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1.
Biochim Biophys Acta Mol Basis Dis ; 1870(6): 167249, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38768929

RESUMO

RET fusion is an oncogenic driver in 1-2 % of patients with non-small cell lung cancer (NSCLC). Although RET-positive tumors have been treated with multikinase inhibitors such as vandetanib or RET-selective inhibitors, ultimately resistance to them develops. Here we established vandetanib resistance (VR) clones from LC-2/ad cells harboring CCDC6-RET fusion and explored the molecular mechanism of the resistance. Each VR clone had a distinct phenotype, implying they had acquired resistance via different mechanisms. Consistently, whole exome-seq and RNA-seq revealed that the VR clones had unique mutational signatures and expression profiles, and shared only a few common remarkable events. AXL and IGF-1R were activated as bypass pathway in different VR clones, and sensitive to a combination of RET and AXL inhibitors or IGF-1R inhibitors, respectively. SMARCA4 loss was also found in a particular VR clone and 55 % of post-TKI lung tumor tissues, being correlated with higher sensitivity to SMARCA4/SMARCA2 dual inhibition and shorter PFS after subsequent treatments. Finally, we detected an increased number of damaged mitochondria in one VR clone, which conferred sensitivity to mitochondrial electron transfer chain inhibitors. Increased mitochondria were also observed in post-TKI biopsy specimens in 13/20 cases of NSCLC, suggesting a potential strategy targeting mitochondria to treat resistant tumors. Our data propose new promising therapeutic options to combat resistance to RET inhibitors in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares , Mitocôndrias , Piperidinas , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-ret , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas de Fusão Oncogênica/antagonistas & inibidores , DNA Helicases/genética , DNA Helicases/metabolismo , DNA Helicases/antagonistas & inibidores , Proteínas do Citoesqueleto
2.
Cancer Sci ; 107(11): 1556-1562, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27575869

RESUMO

Cancer stem cells (CSCs) are thought to be responsible for tumor initiation, drug and radiation resistance, invasive growth, metastasis, and tumor relapse, which are the main causes of cancer-related deaths. Gastrointestinal cancers are the most common malignancies and still the most frequent cause of cancer-related mortality worldwide. Because gastrointestinal CSCs are also thought to be resistant to conventional therapies, an effective and novel cancer treatment is imperative. The first reported CSCs in a gastrointestinal tumor were found in colorectal cancer in 2007. Subsequently, CSCs were reported in other gastrointestinal cancers, such as esophagus, stomach, liver, and pancreas. Specific phenotypes could be used to distinguish CSCs from non-CSCs. For example, gastrointestinal CSCs express unique surface markers, exist in a side-population fraction, show high aldehyde dehydrogenase-1 activity, form tumorspheres when cultured in non-adherent conditions, and demonstrate high tumorigenic potential in immunocompromised mice. The signal transduction pathways in gastrointestinal CSCs are similar to those involved in normal embryonic development. Moreover, CSCs are modified by the aberrant expression of several microRNAs. Thus, it is very difficult to target gastrointestinal CSCs. This review focuses on the current research on gastrointestinal CSCs and future strategies to abolish the gastrointestinal CSC phenotype.


Assuntos
Neoplasias Gastrointestinais/patologia , Células-Tronco Neoplásicas/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Esofágicas/patologia , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neoplasias Pancreáticas/patologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/patologia
3.
PLoS One ; 8(1): e50825, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23382803

RESUMO

During the process of tumor invasion, cells require footholds on extracellular matrices (ECM) that are created by forming focal adhesions (FAs) using integrins. On the other hand, cells must degrade the ECM barrier using extracellular proteases including MMPs in the direction of cell movement. Degradation occurs at the leading edges or invadopodia of cells, which are enriched in proteases and adhesion molecules. Recently, we showed that the phosphoinositide-binding protein ZF21 regulates FA disassembly. ZF21 increased cell migration by promoting the turnover of FAs. In addition, ZF21 promotes experimental tumor metastasis to lung in mice and its depletion suppresses it. However, it is not known whether ZF21 regulates cancer cell invasion in addition to its activity on FAs. In this study, we demonstrate that ZF21 also regulates invasion of tumor cells, whereas it does not affect the overall production of MMP-2, MMP-9, and MT1-MMP by the cells. Also, we observe that the ECM-degrading activity specifically at the invadopodia is severely abrogated. In the ZF21 depleted cells MT1-MMP cannot accumulate to the invadopodia and thereby cannot contribute to the ECM degradation. Thus, this study demonstrates that ZF21 is a key player regulating multiple aspects of cancer cell migration and invasion. Possible mechanisms regulating ECM degradation at the invadopodia are discussed.


