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1.
PLoS One ; 15(9): e0239614, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32986753

RESUMO

Chemotherapy response remains unpredictable in most patients with cancer. In this study, we performed whole-exome sequencing of 79 cancer xenografts derived from human cancer tissues to identify genetic predictors of chemosensitivity to nine cytotoxic anticancer drugs. Xenografts were harvested from 12 organs with cancer and implanted into nude mice. The mice were exposed to one of nine cytotoxic anticancer drugs (5-fluorouracil, nimustine, adriamycin, cyclophosphamide, cisplatin, mitomycin C, methotrexate, vincristine, and vinblastine) to assess the correlation between chemosensitivity response and variant allele frequency. We found 162 candidate variants that were possibly associated with chemosensitivity to one or more of the nine anticancer drugs (P < 0.01). In a subgroup analysis of breast and gastric cancer xenografts, 78 and 67 variants, respectively, were possibly associated with chemosensitivity. This approach may help to contribute to the development of personalized treatments that may allow for the prescription of optimal chemotherapy regimens among patients with cancer.


Assuntos
Antineoplásicos/uso terapêutico , Citotoxinas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Variação Genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/patologia , Resultado do Tratamento , Sequenciamento Completo do Exoma
2.
AAPS PharmSciTech ; 21(6): 235, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32803528

RESUMO

Development of a delivery system to lower systemic toxicity and enhance doxorubicin (DOX) antitumor efficacy against multi-drug resistant (MDR) tumors is of great clinical significance. Here, lipid/hyaluronic acid (HA)-coated DOX-Fe3O4 was characterized to determine its optimal safety and efficacy on a tumor. DOX was first conjugated onto the Fe3O4 NPs surface, which was subsequently coated with phosphatidylcholine (PC) lipids, which consisted of a tumor cell-targeting HA ligand, to generate a dual-targeting nanoparticle (NP). DOX-Fe3O4 synthesis was validated by the Fourier-transform infrared (FT-IR) analysis results. Core-shell PC/HA@DOX-Fe3O4 formation, which had an average particle size of 48.2 nm, was observed based on the transmission electron microscopy (TEM) and dynamic laser light scattering (DLS) results. The saturation magnetization value of PC/HA@DOX-Fe3O4 was discovered to be 28 emu/g using vibrating-sample magnetometry. Furthermore, the designed PC/HA@DOX-Fe3O4 achieved greater MCF-7/ADR cellular uptake and cytotoxicity as compared with DOX. In addition, PC/HA@DOX-Fe3O4 exhibited significant DOX tumor-targeting capabilities and enhanced tumor growth inhibition activity in the xenograft MCF-7/ADR tumor-bearing nude mice following magnetic attraction and ligand-mediated targeting, with less cardiotoxicity. Therefore, PC/HA@DOX-Fe3O4 is a potential candidate for MDR tumor chemotherapy. Graphical abstract.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Compostos Férricos/administração & dosagem , Ácido Hialurônico/administração & dosagem , Nanopartículas/administração & dosagem , Animais , Antibióticos Antineoplásicos/síntese química , Doxorrubicina/síntese química , Compostos Férricos/síntese química , Humanos , Ácido Hialurônico/síntese química , Lipídeos , Células MCF-7 , Camundongos , Camundongos Nus , Nanopartículas/química , Tamanho da Partícula , Distribuição Aleatória , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
3.
Nat Commun ; 11(1): 4153, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32814769

RESUMO

The histone methyltransferase DOT1L methylates lysine 79 (K79) on histone H3 and is involved in Mixed Lineage Leukemia (MLL) fusion leukemogenesis; however, its role in prostate cancer (PCa) is undefined. Here we show that DOT1L is overexpressed in PCa and is associated with poor outcome. Genetic and chemical inhibition of DOT1L selectively impaired the viability of androgen receptor (AR)-positive PCa cells and organoids, including castration-resistant and enzalutamide-resistant cells. The sensitivity of AR-positive cells is due to a distal K79 methylation-marked enhancer in the MYC gene bound by AR and DOT1L not present in AR-negative cells. DOT1L inhibition leads to reduced MYC expression and upregulation of MYC-regulated E3 ubiquitin ligases HECTD4 and MYCBP2, which promote AR and MYC degradation. This leads to further repression of MYC in a negative feed forward manner. Thus DOT1L selectively regulates the tumorigenicity of AR-positive prostate cancer cells and is a promising therapeutic target for PCa.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas c-myc/genética , Receptores Androgênicos/genética , Adenosina/análogos & derivados , Adenosina/farmacologia , Animais , Linhagem Celular Tumoral , Intervalo Livre de Doença , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Compostos de Fenilureia/farmacologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Estabilidade Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Interferência de RNA , Terapêutica com RNAi/métodos , Receptores Androgênicos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
4.
Proc Natl Acad Sci U S A ; 117(37): 22910-22919, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32859758

