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2.
Proc Natl Acad Sci U S A ; 117(35): 21576-21587, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32801214

RESUMO

Toxic environmental carcinogens promote cancer via genotoxic and nongenotoxic pathways, but nongenetic mechanisms remain poorly characterized. Carcinogen-induced apoptosis may trigger escape from dormancy of microtumors by interfering with inflammation resolution and triggering an endoplasmic reticulum (ER) stress response. While eicosanoid and cytokine storms are well-characterized in infection and inflammation, they are poorly characterized in cancer. Here, we demonstrate that carcinogens, such as aflatoxin B1 (AFB1), induce apoptotic cell death and the resulting cell debris stimulates hepatocellular carcinoma (HCC) tumor growth via an "eicosanoid and cytokine storm." AFB1-generated debris up-regulates cyclooxygenase-2 (COX-2), soluble epoxide hydrolase (sEH), ER stress-response genes including BiP, CHOP, and PDI in macrophages. Thus, selective cytokine or eicosanoid blockade is unlikely to prevent carcinogen-induced cancer progression. Pharmacological abrogation of both the COX-2 and sEH pathways by PTUPB prevented the debris-stimulated eicosanoid and cytokine storm, down-regulated ER stress genes, and promoted macrophage phagocytosis of debris, resulting in suppression of HCC tumor growth. Thus, inflammation resolution via dual COX-2/sEH inhibition is an approach to prevent carcinogen-induced cancer.


Assuntos
Citocinas/metabolismo , Eicosanoides/metabolismo , Neoplasias Hepáticas/metabolismo , Aflatoxina B1/efeitos adversos , Animais , Apoptose , Carcinogênese/metabolismo , Carcinógenos/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Citocinas/imunologia , Progressão da Doença , Eicosanoides/imunologia , Epóxido Hidrolases/metabolismo , Células Hep G2 , Humanos , Inflamação/metabolismo , Neoplasias Hepáticas/fisiopatologia , Macrófagos/metabolismo , Camundongos , Processos Neoplásicos
3.
Nat Rev Cancer ; 20(9): 485-503, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32694624

RESUMO

Neutrophils play a key role in defence against infection and in the activation and regulation of innate and adaptive immunity. In cancer, tumour-associated neutrophils (TANs) have emerged as an important component of the tumour microenvironment. Here, they can exert dual functions. TANs can be part of tumour-promoting inflammation by driving angiogenesis, extracellular matrix remodelling, metastasis and immunosuppression. Conversely, neutrophils can also mediate antitumour responses by direct killing of tumour cells and by participating in cellular networks that mediate antitumour resistance. Neutrophil diversity and plasticity underlie the dual potential of TANs in the tumour microenvironment. Myeloid checkpoints as well as the tumour and tissue contexture shape neutrophil function in response to conventional therapies and immunotherapy. We surmise that neutrophils can provide tools to tailor current immunotherapy strategies and pave the way to myeloid cell-centred therapeutic strategies, which would be complementary to current approaches.


Assuntos
Neoplasias/imunologia , Neoplasias/terapia , Neutrófilos/imunologia , Animais , Humanos , Imunoterapia , Processos Neoplásicos , Microambiente Tumoral/imunologia
4.
Nat Rev Cancer ; 20(8): 437-454, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32581320

RESUMO

Immunotherapy with checkpoint blockade induces rapid and durable immune control of cancer in some patients and has driven a monumental shift in cancer treatment. Neoantigen-specific CD8+ T cells are at the forefront of current immunotherapy strategies, and the majority of drug discovery and clinical trials revolve around further harnessing these immune effectors. Yet the immune system contains a diverse range of antitumour effector cells, and these must function in a coordinated and synergistic manner to overcome the immune-evasion mechanisms used by tumours and achieve complete control with tumour eradication. A key antitumour effector is the natural killer (NK) cells, cytotoxic innate lymphocytes present at high frequency in the circulatory system and identified by their exquisite ability to spontaneously detect and lyse transformed or stressed cells. Emerging data show a role for intratumoural NK cells in driving immunotherapy response and, accordingly, there have been renewed efforts to further elucidate and target the pathways controlling NK cell antitumour function. In this Review, we discuss recent clinical evidence that NK cells are a key immune constituent in the protective antitumour immune response and highlight the major stages of the cancer-NK cell immunity cycle. We also perform a new analysis of publicly available transcriptomic data to provide an overview of the prognostic value of NK cell gene expression in 25 tumour types. Furthermore, we discuss how the role of NK cells evolves with tumour progression, presenting new opportunities to target NK cell function to enhance cancer immunotherapy response rates across a more diverse range of cancers.


Assuntos
Antineoplásicos/imunologia , Antineoplásicos/uso terapêutico , Células Matadoras Naturais/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Comunicação Celular/genética , Comunicação Celular/imunologia , Comunicação Celular/fisiologia , Ciclo Celular/imunologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes cdc/efeitos dos fármacos , Genes cdc/genética , Genes cdc/imunologia , Genes cdc/fisiologia , Humanos , Vigilância Imunológica/imunologia , Imunoterapia/métodos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/fisiologia , Processos Neoplásicos , Prognóstico
6.
Proc Natl Acad Sci U S A ; 117(11): 5931-5937, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32127478

