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1.
Artigo em Inglês | MEDLINE | ID: mdl-33822512

RESUMO

The purpose of this study was to investigate the anti-inflammatory, antiproliferatiive, and proapoptotic molecular mechanisms of mangiferin (MGN) against mammary carcinogenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA). Mammary cancer in rats was induced by single-dose subcutaneous injection of 0.5 ml DMBA (80 mg/kg in sesame oil) in the mammary gland. Increased tumor incidence and volume and other tumorigenic properties were observed. Further, we observed in these rats reduced antioxidant enzyme activity and elevated thiobarbituric acid reactive substance (TBARS) levels in plasma and tissues. DMBA-induced rats shows enhanced expression of the inflammatory markers NF-κBp65, COX-2, and iNOS and proliferation of PCNA and Cyclin D1, and overexpression of the antiapoptotic marker Bcl-2. Mangiferin (100 mg/kg body weight), administered orally once per day, significantly enhanced (p < 0.05) antioxidant levels and reduced TBARS levels. Moreover, MGN inhibited NF-κBp65 nucleus transcriptional activation, thereby suppressing inflammation and cell proliferation, and it increased proapoptotic proteins. Apoptosis was confirmed by TUNEL assay. In summary, MGN suppressed DMBA-induced mammary carcinogenesis through enhanced antioxidant levels, NF-κB inhibition, and positive regulation of apoptotic signals.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Mamárias Experimentais/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Xantonas/uso terapêutico , 9,10-Dimetil-1,2-benzantraceno , Animais , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinógenos , Proliferação de Células/efeitos dos fármacos , Feminino , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Xantonas/farmacologia
2.
Nat Commun ; 12(1): 1502, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33686070

RESUMO

It is unclear how genetic aberrations impact the state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) has been shown to arise from luminal progenitors yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that perturbing Brca1/p53 in luminal progenitors induces aberrant alveolar differentiation pre-malignancy accompanied by pro-tumourigenic changes in the immune compartment. Unlike alveolar differentiation during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Based on our data we propose a model where Brca1/p53 LOF inadvertently promotes a differentiation program hardwired in luminal progenitors, highlighting the deterministic role of the cell-of-origin and offering a potential explanation for the tissue specificity of BRCA1 tumours.


Assuntos
Proteína BRCA1/genética , Transformação Celular Neoplásica/genética , Neoplasias Mamárias Experimentais/genética , Fenobarbital/metabolismo , Análise de Célula Única/métodos , Células-Tronco/patologia , Animais , Proteína BRCA1/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Comunicação Celular/fisiologia , Diferenciação Celular/fisiologia , Transformação Celular Neoplásica/metabolismo , Feminino , Humanos , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Mutação , Células-Tronco/fisiologia , Microambiente Tumoral/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
3.
Int J Mol Sci ; 22(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652981

RESUMO

Basal-like breast cancer (BLBC) is an aggressive and deadly subtype of human breast cancer that is highly metastatic, displays stem-cell like features, and has limited treatment options. Therefore, developing and characterizing preclinical mouse models with tumors that resemble BLBC is important for human therapeutic development. ATF3 is a potent oncogene that is aberrantly expressed in most human breast cancers. In the BK5.ATF3 mouse model, overexpression of ATF3 in the basal epithelial cells of the mammary gland produces tumors that are characterized by activation of the Wnt/ß-catenin signaling pathway. Here, we used RNA-Seq and microRNA (miRNA) microarrays to better define the molecular features of BK5.ATF3-derived mammary tumors. These analyses showed that these tumors share many characteristics of human BLBC including reduced expression of Rb1, Esr1, and Pgr and increased expression of Erbb2, Egfr, and the genes encoding keratins 5, 6, and 17. An analysis of miRNA expression revealed reduced levels of Mir145 and Mir143, leading to the upregulation of their target genes including both the pluripotency factors Klf4 and Sox2 as well as the cancer stem-cell-related gene Kras. Finally, we show through knock-down experiments that ATF3 may directly modulate MIR145/143 expression. Taken together, our results indicate that the ATF3 mouse mammary tumor model could provide a powerful model to define the molecular mechanisms leading to BLBC, identify the factors that contribute to its aggressiveness, and, ultimately, discover specific genes and gene networks for therapeutic targeting.