RESUMO

Lymphocyte-based immunotherapy has emerged as a breakthrough in cancer therapy for both hematologic and solid malignancies. In a subpopulation of cancer patients, this powerful therapeutic modality converts malignancy to clinically manageable disease. However, the T cell- and chimeric antigen receptor T (CAR-T) cell-mediated antimetastatic activity, especially their impacts on microscopic metastatic lesions, has not yet been investigated. Here we report a living zebrafish model that allows us to visualize the metastatic cancer cell killing effect by tumor- infiltrating lymphocytes (TILs) and CAR-T cells in vivo at the single-cell level. In a freshly isolated primary human melanoma, specific TILs effectively eliminated metastatic cancer cells in the living body. This potent metastasis-eradicating effect was validated using a human lymphoma model with CAR-T cells. Furthermore, cancer-associated fibroblasts protected metastatic cancer cells from T cell-mediated killing. Our data provide an in vivo platform to validate antimetastatic effects by human T cell-mediated immunotherapy. This unique technology may serve as a precision medicine platform for assessing anticancer effects of cellular immunotherapy in vivo before administration to human cancer patients.


Assuntos
Imunoterapia/métodos , Linfócitos do Interstício Tumoral/metabolismo , Análise de Célula Única/métodos , Animais , Linhagem Celular Tumoral , Citotoxicidade Imunológica/imunologia , Imunoterapia Adotiva/métodos , Ativação Linfocitária/fisiologia , Modelos Animais , Metástase Neoplásica/patologia , Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Peixe-Zebra
5.
BMC Bioinformatics ; 21(1): 288, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32631229

RESUMO

BACKGROUND: Cancer is a highly heterogeneous disease with varying responses to anti-cancer drugs. Although several attempts have been made to predict the anti-cancer therapeutic responses, there remains a great need to develop highly accurate prediction models of response to the anti-cancer drugs for clinical applications toward a personalized medicine. Patient derived xenografts (PDXs) are preclinical cancer models in which the tissue or cells from a patient's tumor are implanted into an immunodeficient or humanized mouse. In the present study, we develop a bioinformatics analysis pipeline to build a predictive gene expression model (GEM) for cancer patients' drug responses based on gene expression and drug activity data from PDX models. RESULTS: Drug sensitivity biomarkers were identified by performing an association analysis between gene expression levels and post-treatment tumor volume changes in PDX models. We built a drug response prediction model (called PDXGEM) in a random-forest algorithm by using a subset of the drug sensitvity biomarkers with concordant co-expression patterns between the PDXs and pretreatment cancer patient tumors. We applied the PDXGEM to several cytotoxic chemotherapies as well as targeted therapy agents that are used to treat breast cancer, pancreatic cancer, colorectal cancer, or non-small cell lung cancer. Significantly accurate predictions of PDXGEM for pathological response or survival outcomes were observed in extensive independent validations on multiple cancer patient datasets obtained from retrospective observational studies and prospective clinical trials. CONCLUSION: Our results demonstrated the strong potential of using molecular profiles and drug activity data of PDX tumors in developing a clinically translatable predictive cancer biomarkers for cancer patients. The PDXGEM web application is publicly available at http://pdxgem.moffitt.org .


Assuntos
Biomarcadores Tumorais/metabolismo , Expressão Gênica/genética , Neoplasias/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Feminino , Humanos , Masculino , Estudos Prospectivos , Estudos Retrospectivos
6.
Nat Commun ; 11(1): 3406, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641768

RESUMO

Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. We also find that this progenitor population contains the majority of the cancer's cycling cells, and, using RNA velocity, is often the originator of the other cell types. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, suggests a possible origin for glioblastoma hierarchy, and helps to identify cancer stem cell-specific targets.


