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1.
Front Immunol ; 13: 929677, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36248881

RESUMO

The rising toll of cancer globally necessitates ingenuity in early detection and therapy. In the last decade, the utilization of immune signatures and immune-based therapies has made significant progress in the clinic; however, clinical standards leave many current and future patients without options. Non-coding RNAs, specifically microRNAs, have been explored in pre-clinical contexts with tremendous success. MicroRNAs play indispensable roles in programming the interactions between immune and cancer cells, many of which are current or potential immunotherapy targets. MicroRNAs mechanistically control a network of target genes that can alter immune and cancer cell biology. These insights provide us with opportunities and tools that may complement and improve immunotherapies. In this review, we discuss immune and cancer cell-derived miRNAs that regulate cancer immunity and examine miRNAs as an integral part of cancer diagnosis, classification, and therapy.


Assuntos
MicroRNAs , Neoplasias , Humanos , Imunoterapia , Neoplasias/tratamento farmacológico , Neoplasias/terapia
2.
Oncoimmunology ; 7(9): e1480286, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30228950

RESUMO

The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors. Activation of RON by its ligand, MSP, altered the gene expression profile of macrophages drastically and upregulated surface levels of CD80 and PD-L1, ligands for T-cell checkpoint receptors CTLA-4 and PD-1. Genetic deletion or pharmacological inhibition of RON in combination with anti-CTLA-4, but not with anti-PD-1, resulted in improved clinical responses against orthotopically transplanted tumors compared to single-agent treatment groups, resulting in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with higher levels of T-cell activation markers and tumor-infiltrating lymphocytes. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in lungs, resulting in clinical responses in nearly 60% of the mice. These findings suggest that RON inhibition can be a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer.

3.
Breast Cancer Res ; 17(1): 132, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26429062

RESUMO

INTRODUCTION: Breast cancer exhibits significant molecular, histological, and pathological diversity. Factors that impact this heterogeneity are poorly understood; however, transformation of distinct normal cell populations of the breast may generate different tumor phenotypes. Our previous study demonstrated that the polyomavirus middle T antigen (PyMT) oncogene can establish diverse tumor subtypes when broadly expressed within mouse mammary epithelial cells. In the present study, we assessed the molecular, histological, and metastatic outcomes in distinct mammary cell populations transformed with the PyMT gene. METHODS: Isolated mouse mammary epithelial cells were transduced with a lentivirus encoding PyMT during an overnight infection and then sorted into hormone receptor-positive luminal (CD133+), hormone receptor-negative luminal (CD133-), basal, and stem cell populations using the cell surface markers CD24, CD49f, and CD133. Each population was subsequently transplanted into syngeneic cleared mouse mammary fat pads to generate tumors. Tumors were classified by histology, estrogen receptor status, molecular subtype, and metastatic potential to investigate whether transformation of different enriched populations affects tumor phenotype. RESULTS: Although enriched mammary epithelial cell populations showed no difference in either the ability to form tumors or tumor latency, differences in prevalence of solid adenocarcinomas and squamous, papillary, and sebaceous-like tumors were observed. In particular, squamous metaplasia was observed more frequently in tumors derived from basal and stem cells than in luminal cells. Interestingly, both molecularly basal and luminal tumors developed from luminal CD133+, basal, and stem cell populations; however, luminal CD133- cells gave rise exclusively to molecularly basal tumors. Tumors arising from the luminal CD133-, basal, and stem cell populations were highly metastatic; however, luminal CD133+ cells generated tumors that were significantly less metastatic, possibly due to an inability of these tumor cells to escape the primary tumor site. CONCLUSIONS: Expression of PyMT within different mammary cell populations influences tumor histology, molecular subtype, and metastatic potential. The data demonstrate that luminal CD133+ cells give rise to less metastatic tumors, luminal CD133- cells preferentially establish basal tumors, and the cell of origin for squamous metaplasia likely resides in the basal and stem cell populations.


Assuntos
Antígenos Transformantes de Poliomavirus/genética , Neoplasias Pulmonares/virologia , Neoplasias Mamárias Experimentais/virologia , Neoplasia de Células Basais/virologia , Antígeno AC133 , Animais , Antígenos CD/metabolismo , Transformação Celular Viral , Células Cultivadas , Células Epiteliais/virologia , Feminino , Glicoproteínas/metabolismo , Neoplasias Pulmonares/secundário , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Experimentais/patologia , Camundongos , Transplante de Neoplasias , Neoplasia de Células Basais/secundário , Peptídeos/metabolismo , Polyomavirus/genética
4.
Oncoimmunology ; 2(9): e25670, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-24327933

RESUMO

The MSP/RON signaling pathway favors the conversion of micrometastatic lesions to overt metastases by suppressing antitumor immune responses. The loss of RON functions in the host potentiates tumor-specific CD8+ T-cell responses, hence inhibiting the outgrowth of metastatic cancer cells. Thus, RON inhibitors may potentially prevent the outgrowth of micrometastases in cancer patients.