Assuntos
Fator 3 Ativador da Transcrição/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Mamárias Animais/genética , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Regulação para Cima , Via de Sinalização Wnt
4.
Mol Carcinog ; 60(3): 213-223, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33544936

RESUMO

The overexpression and amplification of the protooncogene neu (ERBB2) play an important role in the development of aggressive breast cancer (BC) in humans. Ral-interacting protein (RLIP), a modular stress-response protein with pleiotropic functions, is overexpressed in several types of cancer, including BC. Here, we show that blocking RLIP attenuates the deleterious effects caused by the loss of the tumor suppressor p53 and inhibits the growth of human BC both in vitro and in vivo in MMTV-neu mice. In addition, we show that treatment with the diet-derived, RLIP-targeting chemotherapeutic 2'-hydroxyflavanone (2HF), alone or in combination with RLIP-specific antisense RNA or antibodies, significantly reduced the cumulative incidence and/or burden of mammary hyperplasia and carcinoma in MMTV-neu mice. 2HF treatment correlated with reduced tumor cell proliferation and increased apoptosis, and the average number of Ki67-positive (proliferating) cells was significantly lower in the tumors of 2HF-treated mice than in the tumors of control mice. Furthermore, targeting RLIP also resulted in the overexpression of E-cadherin and the infiltration of CD3+ T cells into mammary tumors. Taken together, these results underscore the translational potential of RLIP-targeting agents and provide a strong rationale to validate them in the clinic.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Anticarcinógenos/farmacologia , Neoplasias da Mama/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Neoplasias Mamárias Experimentais/prevenção & controle , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Flavanonas/farmacologia , Proteínas Ativadoras de GTPase/genética , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Glândulas Mamárias Animais/efeitos dos fármacos , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos Transgênicos , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor ErbB-2/metabolismo
5.
ACS Appl Mater Interfaces ; 13(5): 6053-6068, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33525873

RESUMO

Nanomedicine developed to date by means of directly encapsulating cytotoxins suffers from crucial drawbacks, including premature release and detoxification prior to arrival at pharmaceutics targets. To these respects, redox-responsive polymeric prodrugs of platinum (Pt) and camptothecin (CPT), selectively and concomitantly activated in the cytoplasm, were elaborated in manufacture of dual prodrug nanomedicine. Herein, multiple CPTs were conjugated to poly(lysine) (PLys) segments of block copolymeric poly(ethylene glycol) (PEG)-PLys through the redox responsive disulfide linkage [PEG-PLys(ss-CPT)] followed by reversible conversion of amino groups from PLys into carboxyl groups based on their reaction with cis-aconitic anhydride [PEG-PLys(ss-CPT&CAA)]. On the other hand, Pt(IV) in conjugation with dendritic polyamindoamine [(G3-PAMAM-Pt(IV)] was synthesized for electrostatic complexation with PEG-PLys(ss-CPT&CAA) into dual prodrug nanomedicine. Subsequent investigations proved that the elaborated nanomedicine could sequentially respond to intracellular chemical potentials to overcome a string of predefined biological barriers and facilitate intracellular trafficking. Notably, PEG-PLys(ss-CPT&CAA) capable of responding to the acidic endosomal microenvironment for transformation into endosome-disruptive PEG-PLys(ss-CPT), as well as release of G3-PAMAM-Pt(IV) from nanomedicine, prompted transclocation of therapeutic payloads from endosomes into cytosols. Moreover, concurrent activation and liberation of cytotoxic CPT and Pt(II) owing to their facile responsiveness to the cytoplasmic reducing microenvironment have demonstrated overwhelming cytotoxic potencies. Eventually, systemic administration of the dual prodrug construct exerted potent tumor suppression efficacy in treatment of intractable solid breast adenocarcinoma, as well as an appreciable safety profile. The present study illustrated the first example of nanomedicine with a dual prodrug motif, precisely and concomitantly activated by the same subcellular stimuli before approaching pharmaceutic action targets, thus shedding important implication in development of advanced nanomedicine to seek maximized pharmaceutic outcomes.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Citotoxinas/farmacologia , Nanomedicina , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Camptotecina/síntese química , Camptotecina/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citotoxinas/síntese química , Citotoxinas/química , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Tamanho da Partícula , Pró-Fármacos/síntese química , Pró-Fármacos/química , Propriedades de Superfície , Células Tumorais Cultivadas
6.
Nat Commun ; 12(1): 769, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536445

