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1.
Folia Biol (Praha) ; 66(3): 104-110, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33069189

RESUMO

Cancer development is a highly complicated process in which tumour growth depends on the development of its vascularization system. To support their own growth, tumour cells significantly modify their microenvironment. One of such modifications inflicted by tumours is stimulation of endothelial cell migration and proliferation. There is accumulating evidence that extracellular vesicles (EVs) secreted by tumour cells (tumour-derived EVs, TEVs) may be regarded as "messengers" with the potential for affecting the biological activities of target cells. Interaction of TEVs with different cell types occurs in an auto- and paracrine manner and may lead to changes in the function of the latter, e.g., promoting motility, proliferation, etc. This study analysed the proangiogenic activity of EVs derived from human pancreatic adenocarcinoma cell line (HPC-4, TEVHPC) in vitro and their effect in vivo on Matrigel matrix vascularization in severe combined immunodeficient (SCID) mice. TEVHPC enhanced proliferation of HPC-4 cells and induced their motility. Moreover, TEVHPC stimulated human umbilical vein endothelial cell (HUVEC) proliferation and migration in vitro. Additionally, TEVHPC influenced secretion of proangiogenic factors (IL-8, VEGF) by HUVEC cells and supported Matrigel matrix haemoglobinization in vivo. These data show that TEVs may support tumour propagation in an autocrine manner and may support vascularization of the tumour. The presented data are in line with the theory that tumour cells themselves are able to modulate the microenvironment via TEVs to maximize their growth potential.


Assuntos
Carcinoma Ductal Pancreático/patologia , Vesículas Extracelulares/patologia , Neoplasias Pancreáticas/patologia , Animais , Comunicação Autócrina , Divisão Celular , Linhagem Celular Tumoral , Quimiotaxia , Colágeno , Combinação de Medicamentos , Células Endoteliais da Veia Umbilical Humana , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Laminina , Camundongos , Camundongos SCID , Transplante de Neoplasias , Neovascularização Patológica/etiologia , Proteoglicanas , RNA Mensageiro/biossíntese , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
Life Sci ; 259: 118374, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32891613

RESUMO

OBJECTIVE: Dipeptidyl peptidase IV (DPP4) has been indicated as a possible prognostic biomarker in papillary thyroid cancer (PTC). However, the mechanism of DPP4 during metastasis of PTC remains unclear. In this study, we investigated whether lysine acetyltransferase 5 (KAT5) and FBJ murine osteosarcoma viral oncogene homolog B (FosB) synergistically regulate high DPP4 expression in PTC. METHODS: PTC tissues and matched paracancerous tissues were harvested, followed by the establishment of IHH-4 and TPC-1 cells with downregulation of DPP4. The relevance of DPP4 on the metastasis of PTC cells was assessed. Subsequently, the effect of KAT5 on the transcription of DPP4 was verified. The binding relationship between FosB and DPP4 was predicted by a bioinformatics website. Functional rescue experiments were performed to evaluate cell activities after overexpression of KAT5 or FosB in cells with DPP4 knockdown. RESULTS: DPP4 was overexpressed in PTC tissues and cell lines, which was correlated with higher risks for metastases and poorer survival. DPP4 downregulation curtailed cell growth and metastasis. Moreover, KAT5 acetylated DPP4 promoter histone, which promoted transcription activation of DPP4. Subsequently, FosB recruited KAT5 at the DPP4 promoter, thereby enhancing DPP4 transcriptional activation. Further overexpression of KAT5 or FosB in cells with low expression of DPP4 promoted cell activity. Finally, DPP4 expedited p62 nuclear translocation to elevate Keap1/Nrf2 expression, thus facilitating the growth and metastasis of PTC cells. CONCLUSION: FosB enhanced the growth and metastasis of PTC cells by recruiting histone acetyltransferases KAT5 to increase DPP4 transcription and activate the p62/Keap1/Nrf2 signaling.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Lisina Acetiltransferase 5/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Animais , Western Blotting , Linhagem Celular Tumoral , Feminino , Imunofluorescência , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Transplante de Neoplasias , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo
3.
J Environ Pathol Toxicol Oncol ; 39(3): 247-260, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865916

