos Transgênicos , Modelos Biológicos , Neoplasias Pancreáticas/patologia , Transplante Heterólogo
7.
Arch Biochem Biophys ; 545: 69-73, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24393743

RESUMO

Because of lack of effective treatment, pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death by cancer in Western countries, with a very weak improvement of survival rate over the last 40years. Defeat of numerous conventional therapies to cure this cancer makes urgent to develop new tools usable by clinicians for a better management of the disease. Aggressiveness of pancreatic cancer relies on its own hallmarks: a low vascular network as well as a prominent stromal compartment (desmoplasia), which creates a severe hypoxic environment impeding correct oxygen and nutrients diffusion to the tumoral cells. To survive and proliferate in those conditions, pancreatic cancer cells set up specific metabolic pathways to meet their tremendous energetic and biomass demands. However, as PDAC is a heterogenous tumor, a complex reprogramming of metabolic processes is engaged by cancer cells according to their level of oxygenation and nutrients supply. In this review, we focus on the glycolytic activity of PDAC and the glucose-connected metabolic pathways which contribute to the progression and dissemination of this disease. We also discuss possible therapeutic strategies targeting these pathways in order to cure this disease which still until now is resistant to numerous conventional treatments.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Redes e Vias Metabólicas , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/metabolismo , Animais , Carcinoma Ductal Pancreático/patologia , Hipóxia Celular , Glutamina/metabolismo , Glicólise , Glicosilação , Hexosaminas/metabolismo , Humanos , Neoplasias Pancreáticas/patologia
8.
Genes (Basel) ; 15(6)2024 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-38927628

RESUMO

Hereditary sensory and autonomic neuropathy type 1 is an autosomal dominant neuropathy caused by the SPTLC1 or SPTLC2 variants. These variants modify the preferred substrate of serine palmitoyl transferase, responsible for the first step of de novo sphingolipids synthesis, leading to accumulation of cytotoxic deoxysphingolipids. Diagnosis of HSAN1 is based on clinical symptoms, mainly progressive loss of distal sensory keep, and genetic analysis. Aim: Identifying new SPTLC1 or SPTLC2 "gain-of-function" variants raises the question as to their pathogenicity. This work focused on characterizing six new SPTLC1 variants using in silico prediction tools, new meta-scores, 3D modeling, and functional testing to establish their pathogenicity. Methods: Variants from six patients with HSAN1 were studied. In silico, CADD and REVEL scores and the 3D modeling software MITZLI were used to characterize the pathogenic effect of the variants. Functional tests based on plasma sphingolipids quantification (total deoxysphinganine, ceramides, and dihydroceramides) were performed by tandem mass spectrometry. Results: In silico predictors did not provide very contrasting results when functional tests discriminated the different variants according to their impact on deoxysphinganine level or canonical sphingolipids synthesis. Two SPTLC1 variants were newly described as pathogenic: SPTLC1 NM_006415.4:c.998A>G and NM_006415.4:c.1015G>A. Discussion: The combination of the different tools provides arguments to establish the pathogenicity of these new variants. When available, functional testing remains the best option to establish the in vivo impact of a variant. Moreover, the comprehension of metabolic dysregulation offers opportunities to develop new therapeutic strategies for these genetic disorders.


Assuntos
Neuropatias Hereditárias Sensoriais e Autônomas , Mutação de Sentido Incorreto , Serina C-Palmitoiltransferase , Esfingolipídeos , Humanos , Serina C-Palmitoiltransferase/genética , Serina C-Palmitoiltransferase/metabolismo , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Masculino , Feminino , Esfingolipídeos/metabolismo , Adulto , Pessoa de Meia-Idade
9.
Proc Natl Acad Sci U S A ; 106(4): 1111-6, 2009 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-19144925