Assuntos
Neoplasias Encefálicas/genética , Encéfalo/metabolismo , Glioblastoma/genética , Células-Tronco Neoplásicas/metabolismo , Análise de Sequência de RNA/métodos , Transcriptoma/genética , Adulto , Animais , Antineoplásicos Alquilantes/farmacologia , Encéfalo/embriologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Feminino , Feto , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Análise de Célula Única/métodos , Temozolomida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
7.
Toxicol Appl Pharmacol ; 401: 115118, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32619553

RESUMO

Glucocorticoid receptor (GR) modulates extensive biological and pathological processes including tumor progression through diverse mechanisms. The regulatory effects of dexamethasone (DEX), a synthetic glucocorticoid, as well as its interaction with GR have been recognized beyond hematologic cancers. In the present study, we investigated the anti-cancer efficacy of DEX and the correlation with GR in pancreatic cancer, a most aggressive malignancy threatening human health. The differential levels of GR expression were examined in two human pancreatic cancer cell lines, PANC-1 and SW1990, as well as in xenografts and patient tumor tissues. DEX significantly inhibited colony formation, migration, and tumor growth of PANC-1 cells expressing abundant GR. The underlying mechanisms involved suppression of nuclear factor κB (NF-κB) phosphorylation and down-regulation of epithelial-to-mesenchymal transition (EMT), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF). The anti-cancer effects of DEX were partially reversed by GR silencing or combinational administration of GR antagonist, RU486. The dose-dependent efficacy of DEX in tumor growth inhibition was also demonstrated in a GR-positive patient-derived xenograft model along with safety in mice. DEX was less potent, however, in SW1990 cells with poor GR expression. Our findings suggest that DEX effectively inhibits pancreatic tumor growth partially through GR activation. The potential correlation between GR expression and anti-cancer efficacy of DEX may have some clinical implications.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Dexametasona/uso terapêutico , Neoplasias Pancreáticas/metabolismo , Receptores de Glucocorticoides/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Células A549 , Animais , Antineoplásicos Hormonais/farmacologia , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Feminino , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/tratamento farmacológico , Carga Tumoral/fisiologia
8.
Nat Commun ; 11(1): 3326, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620791

RESUMO

Tumour cells adapt to nutrient deprivation in vivo, yet strategies targeting the nutrient poor microenvironment remain unexplored. In melanoma, tumour cells often experience low glutamine levels, which promote cell dedifferentiation. Here, we show that dietary glutamine supplementation significantly inhibits melanoma tumour growth, prolongs survival in a transgenic melanoma mouse model, and increases sensitivity to a BRAF inhibitor. Metabolomic analysis reveals that dietary uptake of glutamine effectively increases the concentration of glutamine in tumours and its downstream metabolite, αKG, without increasing biosynthetic intermediates necessary for cell proliferation. Mechanistically, we find that glutamine supplementation uniformly alters the transcriptome in tumours. Our data further demonstrate that increase in intra-tumoural αKG concentration drives hypomethylation of H3K4me3, thereby suppressing epigenetically-activated oncogenic pathways in melanoma. Therefore, our findings provide evidence that glutamine supplementation can serve as a potential dietary intervention to block melanoma tumour growth and sensitize tumours to targeted therapy via epigenetic reprogramming.


Assuntos
Proliferação de Células/efeitos dos fármacos , Suplementos Nutricionais , Epigênese Genética/efeitos dos fármacos , Glutamina/farmacologia , Melanoma/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Epigênese Genética/genética , Glutamina/administração & dosagem , Histonas/metabolismo , Humanos , Lisina/metabolismo , Masculino , Melanoma/genética , Melanoma/patologia , Metilação/efeitos dos fármacos , Camundongos Nus , Transdução de Sinais/genética , Transcriptoma/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
9.
Nat Commun ; 11(1): 3296, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620799