RESUMO

The anticancer activity of malvidin was studied in Dalton's lymphoma ascites (DLA)-induced solid and ascitic tumor mice models. Malvidin is a natural compound belonging to the family of O-methylated anthocyanidin and plays a predominant role in regulating both short- and long-term cellular activities. Animals were injected with DLA cells (1.5 × 106 cells/animal) to induce solid and ascitic tumors. The administration of malvidin (5 mg/kg bw and 10 mg/kg bw) was carried out for 10 consecutive days from the day of tumor induction for both solid and ascitic tumors. Cyclophosphamide, CTX (25 mg/kg bw), used as the standard drug, was also administered for 10 consecutive days. Treatment with malvidin showed a significant reduction in tumor volume and elevated white blood cell (WBC) count when compared to the DLA-bearing control animals. The treatment also maintained the body weight and hemoglobin level, and decreases in aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) were also noted. This investigation also reported the decreased levels of cellular glutathione (GSH) in ascitic tumor groups. Malvidin reduced inflammatory mediator and cytokine levels, such as tumor necrosis factor level alpha (TNF-α) and interleukin-6 (IL-6), which serve as molecular targets for cancer prevention. A decrease in the level of reactive oxygen species (ROS), like nitric oxide (NO), was observed. Histopathological examination revealed altered morphological changes in tumor tissue and the alleviation of hepatic architecture due to DLA. Immunohistochemical analysis revealed the inhibition of iNOS. This study demonstrated that malvidin exhibited significant in vivo antitumor activity and that it was reasonably imputable to its increasing endogenous mechanism. We accent the pertinence of malvidin as a potential naturally derived drug target for tumor control.


Assuntos
Antocianinas/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Ascite/tratamento farmacológico , Citocinas/sangue , Linfoma/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Antocianinas/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Ascite/metabolismo , Ascite/patologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Linfoma/metabolismo , Linfoma/patologia , Masculino , Camundongos , Transplante de Neoplasias , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Estresse Oxidativo/imunologia
4.
Nat Commun ; 11(1): 4261, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32848136

RESUMO

Metastasis, the spread of malignant cells from a primary tumour to distant sites, causes 90% of cancer-related deaths. The integrin ITGB3 has been previously described to play an essential role in breast cancer metastasis, but the precise mechanisms remain undefined. We have now uncovered essential and thus far unknown roles of ITGB3 in vesicle uptake. The functional requirement for ITGB3 derives from its interactions with heparan sulfate proteoglycans (HSPGs) and the process of integrin endocytosis, allowing the capture of extracellular vesicles and their endocytosis-mediated internalization. Key for the function of ITGB3 is the interaction and activation of focal adhesion kinase (FAK), which is required for endocytosis of these vesicles. Thus, ITGB3 has a central role in intracellular communication via extracellular vesicles, proposed to be critical for cancer metastasis.


Assuntos
Neoplasias da Mama/metabolismo , Comunicação Celular/fisiologia , Vesículas Extracelulares/metabolismo , Integrina beta3/metabolismo , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Meios de Cultivo Condicionados , Endocitose , Feminino , Quinase 1 de Adesão Focal/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Xenoenxertos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Células MCF-7 , Camundongos , Camundongos Nus , Modelos Biológicos , Metástase Neoplásica/patologia , Transplante de Neoplasias
5.
Nat Commun ; 11(1): 3912, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764562

RESUMO

Immunotherapy has emerged as a promising approach to treat cancer, however, its efficacy in highly malignant brain-tumors, glioblastomas (GBM), is limited. Here, we generate distinct imageable syngeneic mouse GBM-tumor models and utilize RNA-sequencing, CyTOF and correlative immunohistochemistry to assess immune-profiles in these models. We identify immunologically-inert and -active syngeneic-tumor types and show that inert tumors have an immune-suppressive phenotype with numerous exhausted CD8 T cells and resident macrophages; fewer eosinophils and SiglecF+ macrophages. To mimic the clinical-settings of first line of GBM-treatment, we show that tumor-resection invigorates an anti-tumor response via increasing T cells, activated microglia and SiglecF+ macrophages and decreasing resident macrophages. A comparative CyTOF analysis of resected-tumor samples from GBM-patients and mouse GBM-tumors show stark similarities in one of the mouse GBM-tumors tested. These findings guide informed choices for use of GBM models for immunotherapeutic interventions and offer a potential to facilitate immune-therapies in GBM patients.


Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Tolerância Imunológica , Imunofenotipagem , Imunoterapia , Isoenxertos , Linfócitos do Interstício Tumoral/classificação , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Microambiente Tumoral/imunologia
6.
Tumour Biol ; 42(7): 1010428320937863, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32686600

RESUMO

Maintaining intracellular pH is crucial for preserving healthy cellular behavior and, when dysregulated, results in increased proliferation, migration, and invasion. The Na+/H+ exchanger isoform 1 is a highly regulated transmembrane antiporter that maintains pH homeostasis by exporting protons in response to intra- and extracellular signals. Activation of Na+/H+ exchanger isoform 1 is exquisitely regulated by the extracellular environment and protein cofactors, including calcineurin B homologous proteins 1 and 2. While Na+/H+ exchanger isoform 1 and calcineurin B homologous protein 1 are ubiquitously expressed, calcineurin B homologous protein 2 shows tissue-specific expression and upregulation in a variety of cancer cells. In addition, calcineurin B homologous protein 2 expression is modulated by tumorigenic extracellular conditions like low nutrients. To understand the role of calcineurin B homologous protein 2 in tumorigenesis and survival in lung cancer, we surveyed existing databases and formed a comprehensive report of Na+/H+ exchanger isoform 1, calcineurin B homologous protein 1, and calcineurin B homologous protein 2 expression in diseased and non-diseased tissues. We show that calcineurin B homologous protein 2 is upregulated during oncogenesis in many adeno and squamous carcinomas. To understand the functional role of calcineurin B homologous protein 2 upregulation, we evaluated the effect of Na+/H+ exchanger isoform 1 and calcineurin B homologous protein 2 depletion on cellular function during cancer progression in situ. Here, we show that calcineurin B homologous protein 2 functions through Na+/H+ exchanger isoform 1 to effect cell proliferation, cell migration, steady-state pHi, and anchorage-independent tumor growth. Finally, we present evidence that calcineurin B homologous protein 2 depletion in vivo has potential to reduce tumor burden in a xenograft model. Together, these data support the tumor-promoting potential of aberrant calcineurin B homologous protein 2 expression and position calcineurin B homologous protein 2 as a potential therapeutic target for the treatment of non-small cell lung cancer.


Assuntos
Calcineurina/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Trocador 1 de Sódio-Hidrogênio/metabolismo , Animais , Calcineurina/genética , Proteínas de Ligação ao Cálcio/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Nus , Transplante de Neoplasias , Isoformas de Proteínas/metabolismo , Transplante Heterólogo
7.
Gene ; 758: 144960, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32687947

RESUMO

As a member of the ubiquitin-specific protease (USP) family, USP22 could remove ubiquitin moieties from its target proteins to control the function of the target proteins. Accumulating studies show that USP22 essentially participates in diverse types of cancer as an oncogene-like protein. However, the roles of USP22 in human pancreatic ductal adenocarcinoma (PDAC) and the underlying mechanism are unknown. Here we report that USP22 promotes the growth of PDAC cells by promoting the expression of dual-specificity tyrosine regulated kinase 1A (DYRK1A). Our results showed that the expression levels of USP22 were up-regulated in human PDAC tissues and cell lines (BxPC-3, AsPC-1, MIA-PaCa-2, PANC-1, and CAPAN-1). Lentivirus-mediated knockdown of USP22 repressed the rate of proliferation and capacity of colony formation of BxPC3 and CAPAN1 cancer cells and USP22 overexpression promoted the proliferation and capacity of the colony formation of BxPC3 and CAPAN1 cancer cells. The further mechanism study showed that USP22 elevated the expression of the mRNA and protein levels of DYRK1A in PDAC cancer cells. Inhibition of DYRK1A with EHT-5732 or lentivirus-mediated knockdown of DYRK1A blocked the function of USP22 overexpression in the regulation of the proliferation and colony formation of PDAC cells. Taken together, our findings demonstrated that USP22 overexpression in PDAC promoted the growth of the cancer cells partially through upregulating the expression of DYRK1A.


