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1.
Anticancer Res ; 39(9): 4699-4709, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519569

RESUMO

BACKGROUND/AIM: Metformin, a drug for type 2 diabetes, also exerts anticancer effects. This study addressed the immunological effects of metformin on peritoneal dissemination. MATERIALS AND METHODS: We developed a mouse model of peritoneal dissemination via intraperitoneal injection of RLmale1, an X-ray-induced leukemia cell line, into BALB/c mice. Cell-surface markers, cytokine production, and myeloid-derived suppressor cells (MDSCs) were examined in cells from spleen and peritoneal lavage fluid. RESULTS: Metformin-treated mice exhibited suppressed intraperitoneal tumor growth and extended survival, and these effects were lost in mice with severe combined immunodeficiency. MDSCs induction was inhibited in metformin-treated mice. Although MDSC mobilization into the peritoneal cavity was correlated with suppression of interferon-γ production by tumor-infiltrating lymphocytes, the T-helper 1 ability of these lymphocytes was preserved in metformin-treated mice. CONCLUSION: Our findings demonstrate the action of metformin on both intraperitoneal tumors and immune-suppressive cells and might contribute to the development of immunotherapy against peritoneal dissemination.


Assuntos
Imunomodulação/efeitos dos fármacos , Metformina/farmacologia , Neoplasias Peritoneais/imunologia , Neoplasias Peritoneais/patologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Animais , Biomarcadores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Imunofenotipagem , Masculino , Camundongos , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Metástase Neoplásica , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/mortalidade , Modelos de Riscos Proporcionais , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Life Sci ; 234: 116781, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31430455

RESUMO

Cancer stem cells (CSCs) are a population of self-renewal cells with high tumorigenic potency. CSCs can adopt easily with changes in the nearby milieu, and are more resistant to conventional therapies than other cells within a tumor. CSC resistance can be induced secondary to radio- and chemotherapy, or even after chemotherapy secession. A combination of both intrinsic and extrinsic factors is contributed to CSC-mediated therapy resistance. CSCs represent protective autophagy and efficient cell cycling, along with highly qualified epithelial-mesenchymal transition (EMT) regulators, reactive oxygen species (ROS) scavengers, drug transporters, and anti-apoptotic and DNA repairing systems. In addition, CSCs develop cross-talking and share some characteristics with other cells within the tumor microenvironment (TME) being more intense in higher stage tumors, and thereby sophisticating tumor-targeted therapies. TME, in fact, is a nest for aggravating resistance mechanisms in CSCs. TME is exposed constantly to the nutritional, metabolic and oxygen deprivation; these conditions promote CSC adaptation. This review is aimed to discuss main (intrinsic and extrinsic) mechanisms of CSC resistance and suggest some strategies to revoke this important promoter of therapy failure.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Células-Tronco Neoplásicas/patologia , Animais , Antineoplásicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos da radiação , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos da radiação
3.
Anticancer Res ; 39(8): 4031-4041, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366485

RESUMO

BACKGROUND/AIM: Eribulin is currently used to treat advanced and metastatic breast cancer in the clinical setting; however, its efficacy is inhibited by resistance acquisition in many cases. Thus, the present study established two eribulin-resistant breast-cancer cell lines, and used these to investigate the mechanisms that underly eribulin-resistance acquisition. MATERIALS AND METHODS: Eribulin-resistant breast-cancer cell lines were generated by culturing MDA-MB-231 and MCF-7 cells with increasing concentrations of eribulin. RESULTS: The eribulin-resistant cells acquired resistance to eribulin, as well as several other anticancer drugs. After eribulin treatment, the eribulin-resistant cell lines showed no morphological change, no increased expression of epithelial-cadherin, nor any significant alteration in cell-cycle distribution. In contrast, the expression levels of programmed death-ligand 1 were increased in the MCF-7/eribulin-resistant compared to MCF-7 cells. CONCLUSION: The herein developed eribulin-resistant cell lines acquired cross-resistance to various anticancer agents, and displayed resistance to eribulin-induced effects on microtubule function and epithelial-mesenchymal transition (EMT).