RESUMO

Some breast tumors metastasize aggressively whereas others remain dormant for years. The mechanism governing metastatic dormancy remains largely unknown. Through high-parametric single-cell mapping in mice, we identify a discrete population of CD39+PD-1+CD8+ T cells in primary tumors and in dormant metastasis, which is hardly found in aggressively metastasizing tumors. Using blocking antibodies, we find that dormancy depends on TNFα and IFNγ. Immunotherapy reduces the number of dormant cancer cells in the lungs. Adoptive transfer of purified CD39+PD-1+CD8+ T cells prevents metastatic outgrowth. In human breast cancer, the frequency of CD39+PD-1+CD8+ but not total CD8+ T cells correlates with delayed metastatic relapse after resection (disease-free survival), thus underlining the biological relevance of CD39+PD-1+CD8+ T cells for controlling experimental and human breast cancer. Thus, we suggest that a primary breast tumor could prime a systemic, CD39+PD-1+CD8+ T cell response that favors metastatic dormancy in the lungs.


Assuntos
Antígenos CD/imunologia , Apirase/imunologia , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias Mamárias Experimentais/imunologia , Receptor de Morte Celular Programada 1/imunologia , Animais , Antígenos CD/metabolismo , Apirase/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Humanos , Imunoterapia , Pulmão/imunologia , Pulmão/patologia , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Knockout , Metástase Neoplásica , Receptor de Morte Celular Programada 1/metabolismo
7.
Anticancer Res ; 41(1): 55-70, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33419799

RESUMO

BACKGROUND/AIM: Our understanding of cancer risk from neutron exposure is limited. We aimed to reveal the characteristics of mammary carcinomas induced by neutrons. MATERIALS AND METHODS: Mammary carcinomas obtained from female Sprague-Dawley rats irradiated at 7 weeks of age with 0.97 Gy neutrons or 4 Gy γ-rays and from non-irradiated rats were classified into luminal and non-luminal subtypes by immunohistochemistry. Their mutational landscapes were determined by whole-exome sequencing. RESULTS: Neutrons significantly raised the incidence of luminal mammary carcinomas over the non-luminal subtype. Somatic mutations were identified in cancer genes involved in several signalling pathways, including Keap1/Nrf2, Pi3k/Akt and Wnt/ß-catenin. Focal copy-number losses involving cancer genes were observed mainly in carcinomas from the irradiated rats. CONCLUSION: Neutrons increase the incidence of luminal mammary carcinomas, probably through gene mutations similar to those found in human breast cancers, and focal copy-number losses including cancer genes that are characteristics of radiation-induced mammary carcinomas.


Assuntos
Variações do Número de Cópias de DNA/efeitos da radiação , Exoma , Neoplasias Mamárias Experimentais/genética , Mutação/efeitos da radiação , Radiação Ionizante , Animais , Biópsia , Biologia Computacional/métodos , Metilação de DNA , Análise Mutacional de DNA , Feminino , Humanos , Mutação INDEL , Imuno-Histoquímica , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/radioterapia , Neoplasias Induzidas por Radiação/genética , Neoplasias Induzidas por Radiação/patologia , Ratos , Sequenciamento Completo do Exoma
8.
J Mater Chem B ; 9(4): 1040-1048, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33392615

RESUMO

Carrier-free nanomedicines without structural modification are attractive for the development of natural small molecules (NSMs) and biomedical applications. Moreover, the combination of NSMs is expected to obtain nanomedicines with high efficacy and low side effects due to their inherent pharmacological activities and health benefits. However, poor water solubility and low bioavailability of NSMs limit their wider biomedical and clinical applications. In this study, we revealed the co-assembly properties of pentacyclic triterpenoids and constructed a series of carrier-free nanodrugs, which are co-assembled nanoparticles (NPs) formed by the combination of two NSMs via a supramolecular assembly strategy. Experimental work and simulation studies were combined to reveal the co-assembly mechanism of non-covalent interactions between NSMs. Not only do co-assembled NPs have rapid cellular uptake ability and passive targeting tumor ability based on the EPR effect, but also their constituent units could arrest the cell cycle at different stages of tumor cells and induce apoptosis, showing synergistic anti-tumor effects (CI < 0.7). Compared with self-assembled NPs and positive control, co-assembled NPs show the strongest therapeutic effect in vivo. Importantly, the co-assembled NPs highlight the unique advantages of NSMs in terms of biosafety and health benefits, and systemic toxicity and histological examination confirm that co-assembled NPs have reliable biosafety, and no side effects and nano toxicity risks were observed.