Assuntos
Proteínas de Transporte/genética , Matriz Extracelular/metabolismo , Invasividade Neoplásica/genética , Neoplasias/metabolismo , Animais , Proteínas de Transporte/metabolismo , Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Matriz Extracelular/genética , Adesões Focais/genética , Adesões Focais/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana , Camundongos , Invasividade Neoplásica/patologia , Neoplasias/patologia
4.
Med Oncol ; 28(1): 219-30, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20107936

RESUMO

Although antigen-specific immune responses including cytotoxic T cells (CTLs) against antigen peptide could be enhanced after tumor antigen peptide vaccinations, the immune responses do not necessarily result in a decrease or eradication of tumor cells in the vaccination trials. We focused on whether antigen-specific CTLs could be damaged by the repeated stimulation of antigenic peptide and whether regulatory T (Treg) cells would be increased by the administration of WT1 peptide. We administered WT1 peptide 22 times over 18 months in a CML patient who was being treated with imatinib. Although WT1 peptide administration every 2 weeks did not show any beneficial effects on the minimal residual disease (copies of bcr-abl transcripts), the transcripts remarkably decreased to the level of major molecular response after changing the administration interval of WT1 peptide from 2 to 4 weeks. An ex vivo study demonstrated that re-stimulation with WT1 peptide made WT1-specific T cells less reactive to WT1 tetramers and the impaired reactivity of CTLs lasted at least for 1 week. In addition, the cytotoxicity of the T cells was hampered by re-stimulation. Treg cells increased up to more than fivefold at the end of the WT1 administration period. The present findings suggested that the administration of the peptide every 4 weeks is superior to every 2 weeks. In addition, the findings that Treg cells increased gradually in accordance with the duration of WT1 peptide administration revealed the significance of manipulating Treg cells for establishing an efficient tumor antigen peptide vaccination.


Assuntos
Vacinas Anticâncer/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Fragmentos de Peptídeos/uso terapêutico , Linfócitos T Citotóxicos/imunologia , Proteínas WT1/imunologia , Antineoplásicos/uso terapêutico , Benzamidas , Terapia Combinada , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Neoplasia Residual/genética , Neoplasia Residual/imunologia , Neoplasia Residual/terapia , Fragmentos de Peptídeos/imunologia , Piperazinas/uso terapêutico , Prognóstico , Pirimidinas/uso terapêutico , Linfócitos T Reguladores/imunologia , Vacinação
5.
Int J Med Sci ; 7(2): 72-81, 2010 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-20428337

RESUMO

Although tyrosine kinase inhibitors is effective for dramatically reducing CML cells, it might be difficult to eradicate completely the CML stem cells. We aimed to clarify the safety and effects of WT1 peptide vaccination in combination with imatinib therapy for a CML patient. A 51 year-old male with CML in CP, who showed a resistance against imatinib therapy for 2.5 years, began to be treated with 9 mer modified-type WT1 peptides in combination with standard dose of imatinib. Although every 2-week-administration of WT1 peptides for 22 weeks did not show definite effects on the quantification of bcr-abl transcripts, by changing the administration from every 2 weeks to 4 weeks bcr-abl transcripts decreased remarkably. After 11 months of every 4-week-administration of the peptides and 12 months post cessation of the peptides bcr-abl transcripts achieved to the level below detection by RQ/RT-PCR (complete molecular response). WT1/MHC tetramer(+)CD8(+) CTLs, which appeared after the second administration of WT1 peptides and remained more than 15 in number among 10(6) CD8(+) T cells throughout the administration of WT1 peptides, are still present in the blood on 14th month post cessation of the peptides. An in vitro study as to the cytotoxicity of lymphocytes induced by mixed lymphocyte peptide culture demonstrated that cultured lymphocytes possessed cytotoxicity against WT1 expressing leukemia cells and the cytotoxicity was WT1-specific and MHC class I restricted. The present study showed that WT1 peptide vaccination in combination with TKI is feasible and effective in the therapy for imatinib-resistant CML.