Assuntos
Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Ubiquitina Tiolesterase/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Oncogenes/genética , Ductos Pancreáticos/patologia , RNA Mensageiro/genética , Transplante Heterólogo
8.
Life Sci ; 257: 118108, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32682920

RESUMO

AIM: Preparation of pegylated gold nanorods (PEG-AuNRs) that are capable of converting near infrared (NIR) light into heat. Evaluation of cancer therapeutic efficacy and long-term toxicity of the proposed photothermal therapy in comparison with other conventional modalities. MATERIALS AND METHODS: Prepared PEG-AuNRs were characterized by measuring their absorption spectra, zeta potential, and transmission electron microscope (TEM). Cancer therapeutic efficacy was assessed by monitoring tumor growth, measuring DNA damage and superoxide dismutase (SOD) and malondialdehyde (MDA) levels in addition to examining tumor histopathology. Further analysis concerning the toxicity of all the proposed treatment modalities was also assessed by evaluating the cytotoxicity and genotoxicity in liver and kidney tissues. KEY FINDINGS: The results demonstrated that both photothermal therapy (PEG-AuNRs + NIR laser) and chemotherapy (cisplatin) have higher efficacy in diminishing Ehrlich tumor growth with significance DNA damage over the other treatment modalities. Concerning the biosafety issue, mice treated photothermally exhibited lower MDA level and higher SOD activity in liver and kidney tissues compared with other treated groups. DNA damage represented by tail moment and olive moment of kidney tissues exhibited lower values for photothermal treated group and higher values for cisplatin treated group. SIGNIFICANCE: Photothermal therapy (PEG-AuNRs + NIR laser) potentiates higher efficacy in treating Ehrlich tumor with minimum toxicity in comparison with other conventional treatment modalities.


Assuntos
Carcinoma de Ehrlich/terapia , Ouro/administração & dosagem , Nanotubos/toxicidade , Fototerapia/métodos , Animais , Carcinoma de Ehrlich/patologia , Ensaio Cometa , Dano ao DNA/efeitos dos fármacos , Feminino , Ouro/uso terapêutico , Ouro/toxicidade , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão , Nanotubos/ultraestrutura , Transplante de Neoplasias , Estresse Oxidativo , Superóxido Dismutase/metabolismo
9.
PLoS One ; 15(6): e0233846, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32502202

RESUMO

Growth Differentiation Factor-15 (GDF15) is a divergent TGF-beta superfamily cytokine that is overexpressed by most cancers and is induced by anticancer therapy. Transgenic and induced animal models suggest that it protects from cancer development but the mechanisms are uncertain. We investigated the role of immunity in GDF15 induced reduction in prostate cancer (PCa) growth. The C57BL/6 transgenic TRAMP prostate cancer prone mice were bred with mice that were immunodeficient and/or systemically overexpressed GDF15. We developed a novel orthotopic TRAMP PCa model in which primary TRAMP tumor cells were implanted into prostates of mice to reduce the study time. These mice were administered recombinant mouse GDF15, antibody to CD8, PD1 or their respective controls. We found that GDF15 induced protection from tumor growth was reversed by lack of adaptive immunity. Flow cytometric evaluation of lymphocytes within these orthotopic tumors showed that GDF15 overexpression was associated with increased CD8 T cell numbers and an increased number and proportion of recently activated CD8+CD11c+ T cells and a reduced proportion of "exhausted" CD8+PD1+ T cells. Further, depletion of CD8 T cells in tumor bearing mice abolished the GDF15 induced protection from tumor growth. Infusion of GDF15 into mice bearing orthotopic TRAMP tumor, substantially reduced tumor growth that was further reduced by concurrent PD1 antibody administration. GDF15 overexpression or recombinant protein protects from TRAMP tumor growth by modulating CD8 T cell mediated antitumor immunity and augments the positive effects of anti-PD1 blockers.


Assuntos
Antineoplásicos/uso terapêutico , Fator 15 de Diferenciação de Crescimento/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Feminino , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transplante de Neoplasias , Neoplasias Experimentais
10.
Nat Commun ; 11(1): 2817, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32499547

RESUMO

Both KRAS and EGFR are essential mediators of pancreatic cancer development and interact with Argonaute 2 (AGO2) to perturb its function. Here, in a mouse model of mutant KRAS-driven pancreatic cancer, loss of AGO2 allows precursor lesion (PanIN) formation yet prevents progression to pancreatic ductal adenocarcinoma (PDAC). Precursor lesions with AGO2 ablation undergo oncogene-induced senescence with altered microRNA expression and EGFR/RAS signaling, bypassed by loss of p53. In mouse and human pancreatic tissues, PDAC progression is associated with increased plasma membrane localization of RAS/AGO2. Furthermore, phosphorylation of AGO2Y393 disrupts both the wild-type and oncogenic KRAS-AGO2 interaction, albeit under different conditions. ARS-1620 (G12C-specific inhibitor) disrupts the KRASG12C-AGO2 interaction, suggesting that the interaction is targetable. Altogether, our study supports a biphasic model of pancreatic cancer development: an AGO2-independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an AGO2-dependent phase wherein the mutant KRAS-AGO2 interaction is critical for PDAC progression.