Assuntos
Antineoplásicos/farmacologia , Nanopartículas/química , Paclitaxel/farmacologia , Triterpenos Pentacíclicos/farmacologia , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nanomedicina , Imagem Óptica , Paclitaxel/química , Tamanho da Partícula , Triterpenos Pentacíclicos/química , Propriedades de Superfície , Células Tumorais Cultivadas
9.
Carbohydr Polym ; 255: 117490, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33436250

RESUMO

To deliver photosensitizers with PEGylated heparin (HP) into tumor cells for photodynamic therapy, we prepared two polyethylene glycol (PEG)-functionalized HP-based polymers conjugated with pyropheophorbide-a (Ppa): a non-GSH-responsive nanoagent (HP-Ppa-mPEG) with the mPEG moiety chemically attached to HP directly; and a GSH-responsive nanoagent (HP-Ppa-SS-mPEG) with the mPEG moiety conjugated to HP via a disulfide linkage. The Ppa-functionalized HP without PEGylation (HP-Ppa) was designed as another control. These amphiphilic polymers could aggregate into nanoparticles. Cellular uptake of three nanoparticles by 4T1 cells led to abundant production of reactive oxygen species after irradiation by a 660 nm laser, inducing cell apoptosis. HP-Ppa-SS-mPEG was found to achieve the highest tumor accumulation, the longest retention time and the best penetration into tumor tissues, resulting in the highest in vivo anticancer efficacy with 94.3 % tumor growth inhibition rate, suggesting that tumor microenvironment-responsive PEGylated HP-based nanomedicines may act as efficient anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Clorofila/análogos & derivados , Heparina/química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Clorofila/química , Feminino , Lasers , Luz , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nanoconjugados/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/síntese química , Polietilenoglicóis/química , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos
10.
J Mater Chem B ; 9(4): 1049-1058, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33399610

RESUMO

It is difficult for drug delivery systems to release drugs as expected, often leading to undesired side effects. To solve this problem, a CuS@MSN/DOX@MnO2@membrane (CMDMm) was reasonably designed. It was introduced to release the drug by a double response, similar to using two keys to open two locks at the same time for one door. CuS@MSN was used as a photothermal therapy (PTT) material and carrier, and then the surface of CuS@MSN/DOX was sealed by MnO2 to prevent drug release in advance. MnO2 could be reduced and degraded in a tumor microenvironment. It was applied in MR imaging due to the T1 magnetism of Mn2+ following the reduction of MnO2. Finally, the 4T1 cell membrane was extracted and coated onto the surface of CuS@MSN/DOX@MnO2, which served as a target for 4T1 tumor cells. A noteworthy phenomenon was that the fluorescence of DOX was quenched by the coordination between DOX and CuS, and this greatly improved the interaction between DOX and CuS@MSN. However, the coordination was weakened when DOX was protonated in a tumor microenvironment (∼pH 5.0), leading to the release of DOX and fluorescence recovery. The drug release experiments showed that the release efficiency was higher at pH 5.0 with 10 mmol L-1 GSH. Through in vitro laser confocal imaging, it was successfully observed that DOX was reliably released in specific tumor cells according to the fluorescence recovery, and that there was no leakage in other cells. In short, effective double response drug release was successfully confirmed.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Cobre/farmacologia , Doxorrubicina/farmacologia , Compostos de Manganês/farmacologia , Nanopartículas/química , Óxidos/farmacologia , Animais , Antibióticos Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cobre/química , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Compostos de Manganês/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Óxidos/química , Tamanho da Partícula , Propriedades de Superfície
11.
J Mater Chem B ; 9(4): 1089-1095, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33427258