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Furanos/administração & dosagem , Cetonas/administração & dosagem , Animais , Antineoplásicos/efeitos adversos , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Furanos/efeitos adversos , Humanos , Cetonas/efeitos adversos , Células MCF-7 , Camundongos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Anticancer Res ; 39(8): 4055-4060, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366487

RESUMO

BACKGROUND/AIM: Tumor-derived exosomes play important roles in tumor metastases. In this report, we observed the fate of tumor-derived exosomes in pancreatic cancer metastatic nude-mouse models using color-coded imaging. MATERIALS AND METHODS: Mia-PaCa-2 human pancreatic cancer cells expressing red fluorescent protein (RFP) were transduced by exosome-specific pCT-CD63-green fluorescent protein (GFP) and injected in the spleen of nude mice. RESULTS: Four weeks after injection of these cells into the spleen, liver metastases developed and tumor-derived exosomes were observed within the metastatic cancer cells and in Kupffer cells. Furthermore, tumor-derived exosomes diffused to bone marrow and lung cells, especially macrophages, without any metastases present. CONCLUSION: In the present study, we visualized the distribution of cancer-derived exosomes for the first time at the cellular level, in a pancreatic-cancer metastatic model.


Assuntos
Linhagem da Célula/genética , Exossomos/genética , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Animais , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/química , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Proteínas Luminescentes/química , Camundongos , Metástase Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Int J Nanomedicine ; 14: 4541-4558, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417257

RESUMO

Background: Tumor metastasis is responsible for most cancer death worldwide, which lacks curative treatment. Purpose: The objective of this study was to eliminate tumor and control the development of tumor metastasis. Methods: Herein, we demonstrated a smart nano-enabled platform, in which 2-[2-[2-chloro-3-[(1,3-dihydro-3,3-dimethyl-1-propyl-2h-indol-2-ylidene)ethylidene]-1-cyclohexen-1-yl]ethenyl]-3,3-dimethyl-1-propylindolium iodide (IR780) and tirapazamine (TPZ) were co-loaded in poly(ε-caprolactone)-poly(ethylene glycol) (PEG-PCL) to form versatile nanoparticles (PEG-PCL-IR780-TPZ NPs). Results: The intelligence of the system was reflected in the triggered and controlled engineering. Specially, PEG-PCL not only prolonged the circulation time of IR780 and TPZ but also promoted tumor accumulation of nanodrugs through enhanced permeability and retention (EPR) effect. Moreover, reactive oxygen species (ROS) generated by IR780 armed by an 808 nm laser irradiation evoked a cargo release. Meanwhile, IR780, as a mitochondria-targeting phototherapy agent exacerbated tumor hypoxic microenvironment and activated TPZ for accomplishing hypoxia-activated chemotherapy. Most significantly, IR780 was capable of triggering immunogenic cell death (ICD) during the synergic treatment. ICD biomarkers as a "danger signal" accelerated dendritic cells (DCs) maturation, and subsequently activated toxic T lymphocytes. Conclusion: Eventually, antitumor immune responses stimulated by combinational phototherapy and hypoxia-activated chemotherapy revolutionized the current landscape of cancer treatment, strikingly inhibiting tumor metastasis and providing a promising prospect in the clinical application.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Fototerapia , Animais , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Imunoterapia , Indóis/uso terapêutico , Lipossomos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/ultraestrutura , Fotoquimioterapia , Fototerapia/métodos , Polietilenoglicóis/química , Espécies Reativas de Oxigênio/metabolismo , Temperatura Ambiente , Tirapazamina/farmacologia , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
7.
Cancer Sci ; 110(10): 3244-3254, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31368625

RESUMO

We retrospectively investigated the impact of the tumor microenvironment (TME) on the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) as first-line treatment in 70 patients with advanced EGFR-mutant non-small cell lung cancer and who were seen at Osaka City University Hospital (Osaka, Japan) between August 2013 and December 2017. Using immunohistochemical staining with 28-8 and D7U8C Abs, the tumor proportion score was assessed for programmed cell death-1 ligand-1 (PD-L1), as high (50% or more) or low (less than 50%), and ligand-2 (PD-L2) expression, respectively. The extent of CD8+ tumor-infiltrating lymphocytes was evaluated on a scale of 0-3, with 0-1 as low and 2-3 as high. The TME of the 52 evaluable pretreatment specimens was categorized into 4 subtypes, according to the respective PD-L1 tumor proportion and CD8+ scores, as follows: (a) high/high (13.5%, n = 7); (b) low/low (42.3%, n = 22); (c) high/low (17.3%, n = 9); and (d) low/high (26.9%, n = 14). Expression of PD-L2 was significantly the highest in type 1 (57.1% vs 4.5% vs 11.1% vs 7.1%, respectively; P = .0090). Response rate was significantly the lowest in type 1 (14.3% vs 81.8% vs 66.7% vs 78.6%, respectively; P = .0085). Progression-free survival was the shortest in type 1 and the longest in type 4 (median, 2.4 vs 11.3 vs 8.4 vs 17.5 months, respectively; P = .00000077). The efficacy of EGFR-TKIs differed according to the TME, and the phenotype with high PD-L1 and CD8+ expression might be the subset that would poorly benefit from such treatment.