Assuntos
Proteínas Argonauta/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Alelos , Animais , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Senescência Celular , Progressão da Doença , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Genótipo , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Transplante de Neoplasias , Neoplasias Pancreáticas/patologia , Fosforilação , Ligação Proteica , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo
11.
Cancer Immunol Immunother ; 69(11): 2357-2369, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32518979

RESUMO

Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are both key immunosuppressive cells that contribute to tumor growth. Metabolism and immunity of tumors depend on the tumor microenvironment (TME). However, the intracellular metabolism of MDSCs and TAMs during tumor growth remains unclear. Here, we characterized CD11b+ cells isolated from a tumor-bearing mouse model to compare intratumoral TAMs and intrasplenic MDSCs. Intratumoral CD11b+ cells and intrasplenic CD11b+ cells were isolated from tumor-bearing mice at early and late stages (14 and 28 days post-cell transplantation, respectively). The cell number of intrasplenic CD11b+ significantly increased with tumor growth. These cells included neutrophils holding segmented leukocytes or monocytes with an oval nucleus and Gr-1hi IL-4Rαhi cells without immunosuppressive function against CD8 T cells. Thus, these cells were classified as MDSC-like cells (MDSC-LCs). Intratumoral CD11b+ cells included macrophages with a round nucleus and were F4/80hi Gr-1lo IL-4Rαhi cells. Early stage intratumoral CD11b+ cells inhibited CD8 T cells via TNFα. Thus, this cell population was classified as TAMs. Metabolomic analyses of intratumoral TAMs and MDSC-LCs during tumor growth were conducted. Metabolic profiles of intratumoral TAMs showed larger changes in various metabolic pathways, e.g., glycolysis, TCA cycle, and glutamic acid pathways, during tumor growth compared with MDSL-LCs. Our findings demonstrated that intratumoral TAMs showed an immunosuppressive capacity from the early tumor stage and underwent intracellular metabolism changes during tumor growth. These results clarify the intracellular metabolism of TAMs during tumor growth and contribute to our understanding of tumor immunity.


Assuntos
Macrófagos/imunologia , Macrófagos/metabolismo , Neoplasias Experimentais/imunologia , Evasão Tumoral/fisiologia , Microambiente Tumoral/fisiologia , Animais , Antígeno CD11b/imunologia , Linhagem Celular Tumoral , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Transplante de Neoplasias , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia
12.
Prostate ; 80(10): 782-794, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32407603

RESUMO

BACKGROUND: Over 70% to 85% of men with advanced prostate cancer (PCa) develop bone metastases characterized by severe bone pain and increased likelihood of bone fracture. These clinical features result in decreased quality of life and act as a predictor of higher mortality. Mechanistically, the skeletal pathologies such as osteolytic lesions and abnormal osteoblastic activity drive these symptoms. The role of immune cells in bone cancer pain remains understudied, here we sought to recapitulate this symptomology in a murine model. METHODS: The prostate cancer bone metastasis-induced pain model (CIBP) was established by transplanting a mouse prostate cancer cell line into the femur of immunocompetent mice. Pain development, gait dynamics, and the changes in emotional activities like depression and anxiety were evaluated. Animal tissues including femurs, dorsal root ganglion (DRG), and spinal cord were collected at killing and microcomputed tomography (µCT), histology/immunohistochemistry, and quantitative immunofluorescent analysis were performed. RESULTS: Mice receiving prostate cancer cells showed a significantly lower threshold for paw withdrawal responses induced by mechanical stimulation compared with their control counterparts. Zero maze and DigiGait analyses indicated reduced and aberrant movement associated emotional activity compared with sham control at 8-weeks postinjection. The µCT analysis showed osteolytic and osteoblastic changes and a 50% reduction of the trabecular volumes within the prostate cancer group. Neurologically we demonstrated, increased calcitonin gene-related peptide (CGRP) and neuronal p75NTR immune-reactivities in both the projected terminals of the superficial dorsal horn and partial afferent neurons in DRG at L2 to L4 level in tumor-bearing mice. Furthermore, our data show elevated nerve growth factor (NGF) and TrkA immunoreactivities in the same segment of the superficial dorsal horn that were, however, not colocalized with CGRP and p75NTR . CONCLUSIONS: This study describes a novel immunocompetent model of CIBP and demonstrates the contribution of NGF and p75NTR to chronic pain in bone metastasis.