RESUMO

Identifying robust, patient-specific, and predictive biomarkers presents a major obstacle in precision oncology. To optimize patient-specific therapeutic strategies, here we couple pathway knowledge with large-scale drug sensitivity, RNAi, and CRISPR-Cas9 screening data from 460 cell lines. Pathway activity levels are found to be strong predictive biomarkers for the essentiality of 15 proteins, including the essentiality of MAD2L1 in breast cancer patients with high BRCA-pathway activity. We also find strong predictive biomarkers for the sensitivity to 31 compounds, including BCL2 and microtubule inhibitors (MTIs). Lastly, we show that Bcl-xL inhibition can modulate the activity of a predictive biomarker pathway and re-sensitize lung cancer cells and tumors to MTI therapy. Overall, our results support the use of pathways in helping to achieve the goal of precision medicine by uncovering dozens of predictive biomarkers.


Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Transdução de Sinais/genética , Animais , Antineoplásicos/farmacologia , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Redes Reguladoras de Genes , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Medicina de Precisão/métodos , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
10.
AAPS PharmSciTech ; 21(5): 171, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32529560

RESUMO

Modifications to the surface chemistry, charge, and hydrophilicity/hydrophobicity of nanoparticles are applicable approaches to the alterations of the in vivo fate of intravenously administered nano-sized drug carriers. The objective of this study is to investigate the in vitro and in vivo antitumor efficacies of curcumin PLGA nanoparticles in relation to their surface structural modification via self-assembling coating with unique fungal hydrophobin. The hydophobin-coated curcumin PLGA nanoparticles (HPB PLGA NPs) were obtained by simply soaking curcumin-loaded PLGA nanoparticles (PLGA NPs) in aqueous fungal hydrophobin solution. The in vitro drug release behavior of the HPB PLGA NPS was also tested. The cytotoxicity and cellular uptake of these nanoparticles were determined in HepG2, A549, and Hela cell lines using MTT assay method and CLSM observation. The in vivo antitumor activity was evaluated in Hela tumor xenografted mice model. Compared with the PLGA NPs, the size and zeta potential of the nanoparticles were changed after hydrophobin coating, whereas similar in vitro release pattern was observed. The pharmacodynamics study showed prolonged blood retention of both nano-formulations than that of free curcumin, but no significant difference between the hydrophobin coated and uncoated nanoparticles. It was found that HPB PLGA NPs had increased cytotoxicities, higher cellular uptake, and improved antitumor efficacy. Surface modification of nanoparticles via self-assembling of hydrophobin is a convenient and promising method of changing particle surface physiochemical properties and antitumor performances. Further investigations, especially on tissue distribution, were needed to assess the potential application of the hydrophobin self-assembling coating in nano-drug delivery carriers.


Assuntos
Antineoplásicos/química , Curcumina/química , Fungos/química , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Células A549 , Animais , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Curcumina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/uso terapêutico , Células HeLa , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
11.
Hum Cell ; 33(4): 919-929, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32537685

RESUMO

Malignancies with extremely low incidences, such as less than 6 per 100,000 people annually, are defined as rare cancers. Approximately 200 malignancies are classified in this category, therefore the total number of patients with rare cancers is greater than that of patients with any single common cancer. However, because of the small numbers of patients, novel therapies have not been developed for individual rare cancers, and clinical outcomes remain dismal. Patient-derived cancer models are indispensable for both basic and pre-clinical studies, and their roles will increase in the era of post-genome medicine. Although patient-derived cancer models have long been used in oncology, they are not well developed for rare cancers. In the context of sarcoma, the presently available cell lines and xenograft models are limited and do not satisfy the needs of research. Indeed, the lack of effective therapies for rare cancers might be attributable to the paucity of adequate patient-derived cancer models for pre-clinical studies. To facilitate the establishment and availability of patient-derived rare cancer models, we need to create effective methods for model establishment, share the valuable clinical samples and established models, and implement guidelines to record the clinical data of donor patients and original tumors. Patient-derived rare cancer models are a public resource, and they should not be used exclusively but should rather be shared among the research community.