Assuntos
Antígeno B7-H1/metabolismo , Antígenos CD8/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Receptores ErbB/genética , Feminino , Humanos , Japão , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos
8.
Cancer Sci ; 110(10): 3215-3224, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432603

RESUMO

Patient-derived xenograft (PDX) models are a useful tool in cancer biology research. However, the number of lung cancer PDX is limited. In the present study, we successfully established 10 PDX, including three adenocarcinoma (AD), six squamous cell carcinoma (SQ) and one large cell carcinoma (LA), from 30 patients with non-small cell lung cancer (NSCLC) (18 AD, 10 SQ, and 2 LA), mainly in SCID hairless outbred (SHO) mice (Crlj:SHO-Prkdcscid Hrhr ). Histology of SQ, advanced clinical stage (III-IV), status of lymph node metastasis (N2-3), and maximum standardized uptake value ≥10 when evaluated using a delayed 18 F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scan was associated with successful PDX establishment. Histological analyses showed that PDX had histology similar to that of patients' surgically resected tumors (SRT), whereas components of the microenvironment were replaced with murine cells after several passages. Next-generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had epidermal growth factor receptor (EGFR) mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and osimertinib. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced that was associated with epithelial-to-mesenchymal transition. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR-TKI resistance.


Assuntos
Adenocarcinoma de Pulmão/patologia , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Pelados , Camundongos SCID , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Anticancer Res ; 39(8): 4539-4548, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366557

RESUMO

BACKGROUND/AIM: The aim of this study was to investigate PD-L1 expression and its association with prognosis in esophageal squamous cell carcinoma (ESCC) before and after neoadjuvant chemotherapy (5-fluorouracil and cisplatin, NAC-FP). PATIENTS AND METHODS: Using a database of 69 ESCC patients, we analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs), as well as the density of CD8+ tumor-infiltrating lymphocytes (TILs) in pretreatment biopsy specimens-versus-surgical specimens after resection. We determined the prognostic significance of these factors. RESULTS: The fraction of ESCC containing ICs expressing PD-L1 and having a high CD8+ TIL density was significantly increased after neoadjuvant treatment. However, PD-L1 expression on TCs or ICs, and CD8+ TIL density, was not significantly associated with patient survival in ESCC patients. CONCLUSION: NAC-FP induced PD-L1 expression on ICs and CD8+ TILs in ESCC patients. This finding suggests that PD-1/PD-L1 blockade could be combined with NAC-FP to treat ESCC patients.


Assuntos
Antígeno B7-H1/genética , Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Receptor de Morte Celular Programada 1/genética , Idoso , Antígeno B7-H1/sangue , Linfócitos T CD8-Positivos/efeitos dos fármacos , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Fluoruracila/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Prognóstico , Receptor de Morte Celular Programada 1/sangue , Microambiente Tumoral/efeitos dos fármacos
10.
J Cancer Res Clin Oncol ; 145(8): 2149-2156, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31273513

RESUMO

BACKGROUND: First-line rituximab therapy together with chemotherapy is the standard care for patients with advanced follicular B-cell lymphoma, as rituximab together with chemotherapy prolongs progression-free and overall survival (Herold et al. 2007; Marcus et al. 2005). However, as not all patient subgroups benefit from combined immuno-chemotherapy, we asked whether the microenvironment may predict benefit from rituximab-based therapy. DESIGN: To address this question, we performed a retrospective immunohistochemical analysis on pathological specimens of 18 patients recruited into a randomized clinical trial, where patients with advanced follicular lymphoma were randomized into either chemotherapy or immuno-chemotherapy with rituximab (Herold et al. 2007). RESULTS: We show here that rituximab exerts beneficial effects, especially in the subgroup of follicular lymphoma patients with low intrafollicular CD3, CD5, CD8, and ZAP70 and high CD56 and CD68 expression. CONCLUSION: Rituximab may overcome immune-dormancy in follicular lymphoma in cases with lower intrafollicular T-cell numbers and higher CD56 and CD68 cell counts. As this was a retrospective analysis on a small subgroup of patients, these data need to be corroborated in larger clinical trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos do Interstício Tumoral/patologia , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/imunologia , Rituximab/administração & dosagem , Linfócitos T/patologia , Clorambucila/administração & dosagem , Feminino , Humanos , Imunoterapia , Células Matadoras Naturais/patologia , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Prednisona/administração & dosagem , Prognóstico , Estudos Retrospectivos , Linfócitos T/efeitos dos fármacos , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
11.
Nat Commun ; 10(1): 2484, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171773