RESUMO

In cancer, DJ-1/PARK7 acts as an oncogene that drives Akt-mediated cell survival. Although amplification of DJ-1 has been described in several types of tumors, the mechanistic basis of DJ-1's oncogenic effect remains incompletely understood. A tumor's ability to adapt to hypoxia is absolutely critical for its survival and progression, and this adaptation is largely mediated by the transcription factor HIF1. The stabilization of HIF1 subunits during hypoxia is at least partly dependent on the PI3K/Akt/mTOR pathway. We hypothesized that DJ-1, a positive regulator of Akt when over-expressed, might be involved in regulating HIF1 transcriptional activity under hypoxic conditions. Our results show that loss of DJ-1 in human cell lines and transformed mouse fibroblasts decreases the transcription of a variety of HIF1-responsive genes during hypoxia. Moreover, DJ-1 expression is critical for the Akt and mTOR activities that sustain HIF1 stability. Surprisingly, DJ-1 also regulates the activity of the metabolic sensor AMPK, especially during hypoxia. Finally, DJ-1 appears to protect cells against hypoxia-induced cell death and is required for their adaptation to severe hypoxic stress. Our work positions DJ-1 as an upstream activator of HIF1 function in cancer cells and establishes that DJ-1's oncogenic activity stems from its ability to increase a cell's resistance to hypoxic stress through DJ-1's regulatory effects on mTOR and AMPK. The discovery of these functions of DJ-1 strengthens the case for the development of therapeutics that target DJ-1 activity in cancer cells.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Oncogênicas/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose , Autofagia , Hipóxia Celular , Linhagem Celular Tumoral , Citoproteção , Regulação da Expressão Gênica , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Peroxirredoxinas , Proteína Desglicase DJ-1 , Proteínas Quinases/metabolismo , Serina-Treonina Quinases TOR
10.
Oncogenesis ; 11(1): 46, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35945203

RESUMO

Lipids are essential constituents for malignant tumors, as they are absolutely required for tumor growth and dissemination. Provided by the tumor microenvironment (TME) or by cancer cells themselves through activation of de novo synthesis pathways, they orchestrate a large variety of pro-tumorigenic functions. Importantly, TME cells, especially immune cells, cancer-associated fibroblasts (CAFs) and cancer-associated adipocytes (CAAs), are also prone to changes in their lipid content, which hinder or promote tumor aggressiveness. In this review, we address the significant findings for lipid contribution in tumor progression towards a metastatic disease and in the poor response to therapeutic treatments. We also highlight the benefits of targeting lipid pathways in preclinical models to slow down metastasis development and overcome chemo-and immunotherapy resistance.

11.
Sci Signal ; 15(745): eabg8191, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35917363

RESUMO

In pancreatic ductal adenocarcinoma (PDAC), signaling from stromal cells is implicated in metastatic progression. Tumor-stroma cross-talk is often mediated through extracellular vesicles (EVs). We previously reported that EVs derived from cancer-associated stromal fibroblasts (CAFs) that are abundant in annexin A6 (ANXA6+ EVs) support tumor cell aggressiveness in PDAC. Here, we found that the cell surface glycoprotein and tetraspanin CD9 is a key component of CAF-derived ANXA6+ EVs for mediating this cross-talk. CD9 was abundant on the surface of ANXA6+ CAFs isolated from patient PDAC samples and from various mouse models of PDAC. CD9 colocalized with CAF markers in the tumor stroma, and CD9 abundance correlated with tumor stage. Blocking CD9 impaired the uptake of ANXA6+ EVs into cultured PDAC cells. Signaling pathway arrays and further analyses revealed that the uptake of CD9+ANXA6+ EVs induced mitogen-activated protein kinase (MAPK) pathway activity, cell migration, and epithelial-to-mesenchymal transition (EMT). Blocking either CD9 or p38 MAPK signaling impaired CD9+ANXA6+ EV-induced cell migration and EMT in PDAC cells. Analysis of bioinformatic datasets indicated that CD9 abundance was an independent marker of poor prognosis in patients with PDAC. Our findings suggest that CD9-mediated stromal cell signaling promotes PDAC progression.


Assuntos
Fibroblastos Associados a Câncer , Carcinoma Ductal Pancreático , Vesículas Extracelulares , Neoplasias Pancreáticas , Animais , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Vesículas Extracelulares/metabolismo , Camundongos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas
12.
FEBS J ; 289(18): 5516-5526, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-34817127

RESUMO

The 4th International meeting Metabolism and Cancer initially programed to take place in Bordeaux (France) was held virtually on May 27-29, 2021. The three-day event was followed by around 600 participants daily from 47 countries around the world. The meeting hosted 21 speakers including selected talks and a keynote lecture from the Nobel Prize winner Sir Peter J. Ratcliffe (Oxford, UK). Presentations and discussions were divided in four scientific sessions: (a) Redox and energy metabolism (b) Redox and hypoxia (c) Metabolic profiling and epigenetic control and (d) Signalling, fuelling and metabolism in cancer and a general public session on cancer and nutrition. This report summarises the presentations and outcomes of the 4th annual Metabolism and Cancer symposium. We provide here a summary of the scientific highlights of this exciting meeting.