RESUMO

Near-infrared fluorophores are emerging as promising molecular tools for cancer theranostics because of their inherent biodegradability, low toxicity, and synthetic flexibility. However, they still suffer from several limitations, such as poor photostability and insufficient organelle-targeting stability during photothermal therapy. In this work, we introduce an "aldehyde functionalization" strategy for simultaneously enhancing photostability and mitochondria-immobilization of near-infrared fluorophores for the first time. Based on the proposed strategy, representative near-infrared organic molecules, namely AF-Cy, were rationally designed and synthesized. Upon aldehyde modification, the AF-Cy dyes displayed both remarkable photostability and mitochondrial-targeting stability. The strong absorption in the near-infrared region confers the AF-Cy dyes with outstanding fluorescent/photoacoustic imaging and photothermal therapy capabilities. Finally, in vitro and in vivo studies revealed the enhanced performance in inhibiting the growth of breast tumors under NIR laser radiation, and these results suggested the strong potential of AF-Cy dyes as efficient multimodal imaging-guided photothermal therapy agents, further highlighting the value of this simple strategy in the design high performance near-infrared fluorophores for tumor theranostics.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Corantes Fluorescentes/farmacologia , Mitocôndrias/efeitos dos fármacos , Imagem Multimodal , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Raios Infravermelhos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Tamanho da Partícula , Processos Fotoquímicos , Propriedades de Superfície
12.
Am J Pathol ; 191(3): 515-526, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33345997

RESUMO

Nerve infiltration into the tumor is a common feature of the tumor microenvironment. The mechanisms of axonogenesis in breast cancer remain unclear. We hypothesized that vascular endothelial growth factor (VEGF), as well as nerve growth factor (NGF), is involved in the axonogenesis of breast cancer. A N-methyl-N-nitrosourea (MNU)-induced rat model of breast cancer was used to explore the presence of axonogenesis in breast tumor and the involvement of VEGF, as well as NGF, in the axonogenesis of breast tumor. Nerve infiltration into the tumor was found in MNU-induced rat model of breast cancer including the sensory and sympathetic nerve fibers. Nerve density was increased following the growth of tumor. The sensory neurons innervating the thoracic and abdominal mammary tumors peaked at T5 to T6 and L1 to L2 dorsal root ganglions, respectively. Either VEGF receptor inhibitor or antibody against VEGF receptor 2, as well as NGF receptor inhibitor, apparently decreased both the nerve density and vascular density of breast tumor. The reduced nerve density was correlated with the decreased vascular density induced by these treatments. In cultured dorsal root ganglion neurons, phosphatidylinositol 3 (PI3K)/Akt, extracellular signal-regulated protein kinase (ERK), and p38 inhibitors significantly attenuated VEGF-induced neurite elongation. These findings provide direct evidence that VEGF, as well as NGF, may control the axonogenesis of breast cancer.


Assuntos
Axônios/patologia , Neoplasias Mamárias Experimentais/patologia , Neuritos/patologia , Neurogênese , Fator A de Crescimento do Endotélio Vascular/metabolismo , Alquilantes/toxicidade , Animais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Sistema de Sinalização das MAP Quinases , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/metabolismo , Metilnitrosoureia/toxicidade , Neuritos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética
13.
Carbohydr Polym ; 254: 117476, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33357929

RESUMO

Herein the nucleic acid aptamers were attached to the polydeoxyadenylic acid (poly(dA)) tail for improving the tumor-targetability and cellular internalization of s-LNT/poly(dA) composite composed of two single chains of triple helical ß-glucan lentinan (s-LNT) and one poly(dA) chain. The in vitro results demonstrate that the cellular uptake of s-LNT/poly(dA) composites in MCF-7 cancer cells was enhanced effectively after attaching the aptamer. The as-prepared fluorescin isothiocyanate (FITC)-labelled LNT (LNT-FITC) through grafting was used for tracing the enhanced tumor-targetability of the composites. As a result, the cellular internalization of the LNT-FITC into MCF-7 and 4T1 cancer cells was further increased by the aptamer conjugated to poly(dA). Meanwhile, the in vivo experiments further demonstrate more s-LNT/poly(dA)-aptamer composites were effectively accumulated at the tumor site compared with s-LNT alone. This work provides a novel strategy for fabricating triplex ß-glucan as delivery vectors with active tumor-targetability.