RESUMO

Tumor-specific antibody drugs can serve as cancer therapy with minimal side effects. A humanized antibody, PRL3-zumab, specifically binds to an intracellular oncogenic phosphatase PRL3, which is frequently expressed in several cancers. Here we show that PRL3-zumab specifically inhibits PRL3+ cancer cells in vivo, but not in vitro. PRL3 antigens are detected on the cell surface and outer exosomal membranes, implying an 'inside-out' externalization of PRL3. PRL3-zumab binds to surface PRL3 in a manner consistent with that in classical antibody-dependent cell-mediated cytotoxicity or antibody-dependent cellular phagocytosis tumor elimination pathways, as PRL3-zumab requires an intact Fc region and host FcγII/III receptor engagement to recruit B cells, NK cells and macrophages to PRL3+ tumor microenvironments. PRL3 is overexpressed in 80.6% of 151 fresh-frozen tumor samples across 11 common cancers examined, but not in patient-matched normal tissues, thereby implicating PRL3 as a tumor-associated antigen. Targeting externalized PRL3 antigens with PRL3-zumab may represent a feasible approach for anti-tumor immunotherapy.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos Imunológicos/farmacologia , Carcinoma Hepatocelular/metabolismo , Citofagocitose/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Microambiente Tumoral/efeitos dos fármacos , Animais , Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais Murinos , Antígenos de Neoplasias/metabolismo , Linfócitos B , Linhagem Celular Tumoral , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Imunoterapia , Células Matadoras Naturais , Macrófagos , Camundongos , Terapia de Alvo Molecular , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Neoplasias/metabolismo , Proteínas Oncogênicas/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Receptores de IgG , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Nat Med ; 25(6): 920-928, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31086347

RESUMO

The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low1-5, highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation6-13. In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 × 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST14) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1-PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNF-α signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.


Assuntos
Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Adulto , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Antígeno B7-H1/antagonistas & inibidores , Cisplatino/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Metástase Neoplásica/imunologia , Metástase Neoplásica/terapia , Nivolumabe/administração & dosagem , Radioterapia Adjuvante , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Neoplasias de Mama Triplo Negativas/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
13.
Artif Cells Nanomed Biotechnol ; 47(1): 1476-1487, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31070063

RESUMO

Polymeric micelles (PMs) play a vital role in multidrug co-delivery and cancer treatment. However, the development of intelligent PMs further allows PMs to accurately -target tumour, selectively release cargo multidrug and increase uptake. Therefore, targets, controlled release and uptake of intelligent PMs should be paid more attention to improvement synergistic therapeutic outcomes and minimize side effects. In this review, tumour targeting of co-delivery intelligent PMs and its intracellular trafficking mechanisms were overviewed. And this review provides a comprehensive summarization of several intelligent co-delivery PMs. Such a system could control the multidrug to be released simultaneously or sequentially by special properties of tumour microenvironment (TME) (including acidic PH, redox, overexpressed enzyme, excessive temperature) and external environment trigger. Additionally, limitations, clinical translation and future perspectives of intelligent co-delivery PMs were also being discussed in this article.


Assuntos
Portadores de Fármacos/química , Micelas , Neoplasias/tratamento farmacológico , Polímeros/química , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Neoplasias/patologia , Microambiente Tumoral/efeitos dos fármacos
14.
Zhonghua Zhong Liu Za Zhi ; 41(5): 321-325, 2019 May 23.
Artigo em Chinês | MEDLINE | ID: mdl-31137163