Assuntos
Doenças Raras , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Linhagem Celular Tumoral , Humanos , Organoides , Sarcoma , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
12.
Nat Commun ; 11(1): 2978, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532977

RESUMO

The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates ß-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Macrófagos/metabolismo , Monoacilglicerol Lipases/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Nucleares/metabolismo , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Autorrenovação Celular/genética , Células Cultivadas , Feminino , Glioblastoma/genética , Glioblastoma/terapia , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Ativação de Macrófagos/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Monoacilglicerol Lipases/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Células-Tronco Neoplásicas/patologia , Proteínas Nucleares/genética , Interferência de RNA , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
13.
Nat Commun ; 11(1): 3015, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32541784

RESUMO

The interplay between glioma stem cells (GSCs) and the tumor microenvironment plays crucial roles in promoting malignant growth of glioblastoma (GBM), the most lethal brain tumor. However, the molecular mechanisms underlying this crosstalk are incompletely understood. Here, we show that GSCs secrete the Wnt-induced signaling protein 1 (WISP1) to facilitate a pro-tumor microenvironment by promoting the survival of both GSCs and tumor-associated macrophages (TAMs). WISP1 is preferentially expressed and secreted by GSCs. Silencing WISP1 markedly disrupts GSC maintenance, reduces tumor-supportive TAMs (M2), and potently inhibits GBM growth. WISP1 signals through Integrin α6ß1-Akt to maintain GSCs by an autocrine mechanism and M2 TAMs through a paracrine manner. Importantly, inhibition of Wnt/ß-catenin-WISP1 signaling by carnosic acid (CA) suppresses GBM tumor growth. Collectively, these data demonstrate that WISP1 plays critical roles in maintaining GSCs and tumor-supportive TAMs in GBM, indicating that targeting Wnt/ß-catenin-WISP1 signaling may effectively improve GBM treatment and the patient survival.


Assuntos
Neoplasias Encefálicas/genética , Proteínas de Sinalização Intercelular CCN/genética , Glioma/genética , Macrófagos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Proteínas de Sinalização Intercelular CCN/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Doxiciclina/farmacologia , Glioma/metabolismo , Glioma/terapia , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Transdução de Sinais/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Células U937 , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
14.
Cell Prolif ; 53(8): e12858, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32592435

RESUMO

OBJECTIVES: Traditional cancer therapy and regular immunotherapy are ineffective for treating triple-negative breast cancer (TNBC) patients. Recently, chimeric antigen receptor-engineered natural killer cells (CAR NK) have been applied to target several hormone receptors on different cancer cells to improve the efficacy of immunotherapy. Furthermore, epidermal growth factor receptor (EGFR) is a potential therapeutic target for TNBC. Here, we demonstrated that EGFR-specific CAR NK cells (EGFR-CAR NK cells) could be potentially used to treat patients with TNBC exhibiting enhanced EGFR expression. MATERIALS AND METHODS: We investigated the cytotoxic effects of EGFR-CAR NK cells against TNBC cells in vitro and in vivo. The two types of EGFR-CAR NK cells were generated by transducing lentiviral vectors containing DNA sequences encoding the single-chain variable fragment (scFv) regions of the two anti-EGFR antibodies. The cytotoxic and anti-tumor effects of the two cell types were examined by performing cytokine release and cytotoxicity assays in vitro, and tumor growth assays in breast cancer cell line-derived xenograft (CLDX) and patient-derived xenograft (PDX) mouse models. RESULTS: Both EGFR-CAR NK cell types were activated by TNBC cells exhibiting upregulated EGFR expression and specifically triggered the lysis of the TNBC cells in vitro. Furthermore, the two EGFR-CAR NK cell types inhibited CLDX and PDX tumors in mice. CONCLUSIONS: This study suggested that treatment with EGFR-CAR NK cells could be a promising strategy for TNBC patients.


Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/metabolismo , Células Matadoras Naturais/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/imunologia , Humanos , Camundongos , Receptores de Antígenos Quiméricos/imunologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
15.
Toxicol Appl Pharmacol ; 401: 115093, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32526215