Assuntos
Antineoplásicos/farmacologia , Aptâmeros de Nucleotídeos/administração & dosagem , Lentinano/farmacologia , Neoplasias Mamárias Experimentais/terapia , Terapia de Alvo Molecular/métodos , Poli A/administração & dosagem , Animais , Antineoplásicos/química , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/genética , Linhagem Celular Tumoral , Portadores de Fármacos , Feminino , Fluoresceína-5-Isotiocianato/química , Corantes Fluorescentes/química , Humanos , Injeções Intravenosas , Lentinano/química , Células MCF-7 , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Poli A/química , Poli A/genética , Coloração e Rotulagem/métodos
14.
J Ethnopharmacol ; 265: 113271, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32853742

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cyclophosphamide (CTX) is a first line chemotherapeutic agent, but often limited for its unstable therapeutic effect and serious side effects. Ginsenosides could facilitate the anti-tumor efficiency of CTX, including benefiting therapeutic effect and decreasing side effects. AIM OF THE STUDY: To investigate the potential mechanism of ginsenosides on benefiting the anti-tumor efficiency of CTX. MATERIALS AND METHODS: Mammary carcinoma mice were applied to investigate the anti-tumor efficiency and potential mechanism of combinational treatment of ginsenosides and CTX. Therapeutic effect was evaluated based on survival rate, tumor burden, tumor growth inhibition rate, and apoptosis and histological changes of tumor tissues. Anti-tumor immunity was studied by measuring serum level of anti-tumor cytokines. Gut mucositis, one of lethal side effects of CTX, was evaluated by diarrhea degree, gut permeability and tight junction proteins expressions. Gut microbial diversity was analyzed by 16S rRNA gene sequencing, and fecal transplant and antibiotics sterilized animals were performed to evaluate the therapeutic effect of gut microbiota on tumor suppression. RESULTS: Ginsenosides facilitated the therapeutic effect of CTX in mice, which manifested as prolonged survival rate, decreased tumor burden, as well as enhanced tumor growth inhibition rate and apoptosis. The favoring effect was related to elevation of anti-tumor immunity which manifested as the increased anti-tumor cytokines (INF-γ, IL-17, IL-2 and IL-6). Further studies indicated the elevation was ascribed to ginsenosides promoted reproduction of gut probiotics including Akkermansia, Bifidobacterium and Lactobacillus. Moreover, co-administration of ginsenosides in mice alleviated CTX-induced gut mucositis, including lower gut permeability, less diarrhea, less epithelium damage and higher tight junction proteins. Further researches suggested the alleviation was related to ginsenosides activated Nrf2 and inhibited NFκB pathways. CONCLUSION: Ginsenosides show dual roles to facilitate the anti-tumor efficiency of CTX, namely promote the anti-tumor immunity through maintaining gut microflora and ameliorate gut mucositis by modulating Nrf2 and NFκB pathways.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ciclofosfamida/farmacologia , Ginsenosídeos/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Apoptose/efeitos dos fármacos , Ciclofosfamida/administração & dosagem , Citocinas/sangue , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Ginsenosídeos/administração & dosagem , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos ICR , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , RNA Ribossômico 16S , Taxa de Sobrevida
15.
Mol Cell ; 81(2): 386-397.e7, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33340488

RESUMO

In tumors, nutrient availability and metabolism are known to be important modulators of growth signaling. However, it remains elusive whether cancer cells that are growing out in the metastatic niche rely on the same nutrients and metabolic pathways to activate growth signaling as cancer cells within the primary tumor. We discovered that breast-cancer-derived lung metastases, but not the corresponding primary breast tumors, use the serine biosynthesis pathway to support mTORC1 growth signaling. Mechanistically, pyruvate uptake through Mct2 supported mTORC1 signaling by fueling serine biosynthesis-derived α-ketoglutarate production in breast-cancer-derived lung metastases. Consequently, expression of the serine biosynthesis enzyme PHGDH was required for sensitivity to the mTORC1 inhibitor rapamycin in breast-cancer-derived lung tumors, but not in primary breast tumors. In summary, we provide in vivo evidence that the metabolic and nutrient requirements to activate growth signaling differ between the lung metastatic niche and the primary breast cancer site.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Mamárias Experimentais/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Fosfoglicerato Desidrogenase/genética , Serina/biossíntese , Animais , Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Ácidos Cetoglutáricos/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Fosfoglicerato Desidrogenase/metabolismo , Ácido Pirúvico/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Sirolimo/farmacologia
16.
Int J Mol Sci ; 21(24)2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33353068