RESUMO

Gastric cancer is the most common gastrointestinal cancer in China. The morbidity and mortality are extremely high and there are significant challenges in the treatment of gastric cancer. Recent studies have shown that the expressions of T lymphocyte subsets vary in the immune microenvironment of gastric cancer patients. T lymphocytes are not only the main effector cells of human cellular immunity, but also the important immunoregulatory cells. T lymphocytes not only reflect the state of the tumor microenvironment, but also closely relate with the prognosis of patients. T lymphocytes play a crucial guiding role in the clinical treatment. Currently, clinical trials related to immunological checkpoint inhibitors are still underway, among which PD-1/PD-L1 monoclonal antibody has been approved for the treatment of gastric cancer. The applications of tumor vaccines and adoptive cell therapies in gastric cancer are also being explored. How to screen patients suitable to immunotherapy, develop the best combination therapy and evaluate the effectiveness of immunotherapy need to be studied and solved.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Imunidade Celular/imunologia , Neoplasias Gástricas/imunologia , Subpopulações de Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Antígeno B7-H1/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Pontos de Checagem do Ciclo Celular/imunologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/imunologia , Proteínas de Ciclo Celular/uso terapêutico , Humanos , Imunidade Celular/efeitos dos fármacos , Imunoterapia , Receptor de Morte Celular Programada 1/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos
15.
Int J Mol Sci ; 20(9)2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060263

RESUMO

Squamous cell carcinomas (SCC), including cutaneous SCCs, are by far the most frequent cancers in humans, accounting for 80% of all newly diagnosed malignancies worldwide. The old dogma that SCC develops exclusively from stem cells (SC) has now changed to include progenitors, transit-amplifying and differentiated short-lived cells. Accumulation of specific oncogenic mutations is required to induce SCC from each cell population. Whilst as fewer as one genetic hit is sufficient to induce SCC from a SC, multiple events are additionally required in more differentiated cells. Interestingly, the level of differentiation correlates with the number of transforming events required to induce a stem-like phenotype, a long-lived potential and a tumourigenic capacity in a progenitor, a transient amplifying or even in a terminally differentiated cell. Furthermore, it is well described that SCCs originating from different cells of origin differ not only in their squamous differentiation status but also in their malignant characteristics. This review summarises recent findings in cutaneous SCC and highlights transforming oncogenic events in specific cell populations. It underlines oncogenes that are restricted either to stem or differentiated cells, which could provide therapeutic target selectivity against heterogeneous SCC. This strategy may be applicable to SCC from different body locations, such as head and neck SCCs, which are currently still associated with poor survival outcomes.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/etiologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/etiologia , Animais , Biomarcadores Tumorais , Carcinoma de Células Escamosas/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Humanos , Mediadores da Inflamação/metabolismo , Terapia de Alvo Molecular , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/patologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
16.
Chin Clin Oncol ; 8(2): 18, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31070038

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most dangerous cancers, and the overall 5-year survival rate is only 8%. The microenvironment of PDAC, which promotes tumorigenesis, disease development and metastasis, consists of fibroblasts, immune cells, pancreatic stellate cells (PaSCs), adipocytes and extracellular matrix (ECM). Because the microenvironment is a part of the tumor, it is also an important target for PDAC treatment. Several therapeutic regimens targeting PDAC microenvironment factors or cells have been investigated, but the treatment effects were poor. More research on the physiological and pathological mechanisms and clinical treatment of PDAC is necessary.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Imunoterapia , Neoplasias Pancreáticas/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Animais , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Humanos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Microambiente Tumoral/imunologia
17.
J Exp Clin Cancer Res ; 38(1): 180, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036057

RESUMO

BACKGROUND: Lung cancer often ranks one of the most prevalent malignancies in the world. One of the most challenging aspects of treating late-stage lung cancer patients is the development of drug resistance, from both conventional chemo- and targeted therapeutic agents. Tumor-associated microphages (TAMs) have been shown to promote the survival and distant metastasis of lung cancer cells. METHODS: This study investigated the TAMs - modulating potential of cisplatin-resistant non-small cell lung cancer (NSCLC) cell lines, A549R and H460R by using bioinformatics approach, immunoblotting, immunofluorescence staining, migration, invasion, colony, lung sphere formation and xenograft tumorigenecity assays. RESULTS: In this study, we first demonstrated the elevated expression of oncogenic and stemenss markers such as Src, Notch1, macrophage inhibitory factor (MIF) and CD155 in trained cisplatin (CDDP)-resistant A549 and H460 cells (A549R and H460R cells). When co-cultured with TAMs, A549R and H460R cells promoted the M2-polarization in TAMs. In addition, A549R and H460R cells showed an increased self-renewal ability as they formed tumor spheres at higher frequency comparing to their parental counterparts. The increased MIF secretion by the A549R and H460R cells could be suppressed by a multiple kinase inhibitor, dasatinib, which resulted in the decreased of oncogenic network of Src, CD155 and MIF expression. Similarly, dasatinib treatment reduced the M2 polarization in TAMs and suppressed self-renewal ability of the A549R and H460R cells. CONCLUSION: In summary, cisplatin resistant lung cancer cells not only showed an increased self-renewal ability but also promoted M2 polarization of TAMs via the secretion of MIF. These findings were linked to the increased Src-associated signaling as dasatinib treatment significantly reversed these phenomena. Thus, kinase inhibitors such as dasatinib may be of potential for treating cisplatin-resistant lung cancer by targeting both tumor and the tumor microenvironment.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Oxirredutases Intramoleculares/genética , Neoplasias Pulmonares/tratamento farmacológico , Fatores Inibidores da Migração de Macrófagos/genética , Receptores Virais/genética , Células A549 , Animais , Carcinogênese/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Dasatinibe/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/genética
18.
J Cancer Res Clin Oncol ; 145(6): 1387-1403, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31037399