5.
Cancer Discov ; 3(7): 751-60, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23612011

RESUMO

Many "nonmetastatic" cancers have spawned undetectable metastases before diagnosis. Eventual outgrowth of these microscopic lesions causes metastatic relapse and death, yet the events that dictate when and how micrometastases convert to overt metastases are largely unknown. We report that macrophage-stimulating protein and its receptor, Ron, are key mediators in conversion of micrometastases to bona fide metastatic lesions through immune suppression. Genetic deletion of Ron tyrosine kinase activity specifically in the host profoundly blocked metastasis. Our data show that loss of Ron function promotes an effective antitumor CD8(+) T-cell response, which specifically inhibits outgrowth of seeded metastatic colonies. Treatment of mice with a Ron-selective kinase inhibitor prevented outgrowth of lung metastasis, even when administered after micrometastatic colonies had already been established. Our findings indicate that Ron inhibitors may hold potential to specifically prevent outgrowth of micrometastases in patients with cancer in the adjuvant setting.


Assuntos
Imunidade/genética , Micrometástase de Neoplasia/genética , Neoplasias/genética , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Micrometástase de Neoplasia/patologia , Neoplasias/patologia , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais
6.
Crit Rev Oncol Hematol ; 81(3): 275-85, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21612942

RESUMO

Autophagy is a physiological process in which cellular components are degraded by the lysosomal machinery. Thereby, organelles are recycled and monomers are produced in order to maintain energy production. Current studies indicate autophagy might suppress or augment survival of cancer cells. Therefore, by elucidating the role of autophagy in cancer pathogenesis, novel therapeutic intervention points may be revealed. Leukemia therapy has advanced in recent years; but a definitive cure is still lacking. Since autophagy often is deregulated in this particular type of cancer, it is clear that future findings will have clinical implications. This review will discuss the current knowledge of autophagy in blood cancers.


Assuntos
Autofagia , Metabolismo Energético , Leucemia/metabolismo , Lisossomos/metabolismo , Animais , Sobrevivência Celular , Humanos , Leucemia/imunologia , Leucemia/terapia , Lisossomos/imunologia
7.
Hematology ; 16(5): 303-7, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21902895

RESUMO

We aimed to examine the growth suppressive effects of quercetin on acute promyelocytic and lymphoblastic leukemia and chronic myeloid leukemia, and to find out whether the growth suppression is related to the blocking of telomerase enzyme activity. Cytotoxic effects of quercetin were shown by trypan blue analyses. Apoptotic effects of quercetin were examined by acridine orange and ethidium bromide staining by fluorescence microscopy. The effects of quercetin on telomerase enzyme activity were shown by hTERT Quantification Kit. Our results demonstrated that quercetin has antiproliferative and apoptotic effects on T-cell acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia, and chronic myeloid leukemia (CML) cells. We also showed for the first time by this study that quercetin suppresses the activity of telomerase in ALL and CML cells. The results of this study show the importance of quercetin for its therapeutic potential in treatment of leukemias.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Leucemia/enzimologia , Quercetina/farmacologia , Telomerase/metabolismo , Antineoplásicos/toxicidade , Antioxidantes/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Células K562 , Leucemia/genética , Quercetina/toxicidade , RNA Mensageiro/metabolismo , Telomerase/genética
8.
Anticancer Agents Med Chem ; 11(4): 385-97, 2011 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21453240

RESUMO

Sphingolipids are major constituents of the cells with emerging roles in the regulation of cellular processes. Deregulation of sphingolipid metabolism is reflected as various pathophysiological conditions including metabolic disorders and several forms of cancer. Ceramides, ceramide-1-phosphate (C1P), glucosyl ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P) are among the bioactive sphingolipid species that have important roles in the regulation of cell death, survival and chemotherapeutic resistance. Some of those species are known to accumulate in the cells upon chemotherapy while some others are known to exhibit an opposite pattern. Even though the length of fatty acid chain has a deterministic effect, in general, upregulation of ceramides and sphingosine is known to induce apoptosis. However, S1P, C1P and GluCer are proliferative for cells and they are involved in the development of chemoresistance. Therefore, sphingolipid metabolism appears as a good target for the development of novel therapeutics or supportive interventions to increase the effectiveness of the chemotherapeutic drugs currently in hand. Some approaches involve manipulation of the synthesis pathways yielding the increased production of apoptotic sphingolipids while the proliferative ones are suppressed. Some others are trying to take advantage of cytotoxic sphingolipids like short chain ceramide analogs by directly delivering them to the malignant cells as a distinct chemotherapeutic intervention. Numerous studies in the literature show the feasibility of those approaches especially in acute and chronic leukemias. This review compiles the current knowledge about sphingolipids and their roles in chemotherapeutic response with the particular attention to leukemias.