Assuntos
Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Dor do Câncer/patologia , Neoplasias da Próstata/patologia , Animais , Comportamento Animal , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/imunologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Dor do Câncer/imunologia , Dor do Câncer/metabolismo , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Imunocompetência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neurônios/metabolismo , Neurônios/patologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Receptores de Fator de Crescimento Neural/imunologia , Receptores de Fator de Crescimento Neural/metabolismo
13.
Yakugaku Zasshi ; 140(5): 641-648, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32378664

RESUMO

Traditionally, anticancer drug discovery research has been conducted based on immortalized cancer cell lines, either cultured in vitro or grown in vivo. In the USA and Europe, patient derived xenograft (PDX) model is rapidly expelling traditional in vitro and in vivo models due to the good predictability of clinical outcome and its nature of retaining characteristics and heterogeneity in the original tumor. Furthermore, a significant association was also reported between drug responses in patient and corresponding PDX as high as 87%. We are preparing a PDX model for Japanese cancer patients including drug resistance examples and rare cancers. Using the established PDX model, we confirmed the possibility that the tumor microenvironment might affect the efficacy and distribution of drugs even if the target receptor is expressed in tumor sites as compared to the cell line (CDX) model, which has been widely used in drug discovery. Interestingly, although expressing a target receptor in viable tumor cells, we also have found a PDX model with a lower distribution of molecular target drug. Therefore we will evaluate the usefulness of the PDX model in drug development by exploring new biomarkers and elucidating the mechanisms of drug resistance in target tumors. Moreover, pharmaco-imaging system will allow us to visualize the exposure and distribution of drugs in tumors at macro and micro levels. Finally, we evaluate relations between distribution of drugs in the tumor microenvironment including target tumor cells, neovessels, stromal cells, immune cells, and fibroblasts.


Assuntos
Antineoplásicos/farmacocinética , Desenvolvimento de Medicamentos , Terapia de Alvo Molecular , Transplante de Neoplasias , Neoplasias/tratamento farmacológico , Animais , Modelos Animais de Doenças , Xenoenxertos , Humanos , Camundongos , Distribuição Tecidual , Microambiente Tumoral
14.
Nat Commun ; 11(1): 2416, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415208

RESUMO

Chemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. Here we identify hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key inducer of chemoresistance by developing chemoresistant TNBC tumors in vivo and characterizing their transcriptomes by RNA-sequencing. Inhibiting LOX reduces collagen cross-linking and fibronectin assembly, increases drug penetration, and downregulates ITGA5/FN1 expression, resulting in inhibition of FAK/Src signaling, induction of apoptosis and re-sensitization to chemotherapy. Similarly, inhibiting FAK/Src results in chemosensitization. These effects are observed in 3D-cultured cell lines, tumor organoids, chemoresistant xenografts, syngeneic tumors and PDX models. Re-expressing the hypoxia-repressed miR-142-3p, which targets HIF1A, LOX and ITGA5, causes further suppression of the HIF-1α/LOX/ITGA5/FN1 axis. Notably, higher LOX, ITGA5, or FN1, or lower miR-142-3p levels are associated with shorter survival in chemotherapy-treated TNBC patients. These results provide strong pre-clinical rationale for developing and testing LOX inhibitors to overcome chemoresistance in TNBC patients.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Proteína-Lisina 6-Oxidase/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/enzimologia , Animais , Apoptose , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Colágeno/química , Regulação para Baixo , Matriz Extracelular/metabolismo , Feminino , Fibronectinas/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Hipóxia , Integrinas/metabolismo , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Transplante de Neoplasias , RNA-Seq , Transdução de Sinais
16.
Nat Neurosci ; 23(7): 842-853, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32424282

RESUMO

Many immunotherapies act by enhancing the ability of cytotoxic T cells to kill tumor cells. Killing depends on T cell recognition of antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. In this study, we showed that medulloblastomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. In vitro, tumor necrosis factor (TNF) or lymphotoxin-ß receptor agonist can rescue expression of Erap1, Tap1 and MHC-I on p53-mutant tumor cells. In vivo, low doses of TNF prolong survival and synergize with immune checkpoint inhibitors to promote tumor rejection. These studies identified p53 as a key regulator of immune evasion and suggest that TNF could be used to enhance sensitivity of tumors to immunotherapy.