RESUMO

Breast cancer incidence is increasing globally and pesticides exposure may impact risk of developing this disease. Hexachlorobenzene (HCB) and chlorpyrifos (CPF) act as endocrine disruptors, inducing proliferation in breast cancer cells. Vascular endothelial growth factor-A (VEGF-A), cyclooxygenase-2 (COX-2) and nitric oxide (NO) are associated with angiogenesis. Our aim was to evaluate HCB and CPF action, both weak aryl hydrocarbon receptor (AhR) ligands, on angiogenesis in breast cancer models. We used: (1) in vivo xenograft model with MCF-7 cells, (2) in vitro breast cancer model with MCF-7, and (3) in vitro neovasculogenesis model with endothelial cells exposed to conditioned medium from MCF-7. Results show that HCB (3 mg/kg) and CPF (0.1 mg/kg) stimulated vascular density in the in vivo model. HCB and CPF low doses enhanced VEGF-A and COX-2 expression, accompanied by increased levels of nitric oxide synthases (NOS), and NO release in MCF-7. HCB and CPF high doses intensified VEGF-A and COX-2 levels but rendered different effects on NOS, however, both pesticides reduced NO production. Moreover, our data indicate that HCB and CPF-induced VEGF-A expression is mediated by estrogen receptor and NO, while the increase in COX-2 is through AhR and NO pathways in MCF-7. In conclusion, we demonstrate that HCB and CPF environmental concentrations stimulate angiogenic switch in vivo. Besides, pesticides induce VEGF-A and COX-2 expression, as well as NO production in MCF-7, promoting tubulogenesis in endothelial cells. These findings show that pesticide exposure could stimulate angiogenesis, a process that has been demonstrated to contribute to breast cancer progression.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Clorpirifos/metabolismo , Hexaclorobenzeno/metabolismo , Neovascularização Patológica/induzido quimicamente , Neovascularização Patológica/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Células A549 , Animais , Clorpirifos/toxicidade , Relação Dose-Resposta a Droga , Feminino , Fungicidas Industriais/metabolismo , Fungicidas Industriais/toxicidade , Hexaclorobenzeno/toxicidade , Humanos , Inseticidas/metabolismo , Inseticidas/toxicidade , Ligantes , Células MCF-7 , Camundongos , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Toxicol Appl Pharmacol ; 401: 115112, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32540278

RESUMO

Cancer stem cells (CSCs) accounts for recurrence and resistance to chemotherapy in various tumors. Efficacy of chemotherapeutic drugs is limited by tumor stromal barriers, which hinder their penetration into deep tumor sites. We have earlier shown telmisartan (Tel) pretreatment prior to Docetaxel (DTX) administration enhances anti-cancer effects in non-small cell lung cancer (NSCLC). Herein, we demonstrated for the first time the efficacy of Docetaxel liposomes (DTXPL) in combination with Tel in 3D cultures of H460 cells by using polysaccharide-based hydrogels (TheWell Biosciences) and also in xenograft model of DTX resistant H460 derived CD133+ lung tumors. DTXPL and Tel combination showed enhanced cytotoxicity in H460 WT 3D cultures by two folds. In H460 3D cultures, Tel pretreatment showed increased liposomal uptake. DTXPL and Tel combination treated tumors showed reduction in tumor volume (p < .001), increased apoptosis and downregulation of CSC markers (p < .01) in H460 WT and DTX resistant CD133+ xenograft models.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Docetaxel/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Células-Tronco Neoplásicas/efeitos dos fármacos , Telmisartan/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Feminino , Humanos , Lipossomos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo
17.
Nat Commun ; 11(1): 2858, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32504051

RESUMO

Metastatic melanoma is challenging to manage. Although targeted- and immune therapies have extended survival, most patients experience therapy resistance. The adaptability of melanoma cells in nutrient- and therapeutically-challenged environments distinguishes melanoma as an ideal model for investigating therapy resistance. In this review, we discuss the current available repertoire of melanoma models including two- and three-dimensional tissue cultures, organoids, genetically engineered mice and patient-derived xenograft. In particular, we highlight how each system recapitulates different features of melanoma adaptability and can be used to better understand melanoma development, progression and therapy resistance.