RESUMO

PURPOSE: Aspirin, one of the most commonly used nonsteroidal anti-inflammatory drugs (NAIDS), not only shows cancer chemoprevention effects but also improves cancer therapeutic effects when combined with other therapies. Studies that focus on aspirin regulation of the hallmarks of cancer and the associated molecular mechanisms facilitate a more thorough understanding of aspirin in mediating chemoprevention and may supply additional information for the development of novel cancer therapeutic agents. METHODS: The relevant literatures from PubMed have been reviewed in this article. RESULTS: Current studies have revealed that aspirin regulates almost all the hallmarks of cancer. Within tumor tissue, aspirin suppresses the bioactivities of cancer cells themselves and deteriorates the tumor microenvironment that supports cancer progression. In addition to tumor tissues, blocking of platelet activation also contributes to the ability of aspirin to inhibit cancer progression. In terms of the molecular mechanism, aspirin targets oncogenes and cancer-related signaling pathways and activates certain tumor suppressors. CONCLUSION: Beyond a chemopreventive agent, aspirin is a master regulator of the hallmarks of cancer.


Assuntos
Aspirina/farmacologia , Neoplasias/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anticarcinógenos , Metabolismo Energético , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/prevenção & controle , Ativação Plaquetária/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
19.
Mar Drugs ; 17(5)2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035725

RESUMO

Melanoma is one of the most malignant and aggressive types of cancer worldwide. Fibroblast growth factor 2 (FGF2) is one of the critical regulators of melanoma angiogenesis and metastasis; thus, it might be an effective anti-cancer strategy to explore FGF2-targeting drug candidates from existing drugs. In this study, we evaluate the effect of the marine drug propylene glycol alginate sodium sulfate (PSS) on FGF2-mediated angiogenesis and invasion. The data shows that FGF2 selectively bound to PSS with high affinity. PSS inhibited FGF2-mediated angiogenesis in a rat aortic ring model and suppressed FGF2-mediated invasion, but not the migration of murine melanoma B16-F10 cells. The further mechanism study indicates that PSS decreased the expression of activated matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9), and also suppressed their activity. In addition, PSS was found to decrease the level of Vimentin in B16-F10 cells, which is known to participate in the epithelial-mesenchymal transition. Notably, PSS did not elicit any changes in cancer cell viability. Based on the results above, we conclude that PSS might be a potential drug to regulate the tumor microenvironment in order to facilitate the recovery of melanoma patients.


Assuntos
Alginatos/farmacologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Melanoma Experimental/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Alginatos/uso terapêutico , Animais , Aorta/efeitos dos fármacos , Organismos Aquáticos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide , Avaliação Pré-Clínica de Medicamentos , Transição Epitelial-Mesenquimal , Humanos , Laminaria/química , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/patologia , Camundongos , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Neovascularização Patológica/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Ratos , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/patologia , Microambiente Tumoral/efeitos dos fármacos
20.
Int J Mol Sci ; 20(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096713

RESUMO

Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed-Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They evade antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation and "educate" (i.e. reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies are being developed to target not only tumor cells but also the tumor microenvironment. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.


Assuntos
Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/imunologia , Imunossupressores/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Imunossupressores/uso terapêutico , Células Matadoras Naturais , Maraviroc/farmacologia , Nivolumabe/farmacologia , Prognóstico , Receptores CCR5/efeitos dos fármacos , Células de Reed-Sternberg/efeitos dos fármacos , Células de Reed-Sternberg/imunologia , Linfócitos T , Trabectedina/farmacologia , Triptofano/análogos & derivados , Triptofano/farmacologia , Evasão Tumoral/efeitos dos fármacos , Ácido Zoledrônico/farmacologia
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