Assuntos
Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Vacinação , Proteínas WT1/genética , Benzamidas , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Peptídeos/genética , Piperazinas , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Citotóxicos/química , Linfócitos T Citotóxicos/metabolismo , Tumor de Wilms/genética
6.
Leuk Res ; 34(11): 1517-24, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20338639

RESUMO

We investigated the transformation from pDCs to mDCs in a pDC line (PMDC05) which was established from a patient with pDC leukemia in our laboratory. PMDC05 cells were separated into two fractions according to the expression of BDCA1 and CD123. BDCA1(-)CD123(+) cells were found to be pDC-like cells by their morphology, surface phenotypes, mRNA expression and the function. In addition, BDCA1(-)CD123(+) cells were demonstrated to have a proliferating capacity and revealed the ability to transform to BDCA1(+)CD123(-) cells which showed mDC-like properties. Our data demonstrated the possibility of transformation from pDCs to mDCs in human DC lineage.


Assuntos
Transformação Celular Neoplásica , Células Dendríticas/patologia , Leucemia/patologia , Linhagem Celular Tumoral , Linhagem da Célula , Células Cultivadas , Humanos
7.
Leuk Res ; 33(9): 1224-32, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19443030

RESUMO

We established a plasmacytoid dendritic cell (pDC) line (PMDC05) from leukemia cells of pDC leukemia. PMDC05 cells were positive for CD4, CD56, CD33, HLA-DR, CD123 (IL-3Ralpha) and CD86 in the absence of lineage markers. mRNA of TLR1, TLR2, TLR4, TLR7 and TLR9 was clearly expressed and among these TLRs, TLR7 was prominent. Production of IFN-alpha and IL-12 in PMDC05 was enhanced by the stimulation with CpG-A and LPS, respectively. PMDC05 possessed a considerable antigen presenting ability, which was enhanced by culturing with IL3, influenza virus or LPS. PMDC05 could be a useful tool for investigating the pathophysiology of pDCL.


Assuntos
Células Dendríticas/metabolismo , Interferon-alfa/metabolismo , Leucemia Plasmocitária/metabolismo , Linfócitos T/imunologia , Receptores Toll-Like/fisiologia , Antígenos/imunologia , Sequência de Bases , Linhagem Celular Tumoral , Primers do DNA , Células Dendríticas/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Cariotipagem , Leucemia Plasmocitária/imunologia , Leucemia Plasmocitária/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
Med Oncol ; 26(4): 429-36, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19058036

RESUMO

To evaluate the usefulness of monocyte-derived dendritic cells transfected with tumor antigen mRNA for dendritic cell-based antitumor immunotherapy, we attempted to generate antigen-specific cytotoxic T cells by priming lymphocytes with monocyte-derived dendritic cells transfected with in vitro-transcribed tumor antigen mRNA. Mature monocyte-derived dendritic cells were generated from microbeads-separated CD14(+) cells by culturing with GM-CSF/IL-4 for 7 days and with TNF-alpha, IL-1alpha, IL-6, and PGE(2) for the last one day. Monocyte-derived dendritic cells, lymphocytes, and target cells, which were positive for HLA-A24, were used in the present study. Although lymphocytes prestimulated with untransfected monocyte-derived dendritic cells did not possess the cytotoxic ability against the target cells in a (51)Cr-release cytotoxicity assay, lymphocytes primed with tumor antigen RNA-transfected monocyte-derived dendritic cells were cytotoxic against the tumor antigen-expressing cells but not against the target cells without the expression of the antigen. The cytotoxic ability of the lymphocytes was blocked by the addition of antibodies against MHC class I but not by antibodies against MHC class II. These findings revealed that monocyte-derived dendritic cells transfected with WT1 or SART1 mRNA are able to induce tumor antigen-specific cytotoxic T cells and applicable for antitumor dendritic cell-based cellular immunotherapy.