Assuntos
Metabolismo , Neoplasias , Humanos , Neoplasias/metabolismo , Sociedades Médicas
13.
Commun Biol ; 4(1): 987, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413441

RESUMO

Despite clinical advances in diagnosis and treatment, pancreatic ductal adenocarcinoma (PDAC) remains the third leading cause of cancer death, and is still associated with poor prognosis and dismal survival rates. Identifying novel PDAC-targeted tools to tackle these unmet clinical needs is thus an urgent requirement. Here we use a peptide conjugate that specifically targets PDAC through low-density lipoprotein receptor (LDLR). We demonstrate by using near-infrared fluorescence imaging the potential of this conjugate to specifically detect and discriminate primary PDAC from healthy organs including pancreas and from benign mass-forming chronic pancreatitis, as well as detect metastatic pancreatic cancer cells in healthy liver. This work paves the way towards clinical applications in which safe LDLR-targeting peptide conjugate promotes tumor-specific delivery of imaging and/or therapeutic agents, thereby leading to substantial improvements of the PDAC patient's outcome.


Assuntos
Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Receptores de LDL/genética , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Receptores de LDL/metabolismo
14.
Cells ; 10(9)2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34572146

RESUMO

Bone complications of cystinosis have been recently described. The main objectives of this paper were to determine in vitro the impact of CTNS mutations and cysteamine therapy on human osteoclasts and to carry out a genotype-phenotype analysis related to osteoclastic differentiation. Human osteoclasts were differentiated from peripheral blood mononuclear cells (PBMCs) and were treated with increasing doses of cysteamine (0, 50, 200 µM) and then assessed for osteoclastic differentiation. Results are presented as median (min-max). A total of 17 patients (mainly pediatric) were included, at a median age of 14 (2-61) years, and a eGFR of 64 (23-149) mL/min/1.73 m2. Most patients (71%) were under conservative kidney management (CKM). The others were kidney transplant recipients. Three functional groups were distinguished for CTNS mutations: cystinosin variant with residual cystin efflux activity (RA, residual activity), inactive cystinosin variant (IP, inactive protein), and absent protein (AP). PBMCs from patients with residual cystinosin activity generate significantly less osteoclasts than those obtained from patients of the other groups. In all groups, cysteamine exerts an inhibitory effect on osteoclastic differentiation at high doses. This study highlights a link between genotype and osteoclastic differentiation, as well as a significant impact of cysteamine therapy on this process in humans.


Assuntos
Cisteamina/farmacologia , Cistinose/genética , Osteoclastos/metabolismo , Adolescente , Adulto , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Diferenciação Celular/efeitos dos fármacos , Criança , Pré-Escolar , Cisteamina/metabolismo , Cistinose/metabolismo , Cistinose/fisiopatologia , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Mutação , Osteoclastos/efeitos dos fármacos , Fenótipo
15.
Cancer Res ; 80(16): 3359-3371, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32554750

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a deadly and aggressive cancer. Understanding mechanisms that drive preneoplastic pancreatic lesions is necessary to improve early diagnostic and therapeutic strategies. Mutations and inactivation of activin-like kinase (ALK4) have been demonstrated to favor PDAC onset. Surprisingly, little is known regarding the ligands that drive ALK4 signaling in pancreatic cancer or how this signaling pathway limits the initiation of neoplastic lesions. In this study, data mining and histologic analyses performed on human and mouse tumor tissues revealed that activin A is the major ALK4 ligand that drives PDAC initiation. Activin A, which is absent in normal acinar cells, was strongly induced during acinar-to-ductal metaplasia (ADM), which was promoted by pancreatitis or the activation of KrasG12D in mice. Activin A expression during ADM was associated with the cellular senescence program that is induced in precursor lesions. Blocking activin A signaling through the use of a soluble form of activin receptor IIB (sActRIIB-Fc) and ALK4 knockout in mice expressing KrasG12D resulted in reduced senescence associated with decreased expression of p21, reduced phosphorylation of H2A histone family member X (H2AX), and increased proliferation. Thus, this study indicates that activin A acts as a protective senescence-associated secretory phenotype factor produced by Kras-induced senescent cells during ADM, which limits the expansion and proliferation of pancreatic neoplastic lesions. SIGNIFICANCE: This study identifies activin A to be a beneficial, senescence-secreted factor induced in pancreatic preneoplastic lesions, which limits their proliferation and ultimately slows progression into pancreatic cancers.