Assuntos
Leucemia/tratamento farmacológico , Leucemia/metabolismo , Esfingolipídeos/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia/genética , Leucemia/patologia , Esfingolipídeos/genética
9.
Hematology ; 16(2): 95-9, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21418740

RESUMO

Imatinib is a chemotherapeutic drug used for the treatment of chronic myeloid leukemia (CML). Recent data showed imatinib-induced cell death in various types of cancers. Autophagy is the physiological process in which cellular components are broken down by the lysosomal activation. In this study, we aimed to examine the effects of imatinib on autophagy in addition to apoptosis in CML cells. Results suggested that imatinib induces autophagy in CML cells through inducing over-expression of BECLIN-1 and ATG5 genes with the statistical significance. Our results demonstrated that autophagy might be involved in imatinib-induced cell death.


Assuntos
Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Proteínas de Membrana/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/efeitos dos fármacos , Piperazinas/farmacologia , Pirimidinas/farmacologia , Autofagia/genética , Proteína 5 Relacionada à Autofagia , Proteína Beclina-1 , Benzamidas , Linhagem Celular Tumoral , Humanos , Mesilato de Imatinib , Immunoblotting , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Reação em Cadeia da Polimerase Via Transcriptase Reversa
10.
Leuk Lymphoma ; 51(10): 1895-901, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20849385

RESUMO

STAT proteins are cytoplasmic transcription factors that are involved in the regulation of numerous cellular activities such as cell growth, differentiation, and survival. In this study, we aimed to identify the expression pattern of STAT genes in imatinib-sensitive and -resistant K562 cells, and further, to reveal the effects of STAT5A siRNA knockdown on cell growth and apoptosis induction. The XTT cell proliferation assay showed that both sensitive and resistant K562 cells were sensitized to imatinib upon transfection with STAT5A siRNA. Caspase-3 enzyme activity was increased significantly in both cells. These results may open up new opportunities to overcome chemotherapeutic resistance in leukemia.


Assuntos
Piperazinas/farmacologia , Pirimidinas/farmacologia , Interferência de RNA , Fator de Transcrição STAT5/genética , Proteínas Supressoras de Tumor/genética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Benzamidas , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Ativação Enzimática/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , Mesilato de Imatinib , Células K562 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/genética
11.
Int J Cancer ; 127(7): 1497-506, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20503271

RESUMO

Sphingolipids are sphingosine-based lipid molecules that have important functions in cellular signal transduction and in a variety of cellular processes including proliferation, differentiation, programmed cell death (apoptosis) and responses to stressful conditions. Ceramides, dihydroceramide, sphingosine and sphingosine-1-phosphate are examples of those bioactive sphingolipids. They have a major impact on determination of the cell fate by contributing to the cell survival or cell death through apoptosis. Despite the number of carbon atoms in the fatty acid chain changes the physiological role; ceramides generally exert suppressive roles on the cell proliferation. There have been several enzymes identified in this pathway that are responsible for the conversion of ceramide into other sphingolipid derivatives. Those derivatives also have differential roles on those cellular processes. Sphingosine-1-phosphate is an example of such sphingolipid derivatives which has antiapoptotic effects. As they have significant impacts particularly on the cell death and survival, bioactive sphingolipids have a great potential to be targets in cancer therapy. Increasing number of studies indicates that sphingolipid derivatives are important in the progression of hematological malignancies, and they are also involved in the resistance to current chemotherapeutic options. This review compiles the current knowledge in this area for enlightening the therapeutic potentials of bioactive sphingolipids in various leukemias.


Assuntos
Neoplasias Hematológicas/tratamento farmacológico , Esfingolipídeos/uso terapêutico , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ceramidas/fisiologia , Ceramidas/uso terapêutico , Neoplasias Hematológicas/patologia , Homeostase , Humanos , Esfingolipídeos/fisiologia , Esfingosina/fisiologia
12.
Hematology ; 15(1): 33-8, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20132660

RESUMO

Chronic myeloid leukemia (CML) is a hematological malignancy characterized by high levels of immature white blood cells. CML is caused by the translocation between chromosomes 9 and 22 (which results in the formation of the Philadelphia chromosome) creating BCR-ABL fusion protein. Imatinib and nilotinib are chemotherapeutic drugs which specifically bind to the BCR-ABL and inhibit cancer cells. Nilotinib is more effective in this respect than imatinib. We have shown that nilotinib induces apoptosis in imatinib-resistant K562 CML cells which have the wild-type BCR-ABL fusion gene almost to the same extent as it does in the parental sensitive cells by the increase in caspase-3 enzyme activity and the decrease in mitochondrial membrane potential. This effect of nilotinib, even in low concentrations, may indicate the efficacy of the usage of nilotinib in imatinib-resistant CML with less risk of undesired cytotoxic effects in the remaining cells of the body.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Células K562/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sequência de Bases , Benzamidas , Caspase 3/metabolismo , Divisão Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Concentração Inibidora 50 , Células K562/citologia , Células K562/enzimologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Dados de Sequência Molecular , Proteínas de Neoplasias/genética , Análise de Sequência de DNA
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