Assuntos
Antígenos de Neoplasias/imunologia , Células Dendríticas/imunologia , Neoplasias Esofágicas/imunologia , Monócitos/imunologia , RNA Mensageiro/genética , Ribonucleoproteínas Nucleares Pequenas/imunologia , Linfócitos T Citotóxicos/imunologia , Proteínas WT1/imunologia , Apresentação de Antígeno , Antígenos de Neoplasias/genética , Células Cultivadas , Células Dendríticas/citologia , Neoplasias Esofágicas/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Antígenos HLA-A/metabolismo , Antígeno HLA-A24 , Humanos , Interleucina-4/farmacologia , Interleucina-6/farmacologia , Células Progenitoras de Megacariócitos/citologia , Células Progenitoras de Megacariócitos/efeitos dos fármacos , Células Progenitoras de Megacariócitos/metabolismo , Monócitos/citologia , Ribonucleoproteínas Nucleares Pequenas/genética , Transfecção , Fator de Necrose Tumoral alfa/farmacologia , Proteínas WT1/genética
9.
Acta Haematol ; 120(2): 91-9, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18948686

RESUMO

We report 2 patients with plasmacytoid dendritic cell leukemia (pDCL) expressing CD4, CD56, CD33, CD36, HLA-DR, CD123, CD86 and CD83 in the absence of lineage markers (myeloid, B, T or natural killer cells) except for CD33. Culturing leukemic blasts of both cases with IL-3 for 4 days increased the expression of surface molecules associated with antigen presentation, e.g. CD1a and CD40. Leukemic blasts of both cases possessed a considerable level of antigen-presenting ability to allogeneic lymphocytes in mixed leukocyte cultures. Culturing the blasts with IL-3 for 4 days markedly increased allogeneic antigen presenting ability. Combined with data showing evident graft-versus-leukemia effects without graft-versus-host disease in a cord blood stem cell transplanted pDCL case, leukemic cells in pDCL may act as potent antigen presenting cells in vivo, too.


Assuntos
Apresentação de Antígeno , Células Dendríticas/imunologia , Leucemia/patologia , Idoso , Linhagem da Célula , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Células Dendríticas/patologia , Efeito Enxerto vs Leucemia , Humanos , Imunofenotipagem , Interleucina-3/farmacologia , Leucemia/imunologia , Leucemia/terapia , Masculino
10.
Med Oncol ; 25(2): 137-47, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18488155

RESUMO

In order to establish an efficient gammadelta T cell-mediated immunotherapy for hematological malignancies, we attempted to evaluate cytotoxicity against tumor cells by gammadelta T cells, which were generated from blood cells of patients with myeloma and lymphoma by culturing with zoledronate and a low dose of IL-2. Although gammadelta T cells were expanded in patients with myeloma and lymphoma as well as normal persons, the amplification rates of gammadelta T cells before and after culturing varied from patient to patient in myeloma and lymphoma. gammadelta T cells generated in patients with myeloma and lymphoma showed a potent cytotoxic ability against myeloma/lymphoma cell lines as shown in gammadelta T cells generated in normal subjects. In addition, gammadelta T cells generated in a patient with myeloma showed a cytotoxic ability against self myeloma cells freshly prepared from bone marrow. However, the same gammadelta T cells were demonstrated to be non-cytotoxic to normal cells of the patient. These data demonstrated that gammadelta T cells, which could be expanded in vitro from blood cells of patients with myeloma and lymphoma by culturing with zoledronate and IL-2, possess a sufficient cytotoxic ability against tumor cells. These findings suggested that in vitro generated patients' gammadelta T cells could be applied to gammadelta T cell-mediated immunotherapy for hematological malignancies.


Assuntos
Citotoxicidade Imunológica , Linfoma/terapia , Mieloma Múltiplo/terapia , Receptores de Antígenos de Linfócitos T gama-delta/análise , Linfócitos T/imunologia , Humanos , Imunoterapia Adotiva , Linfoma/imunologia , Mieloma Múltiplo/imunologia
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