Assuntos
Receptores de Ativinas Tipo I/metabolismo , Ativinas/biossíntese , Carcinoma Ductal Pancreático/etiologia , Senescência Celular/fisiologia , Neoplasias Pancreáticas/etiologia , Lesões Pré-Cancerosas/etiologia , Receptores de Ativinas Tipo I/genética , Receptores de Activinas Tipo II/metabolismo , Ativinas/antagonistas & inibidores , Animais , Carcinoma Ductal Pancreático/metabolismo , Progressão da Doença , Genes ras , Humanos , Camundongos , Neoplasias Pancreáticas/metabolismo , Fosforilação , Lesões Pré-Cancerosas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Ativação Transcricional
16.
Front Oncol ; 8: 117, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29725585

RESUMO

As with castles, tumor cells are fortified by surrounding non-malignant cells, such as cancer-associated fibroblasts, immune cells, but also nerve fibers and extracellular matrix. In most cancers, this fortification creates a considerable solid pressure which limits oxygen and nutrient delivery to the tumor cells and causes a hypoxic and nutritional stress. Consequently, tumor cells have to adapt their metabolism to survive and proliferate in this harsh microenvironment. To satisfy their need in energy and biomass, tumor cells develop new capacities to benefit from metabolites of the microenvironment, either by their uptake through the macropinocytosis process or through metabolite transporters, or by a cross-talk with stromal cells and capture of extracellular vesicles that are released by the neighboring cells. However, the microenvironments of primary tumor and metastatic niches differ tremendously in their cellular/acellular components and available nutrients. Therefore, cancer cells must develop a metabolic flexibility conferring on them the ability to satisfy their biomass and energetic demands at both primary and metastasis sites. In this review, we propose a brief overview of how proliferating cancer cells take advantage of their surrounding microenvironment to satisfy their high metabolic demand at both primary and metastasis sites.

17.
Cancer Res ; 78(4): 909-921, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29269518

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive stroma and pathogenic modifications to the peripheral nervous system that elevate metastatic capacity. In this study, we show that the IL6-related stem cell-promoting factor LIF supports PDAC-associated neural remodeling (PANR). LIF was overexpressed in tumor tissue compared with healthy pancreas, but its receptors LIFR and gp130 were expressed only in intratumoral nerves. Cancer cells and stromal cells in PDAC tissues both expressed LIF, but only stromal cells could secrete it. Biological investigations showed that LIF promoted the differentiation of glial nerve sheath Schwann cells and induced their migration by activating JAK/STAT3/AKT signaling. LIF also induced neuronal plasticity in dorsal root ganglia neurons by increasing the number of neurites and the soma area. Notably, injection of LIF-blocking antibody into PDAC-bearing mice reduced intratumoral nerve density, supporting a critical role for LIF function in PANR. In serum from human PDAC patients and mouse models of PDAC, we found that LIF titers positively correlated with intratumoral nerve density. Taken together, our findings suggest LIF as a candidate serum biomarker and diagnostic tool and a possible therapeutic target for limiting the impact of PANR in PDAC pathophysiology and metastatic progression.Significance: This study suggests a target to limit neural remodeling in pancreatic cancer, which contributes to poorer quality of life and heightened metastatic progression in patients. Cancer Res; 78(4); 909-21. ©2017 AACR.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Fator Inibidor de Leucemia/metabolismo , Neurônios/metabolismo , Neoplasias Pancreáticas/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Feminino , Xenoenxertos , Humanos , Fator Inibidor de Leucemia/genética , Masculino , Camundongos , Neurônios/patologia , Pâncreas/inervação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosforilação , Células RAW 264.7 , Transdução de Sinais
18.
Clin Cancer Res ; 12(1): 235-41, 2006 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-16397047