Assuntos
Neoplasias Cerebelares/imunologia , Meduloblastoma/imunologia , Evasão Tumoral/imunologia , Fator de Necrose Tumoral alfa/imunologia , Proteína Supressora de Tumor p53/imunologia , Animais , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Meduloblastoma/genética , Meduloblastoma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Fator de Necrose Tumoral alfa/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
17.
Biomed Khim ; 66(2): 151-155, 2020 Feb.
Artigo em Russo | MEDLINE | ID: mdl-32420896

RESUMO

The aim of the study was to determine the level of sex steroid hormones in white matter of the brain of rats with tumors combined with chronic neurogenic pain (CNP), which was modeled by bilateral sciatic nerve ligation. The study included albino male rats (n=74). In the main group, M1 sarcoma was transplanted subcutaneously (n=11) or into the subclavian vein (n=11) 45 days after CNP modeling. Two comparison groups (n=13 each) included sham operated animals (without CNP) with M1 sarcoma transplanted subcutaneously and intravenously. Control groups included animals with CNP and sham operated animals. Rats were euthanized on day 21 of the carcinogenesis. Levels of total and free testosterone (T), estrone (E1), estradiol (E2), estriol (E3) and progesterone (P4) in the brain white matter were measured using ELISA kits ("Cusabio", China). CNP caused a decrease in the total and free T by 1.5 times (p<0.05), E2 and P4 by 1.9 and 3 times, respectively, E3 by 1.6 times (p<0.05), as well as an increase in E1 by 1.4 times (p<0.05) as compared to the corresponding levels in the brain white matter of rats without CNP. CNP stimulated M1 sarcoma growth in both subcutaneous and intravenous transplantation. Regardless of the tumor site, the dynamics of total T, E2 and E3 in the brain had similar features, but the dynamics of free T, P4 and E1 differed. Thus, changes in the level of neurosteroids in the white matter of rat brain with CNP and tumor growth alone or associated with CNP are a reaction to stress.


Assuntos
Química Encefálica , Neoplasias Experimentais/patologia , Neuroesteroides/análise , Dor/patologia , Sarcoma/patologia , Animais , Estradiol , Estrona , Masculino , Transplante de Neoplasias , Progesterona , Ratos
18.
Chin J Nat Med ; 18(3): 178-185, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32245587

RESUMO

Enhanced glucose metabolism is one of the hallmarks of pancreatic cancer. MUC1, a transmembrane protein, is a global regulator of glucose metabolism and essential for progression of pancreatic cancer. To clarify the role of MUC1 in glucose metabolism, we knocked out MUC1 in Capan-1 and CFPAC-1 cells. MUC1 knockout (KO) cells uptook less glucose and secreted less lactate with a much lower proliferating rate. The mRNA level of key enzymes in glycolysis also decreased significantly in MUC1 KO cells. We also observed increased expression of breast cancer type 1 susceptibility protein (BRCA1) in MUC1 KO cells. Since BRCA1 has a strong inhibitory effect on glycolysis, we want to know whether the decreased glucose metabolism in MUC1 KO cells is due to increased BRCA1 expression. We treated wild type (WT) and MUC1 KO cells with BRCA1 inhibitor. BRCA1 inhibition significantly enhanced glucose uptake and lactate secretion in both WT and MUC1 KO cells. Expression of key enzymes in glycolysis also elevated after BRCA1 inhibition. Elevated glucose metabolism is known to facilitate cancer cells to gain chemoresistance. We treated MUC1 KO cells with gemcitabine and FOLFIRINOX in vitro and in vivo. The results showed that MUC1 KO sensitized pancreatic cancer cells to chemotherapy both in vitro and in vivo. In conclusion, we demonstrated that MUC1 promotes glycolysis through inhibiting BRCA1 expression. MUC1 may be a therapeutic target in pancreatic cancer treatment.