RESUMO

Breast cancer is one of the most frequently diagnosed malignancies and common causes of cancer death in women. Recent studies suggest that environmental exposures to certain chemicals, such as 7,12-Dimethylbenzanthracene (DMBA), a chemical present in tobacco, may increase the risk of developing breast cancer later in life. The first-line treatments for breast cancer (surgery, chemotherapy or a combination of both) are generally invasive and frequently associated with severe side effects and high comorbidity. Consequently, novel approaches are strongly required to find more natural-like experimental models that better reflect the tumors' etiology, physiopathology and response to treatments, as well as to find more targeted, efficient and minimally invasive treatments. This study proposes the development and an in deep biological characterization of an experimental model using DMBA-tumor-induction in Sprague-Dawley female rats. Moreover, a photothermal therapy approach using a near-infrared laser coupled with gold nanoparticles was preliminarily assessed. The gold nanoparticles were functionalized with Epidermal Growth Factor, and their physicochemical properties and in vitro effects were characterized. DMBA proved to be a very good and selective inductor of breast cancer, with 100% incidence and inducing an average of 4.7 tumors per animal. Epigenetic analysis showed that tumors classified with worst prognosis were hypomethylated. The tumor-induced rats were then subjected to a preliminary treatment using functionalized gold nanoparticles and its activation by laser (650-900 nm). The treatment outcomes presented very promising alterations in terms of tumor histology, confirming the presence of necrosis in most of the cases. Although this study revealed encouraging results as a breast cancer therapy, it is important to define tumor eligibility and specific efficiency criteria to further assess its application in breast cancer treatment on other species.


Assuntos
5-Metilcitosina/metabolismo , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Hipertermia Induzida , Neoplasias Mamárias Experimentais/terapia , Nanopartículas Metálicas/administração & dosagem , Modelos Teóricos , Animais , Peso Corporal , Feminino , Ouro/química , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/patologia , Nanopartículas Metálicas/química , Ratos , Ratos Sprague-Dawley
17.
PLoS One ; 15(12): e0234893, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382695

RESUMO

Breast cancer is the second leading cause of cancer-related mortality in women. Various nutritional compounds possess anti-carcinogenic properties which may be mediated through their effects on the gut microbiota and its production of short-chain fatty acids (SCFAs) for the prevention of breast cancer. We evaluated the impact of broccoli sprouts (BSp), green tea polyphenols (GTPs) and their combination on the gut microbiota and SCFAs metabolism from the microbiota in Her2/neu transgenic mice that spontaneously develop estrogen receptor-negative [ER(-)] mammary tumors. The mice were grouped based on the dietary treatment: control, BSp, GTPs or their combination from beginning in early life (BE) or life-long from conception (LC). We found that the combination group showed the strongest inhibiting effect on tumor growth volume and a significant increase in tumor latency. BSp treatment was integrally more efficacious than the GTPs group when compared to the control group. There was similar clustering of microbiota of BSp-fed mice with combination-fed mice, and GTPs-fed mice with control-fed mice at pre-tumor in the BE group and at pre-tumor and post-tumor in the LC group. The mice on all dietary treatment groups incurred a significant increase of Adlercreutzia, Lactobacillus genus and Lachnospiraceae, S24-7 family in the both BE and LC groups. We found no change in SCFAs levels in the plasma of BSp-fed, GTPs-fed and combination-fed mice of the BE group. Marked changes were observed in the mice of the LC group consisting of significant increases in propionate and isobutyrate in GTPs-fed and combination-fed mice. These studies indicate that nutrients such as BSp and GTPs differentially affect the gut microbial composition in both the BE and LC groups and the key metabolites (SCFAs) levels in the LC group. The findings also suggest that temporal factors related to different time windows of consumption during the life-span can have a promising influence on the gut microbial composition, SCFAs profiles and ER(-) breast cancer prevention.