RESUMO

Gemcitabine is the only available chemotherapeutic treatment of pancreatic cancers. It is, however, moderately effective, showing a tumor response rate of only 12%. The aim of this work was to identify new pathways involved in the resistance of pancreatic cancer cells to gemcitabine, in the hope of developing new adjuvant strategies to enhance its therapeutic efficacy. Comparison of gene expression patterns of five human pancreatic cancer cell lines showing different degrees of resistance to gemcitabine revealed specific overexpression of several genes in the most resistant. One of them encoded the antiapoptotic p8 protein. We found that (a) knocking down p8 expression in gemcitabine-resistant cells promoted cell death and increased caspase-3 activity; (b) forced overexpression of p8 in gemcitabine-sensitive cells increased their resistance to gemcitabine-induced apoptosis; and (c) gemcitabine down-regulated p8 mRNA expression. These results suggest that, in pancreatic cancer cells, a large part of gemcitabine-induced apoptosis results from the inhibition of the constitutive antiapoptotic activity of p8. Hence, targeting the p8-associated pathway could be a new adjuvant therapy improving the response of patients with pancreatic cancer to gemcitabine treatment.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/metabolismo , Apoptose/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/efeitos dos fármacos , Linhagem Celular Tumoral , Desoxicitidina/farmacologia , Citometria de Fluxo , Expressão Gênica , Humanos , Proteínas de Neoplasias/efeitos dos fármacos , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Pancreáticas/genética , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Gencitabina
19.
Sci Rep ; 7: 45136, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28332584

RESUMO

Metabolic reprogramming is a hallmark of cancer development, mediated by genetic and epigenetic alterations that may be pharmacologically targeted. Among oncogenes, the kinase Akt is commonly overexpressed in tumors and favors glycolysis, providing a rationale for using Akt inhibitors. Here, we addressed the question of whether and how inhibiting Akt activity could improve therapy of non-small cell lung cancer (NSCLC) that represents more than 80% of all lung cancer cases. First, we demonstrated that Akt inhibitors interacted synergistically with Microtubule-Targeting Agents (MTAs) and specifically in cancer cell lines, including those resistant to chemotherapy agents and anti-EGFR targeted therapies. In vivo, we further revealed that the chronic administration of low-doses of paclitaxel - i.e. metronomic scheduling - and the anti-Akt perifosine was the most efficient and the best tolerated treatment against NSCLC. Regarding drug mechanism of action, perifosine potentiated the pro-apoptotic effects of paclitaxel, independently of cell cycle arrest, and combining paclitaxel/perifosine resulted in a sustained suppression of glycolytic and mitochondrial metabolism. This study points out that targeting cancer cell bioenergetics may represent a novel therapeutic avenue in NSCLC, and provides a strong foundation for future clinical trials of metronomic MTAs combined with Akt inhibitors.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Metabolismo Energético/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Técnicas de Cultura de Células , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Glicólise , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Camundongos , Mitocôndrias/metabolismo , Paclitaxel/farmacologia , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Nat Commun ; 8: 16031, 2017 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-28685754

RESUMO

Tissue architecture contributes to pancreatic ductal adenocarcinoma (PDAC) phenotypes. Cancer cells within PDAC form gland-like structures embedded in a collagen-rich meshwork where nutrients and oxygen are scarce. Altered metabolism is needed for tumour cells to survive in this environment, but the metabolic modifications that allow PDAC cells to endure these conditions are incompletely understood. Here we demonstrate that collagen serves as a proline reservoir for PDAC cells to use as a nutrient source when other fuels are limited. We show PDAC cells are able to take up collagen fragments, which can promote PDAC cell survival under nutrient limited conditions, and that collagen-derived proline contributes to PDAC cell metabolism. Finally, we show that proline oxidase (PRODH1) is required for PDAC cell proliferation in vitro and in vivo. Collectively, our results indicate that PDAC extracellular matrix represents a nutrient reservoir for tumour cells highlighting the metabolic flexibility of this cancer.


Assuntos
Carcinoma Ductal Pancreático/genética , Colágeno/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , Prolina Oxidase/genética , Prolina/metabolismo , Animais , Transporte Biológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Colágeno/química , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Humanos , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Transgênicos , Transplante de Neoplasias , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pró-Colágeno-Prolina Dioxigenase/genética , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Prolina Oxidase/metabolismo , Transdução de Sinais
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