Assuntos
Proteína BRCA1/genética , Glucose/metabolismo , Glicólise , Mucina-1/metabolismo , Neoplasias Pancreáticas/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Irinotecano/farmacologia , Ácido Láctico/metabolismo , Leucovorina/farmacologia , Masculino , Camundongos Nus , Transplante de Neoplasias , Oxaliplatina/farmacologia , Neoplasias Pancreáticas/genética
19.
PLoS One ; 15(4): e0228511, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348309

RESUMO

OBJECTIVE: To evaluate intraperitoneal (IP) tumor engraftment, metastasis and growth in a pre-clinical murine epithelial ovarian cancer (EOC) model using both transabdominal ultrasound (TAUS) and bioluminescence in vivo imaging system (IVIS). METHODS: Ten female C57Bl/6J mice at six weeks of age were included in this study. Five mice underwent IP injection of 5x106 ID8-luc cells (+ D- luciferin) and the remaining five mice underwent IP injection of ID8-VEGF cells. Monitoring of tumor growth and ascites was performed weekly starting at seven days post-injection until study endpoint. ID8-luc mice were monitored using both TAUS and IVIS, and ID8-VEGF mice underwent TAUS monitoring only. Individual tumor implant dimension and total tumor volume were calculated. Average luminescent intensity was calculated and reported per mouse abdomen. Tumor detection was confirmed by gross evaluation and histopathology. All data are presented as mean +/- standard deviation. RESULTS: Overall, tumors were successfully detected in all ten mice using TAUS and IVIS, and tumor detection correlated with terminal endpoint histology/ H&E staining. For TAUS, the smallest confirmed tumor measurements were at seven days post-injection with mean long axis of 2.23mm and mean tumor volume of 4.17mm3. However, IVIS imaging was able to detect tumor growth at 14 days post-injection. Ascites formation was detected in mice at 21 days post-injection. CONCLUSIONS: TAUS is highly discriminatory for monitoring EOC in pre-clinical murine model, allowing for detection of tumor dimension as small as 2 mm and as early as seven days post-injection compared to IVIS. In addition, TAUS provides relevant information for ascites development and detection of multiple small metastatic tumor implants. TAUS provides an accurate and reliable method to detect and monitor IP EOC growth in mouse xenografts.


Assuntos
Abdome/diagnóstico por imagem , Carcinoma Epitelial do Ovário/diagnóstico por imagem , Carcinoma Epitelial do Ovário/patologia , Transplante de Neoplasias , Neoplasias Peritoneais/diagnóstico por imagem , Neoplasias Peritoneais/patologia , Ultrassonografia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Feminino , Vetores Genéticos/metabolismo , Lentivirus/genética , Luciferases/genética , Camundongos Endogâmicos C57BL , Necrose , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Toxicol Appl Pharmacol ; 396: 115001, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32277947

RESUMO

Mebendazole (MBZ) is a tubulin-suppressive antihelmintic agent with low toxicity, which has been repurposed to treat different types of tumors. Chemoresistance is quite common in refractory or relapsed T cell acute lymphoblastic leukemia (T-ALL), which leads to dismal chances of recovery. In this study, MBZ was found to suppress the proliferation and reduce the viability of T-ALL cell line, CCRF-CEM, and its chemoresistant derivative, CEM/C1, at nanomolar concentrations. The inhibitive effects were found to be dose-dependent and not to be affected by the chemoresistance of CEM/C1 cells. Cell cycle arrest, caspase 3/7 activation and tubulin disruption were found in the MBZ-treated T-ALL cells. Notch1 signaling, which is often aberrantly activated in T-ALL cells, was showed to be suppressed by MBZ treatments. MBZ administration in murine T-ALL models also suppressed the growth of CEM/C1 cells, indicating that MBZ may be developed as a therapeutic agent for chemoresistant T-ALLs. The mRNA levels of the Notch1 and Hes1 were also confirmed to be suppressed by MBZ in vivo, which was consistent with the in vitro observations. This study demonstrated, for the first time, that MBZ could inhibit chemoresistant T-ALL cells both in vitro and in vivo, and the Notch1 signaling pathway was suppressed by MBZ treatment.


Assuntos
Antineoplásicos/uso terapêutico , Mebendazol/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Moduladores de Tubulina/uso terapêutico , Animais , Western Blotting , Caspase 3/metabolismo , Caspase 7/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Receptor Notch1/metabolismo , Tubulina (Proteína)/metabolismo
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