Assuntos
Antinematódeos/farmacologia , Modelos Animais de Doenças , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antinematódeos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Camundongos , Camundongos Transgênicos , Organoides , Pele/citologia , Pele/imunologia , Pele/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Esferoides Celulares
18.
J Med Chem ; 63(10): 5421-5441, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32352777

RESUMO

Herein, a series of HSP90 inhibitor-SN38 conjugates through ester and carbamate linkage in the 20-OH and 10-OH positions of SN38 were developed for improving the tumor-specific penetration and accumulation of SN38 via extracellular HSP90 (eHSP90)-mediated endocytosis. Mechanistic analyses confirmed that these novel conjugates could bind to eHSP90 and be selectively internalized into the tumor cells, which led to prolonged tumor regression in multiple models of cancer. Among all studied conjugates, compound 18b showed excellent in vitro activities, including acceptable HSP90α affinity and potent antitumor activity. Moreover, compound 18b exhibited superior antitumor activity and low toxicity in HCT116 and Capan-1 xenograft models. Pharmacokinetic analyses in HCT116 and Capan-1 xenografts further confirmed that compound 18b treatment could lead to effective cleavage and extended SN38 exposure at tumor sites. All these encouraging data indicate that this compound is a promising new candidate for cancer therapy and merits further chemical and biological evaluation.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Sistemas de Liberação de Medicamentos/métodos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Irinotecano/administração & dosagem , Irinotecano/síntese química , Células A549 , Animais , Antineoplásicos/metabolismo , Desenho de Fármacos , Células HCT116 , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Irinotecano/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
19.
Nat Commun ; 11(1): 1755, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32273511

RESUMO

Asparagine synthetase (ASNS) catalyses the ATP-dependent conversion of aspartate to asparagine. However, both the regulation and biological functions of asparagine in tumour cells remain largely unknown. Here, we report that p53 suppresses asparagine synthesis through the transcriptional downregulation of ASNS expression and disrupts asparagine-aspartate homeostasis, leading to lymphoma and colon tumour growth inhibition in vivo and in vitro. Moreover, the removal of asparagine from culture medium or the inhibition of ASNS impairs cell proliferation and induces p53/p21-dependent senescence and cell cycle arrest. Mechanistically, asparagine and aspartate regulate AMPK-mediated p53 activation by physically binding to LKB1 and oppositely modulating LKB1 activity. Thus, we found that p53 regulates asparagine metabolism and dictates cell survival by generating an auto-amplification loop via asparagine-aspartate-mediated LKB1-AMPK signalling. Our findings highlight a role for LKB1 in sensing asparagine and aspartate and connect asparagine metabolism to the cellular signalling transduction network that modulates cell survival.


Assuntos
Asparagina/metabolismo , Ácido Aspártico/metabolismo , Neoplasias do Colo/metabolismo , Homeostase , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Asparagina/genética , Aspartato-Amônia Ligase/genética , Aspartato-Amônia Ligase/metabolismo , Ácido Aspártico/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Neoplasias do Colo/genética , Neoplasias do Colo/terapia , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
20.
Clin Exp Metastasis ; 37(3): 413-424, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32335861

RESUMO

Patient-derived orthotopic xenograft (PDOX) models have been verified as a useful method for studying human cancers in mice. Previous studies on the extent of metastases in these models have been limited by the necessity of welfare euthanasia (primary tumors reaching threshold size), at which point metastases may only be micrometers in diameter, few in number, and solely identified by step-sectioning of formalin-fixed paraffin-embedded tissue. These small micro-metastases are less suitable for many downstream molecular analyses than macro-metastases. Resection of the primary tumor by survival surgery has been proven to allow further time for metastases to grow. Although PDOX models of triple-negative breast cancer (TNBC) shed circulating tumor cells (CTCs) into the bloodstream and metastasize, similar to human TNBC, little data has been collected in these TNBC PDOX models regarding the association between CTC characteristics and distant metastasis following excision of the primary tumor xenograft. This study assembles a timeline of PDOX tumor shedding and metastatic tumor progression before and after tumor excision surgery. We report the ability to use tumorectomies to increase the lifespan of TNBC PDOX models with the potential to obtain larger metastases. CTC clusters and CTCs expressing a mesenchymal marker (vimentin) were associated with metastatic burden in lung and liver. The data collected through these experiments will guide the further use of PDOX models in studying metastatic TNBC.


Assuntos
Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Micrometástase de Neoplasia/patologia , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Contagem de Células , Progressão da Doença , Feminino , Humanos , Camundongos , Células Neoplásicas Circulantes/patologia , Neoplasias de Mama Triplo Negativas/cirurgia , Vimentina/metabolismo
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