Assuntos
Dieta/métodos , Ácidos Graxos Voláteis/sangue , Microbioma Gastrointestinal/efeitos dos fármacos , Neoplasias Mamárias Experimentais/prevenção & controle , Polifenóis/farmacologia , Plântula/química , Actinobacteria/efeitos dos fármacos , Actinobacteria/isolamento & purificação , Actinobacteria/fisiologia , Animais , Brassica/química , Clostridiales/efeitos dos fármacos , Clostridiales/isolamento & purificação , Clostridiales/fisiologia , Feminino , Microbioma Gastrointestinal/fisiologia , Expressão Gênica , Lactobacillus/efeitos dos fármacos , Lactobacillus/isolamento & purificação , Lactobacillus/fisiologia , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/sangue , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Knockout , Polifenóis/química , Receptor ErbB-2/deficiência , Receptor ErbB-2/genética , Receptores Estrogênicos/deficiência , Receptores Estrogênicos/genética , Chá/química
18.
Nat Commun ; 11(1): 5436, 2020 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-33116123

RESUMO

Harmful effects of high fructose intake on health have been widely reported. Although fructose is known to promote cancer, little is known about the underlying mechanisms. Here, we found that fructose triggers breast cancer metastasis through the ketohexokinase-A signaling pathway. Molecular experiments showed that ketohexokinase-A, rather than ketohexokinase-C, is necessary and sufficient for fructose-induced cell invasion. Ketohexokinase-A-overexpressing breast cancer was found to be highly metastatic in fructose-fed mice. Mechanistically, cytoplasmic ketohexokinase-A enters into the nucleus during fructose stimulation, which is mediated by LRRC59 and KPNB1. In the nucleus, ketohexokinase-A phosphorylates YWHAH at Ser25 and the YWHAH recruits SLUG to the CDH1 promoter, which triggers cell migration. This study provides the effect of nutrition on breast cancer metastasis. High intake of fructose should be restricted in cancer patients to reduce the risk of metastasis. From a therapeutic perspective, the ketohexokinase-A signaling pathway could be a potential target to prevent cancer metastasis.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Frutoquinases/metabolismo , Frutose/administração & dosagem , Frutose/metabolismo , Proteínas 14-3-3/antagonistas & inibidores , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Animais , Carcinógenos/administração & dosagem , Carcinógenos/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Invasividade Neoplásica/patologia , Metástase Neoplásica/patologia , Fosforilação , Transdução de Sinais , beta Carioferinas/metabolismo
19.
Nat Commun ; 11(1): 5156, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33056990

RESUMO

The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Mutations in TP53 lead to the inhibition of the tumour and metastasis suppressor TAp63, a p53 family member. By performing a mouse-human cross species analysis between the TAp63 metastatic mammary adenocarcinoma mouse model and models of human breast cancer progression, we identified two TAp63-regulated oncogenic lncRNAs, TROLL-2 and TROLL-3. Further, using a pan-cancer analysis of human cancers and multiple mouse models of tumour progression, we revealed that these two lncRNAs induce the activation of AKT to promote cancer progression by regulating the nuclear to cytoplasmic translocation of their effector, WDR26, via the shuttling protein NOLC1. Our data provide preclinical rationale for the implementation of these lncRNAs and WDR26 as therapeutic targets for the treatment of human tumours dependent upon mutant TP53 and/or the PI3K/AKT pathway.


Assuntos
Adenocarcinoma/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Mamárias Experimentais/genética , RNA Longo não Codificante/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma/patologia , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Glândulas Mamárias Animais/citologia , Neoplasias Mamárias Experimentais/patologia , Camundongos , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA-Seq , Transdução de Sinais/genética , Análise Serial de Tecidos , Transativadores/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Anticancer Res ; 40(9): 4869-4874, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878774

RESUMO

BACKGROUND/AIM: In the present study, we evaluated the efficacy of adjuvant administration of oral recombinant methioninase (o-rMETase) against recurrence and metastasis in a 4T1 murine breast-cancer syngeneic model. MATERIALS AND METHODS: 4T1 cells were orthotopically implanted into the 2nd mammary fat pad of BALB/c mice. The 4T1 orthotopic syngeneic models were randomized into 2 groups after primary tumor resection: untreated control and o-rMETase (100 units, oral, daily, 2 weeks). RESULTS: The frequency and extent of local recurrence were reduced by o-rMETase. The number of individual cancer cells and metastatic nodules on the lung surface was significantly lower in the o-rMETase-treated mice than the untreated control mice. CONCLUSION: Adjuvant o-rMETase inhibited local recurrence and lung metastasis after primary tumor resection.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Liases de Carbono-Enxofre/administração & dosagem , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/tratamento farmacológico , Administração Oral , Animais , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Esquema de Medicação , Feminino , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/cirurgia , Camundongos , Camundongos Endogâmicos BALB C , Recidiva Local de Neoplasia/prevenção & controle , Proteínas Recombinantes/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
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