RESUMO

E-cadherin is a tumor suppressor protein, and the loss of its expression in association with the epithelial mesenchymal transition (EMT) occurs frequently during tumor metastasis. However, many metastases continue to express E-cadherin, and a full EMT is not always necessary for metastasis; also, positive roles for E-cadherin expression in metastasis have been reported. We hypothesize instead that changes in the functional activity of E-cadherin expressed on tumor cells in response to environmental factors is an important determinant of the ability of the tumor cells to metastasize. We find that E-cadherin expression persists in metastatic lung nodules and circulating tumor cells (CTCs) in two mouse models of mammary cancer: genetically modified MMTV-PyMT mice and orthotopically grafted 4T1 tumor cells. Importantly, monoclonal antibodies that bind to and activate E-cadherin at the cell surface reduce lung metastasis from endogenous genetically driven tumors and from tumor cell grafts. E-cadherin activation inhibits metastasis at multiple stages, including the accumulation of CTCs from the primary tumor and the extravasation of tumor cells from the vasculature. These activating mAbs increase cell adhesion and reduce cell invasion and migration in both cell culture and three-dimensional spheroids grown from primary tumors. Moreover, activating mAbs increased the frequency of apoptotic cells without affecting proliferation. Although the growth of the primary tumors was unaffected by activating mAbs, CTCs and tumor cells in metastatic nodules exhibited increased apoptosis. Thus, the functional state of E-cadherin is an important determinant of metastatic potential beyond whether the gene is expressed.


Assuntos
Neoplasias da Mama/metabolismo , Caderinas/antagonistas & inibidores , Caderinas/metabolismo , Neoplasias Pulmonares/metabolismo , Metástase Neoplásica , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/genética , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Metástase Neoplásica/tratamento farmacológico , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Processos Neoplásicos
7.
Proc Natl Acad Sci U S A ; 117(11): 5923-5930, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123095

RESUMO

Arachidonic acid epoxides generated by cytochrome P450 (CYP) enzymes have been linked to increased tumor growth and metastasis, largely on the basis of overexpression studies and the application of exogenous epoxides. Here we studied tumor growth and metastasis in Cyp2c44-/- mice crossed onto the polyoma middle T oncogene (PyMT) background. The resulting PyMT2c44 mice developed more primary tumors earlier than PyMT mice, with increased lymph and lung metastasis. Primary tumors from Cyp2c44-deficient mice contained higher numbers of tumor-associated macrophages, as well as more lymphatic endothelial cells than tumors from PyMT mice. While epoxide and diol levels were comparable in tumors from both genotypes, prostaglandin (PG) levels were higher in the PyMTΔ2c44 tumors. This could be accounted for by the finding that Cyp2c44 metabolized the PG precursor, PGH2 to 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT), thus effectively reducing levels of effector PGs (including PGE2). Next, proteomic analyses revealed an up-regulation of WD repeating domain FYVE1 (WDFY1) in tumors from PyMTΔ2c44 mice, a phenomenon that was reproduced in Cyp2c44-deficient macrophages as well as by PGE2 Mechanistically, WDFY1 was involved in Toll-like receptor signaling, and its down-regulation in human monocytes attenuated the LPS-induced phosphorylation of IFN regulatory factor 3 and nuclear factor-κB. Taken together, our results indicate that Cyp2c44 protects against tumor growth and metastasis by preventing the synthesis of PGE2 The latter eicosanoid influenced macrophages at least in part by enhancing Toll-like receptor signaling via the up-regulation of WDFY1.


Assuntos
Neoplasias da Mama/metabolismo , Família 2 do Citocromo P450/metabolismo , Linfangiogênese/fisiologia , Prostaglandinas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Família 2 do Citocromo P450/genética , Modelos Animais de Doenças , Células Endoteliais/patologia , Ácidos Graxos Insaturados/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Linfangiogênese/genética , Macrófagos , Camundongos , Camundongos Knockout , Monócitos , Processos Neoplásicos , Proteômica , Transdução de Sinais , Receptores Toll-Like , Regulação para Cima
8.
Nat Rev Cancer ; 20(3): 139, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32020065
9.
Proc Natl Acad Sci U S A ; 117(5): 2588-2596, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31969449

RESUMO

Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of KrasG12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes KrasG12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals.


Assuntos
Adenocarcinoma de Pulmão/enzimologia , Neoplasias Pulmonares/enzimologia , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Humanos , Pulmão/enzimologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 14 Ativada por Mitógeno/genética , Processos Neoplásicos , Proteínas Proto-Oncogênicas p21(ras)/genética
10.
Sci Rep ; 10(1): 357, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941916

RESUMO

The developmental regulator SOX9 is linked to cancer progression mainly as a result of its role in the regulation of cancer stem cells (CSCs). However, its activity in the differentiated cells that constitute the heterogeneous tumor bulk has not been extensively studied. In this work, we addressed this aspect in gastric cancer, glioblastoma and pancreatic adenocarcinoma. SOX9 silencing studies revealed that SOX9 is required for cancer cell survival, proliferation and evasion of senescence in vitro and tumor growth in vivo. Gain of-SOX9 function showed that high levels of SOX9 promote tumor cell proliferation in vitro and in vivo. Mechanistically, the modulation of SOX9 changed the expression of the transcriptional repressor BMI1 in the same direction in the three types of cancer, and the expression of the tumor suppressor p21CIP in the opposite direction. In agreement with this, SOX9 expression positively correlated with BMI1 levels and inversely with p21CIP in clinical samples of the different cancers. Moreover, BMI1 re-establishment in SOX9-silenced tumor cells restored cell viability and proliferation as well as decreased p21CIP in vitro and tumor growth in vivo. These results indicate that BMI1 is a critical effector of the pro-tumoral activity of SOX9 in tumor bulk cells through the repression of p21CIP. Our results highlight the relevance of the SOX9-BMI1-p21CIP axis in tumor progression, shedding novel opportunities for therapeutic development.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Neoplasias/genética , Complexo Repressor Polycomb 1/metabolismo , Fatores de Transcrição SOX9/metabolismo , Adenocarcinoma , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Glioblastoma , Humanos , Neoplasias/metabolismo , Processos Neoplásicos , Neoplasias Pancreáticas , Fatores de Transcrição SOX9/genética , Neoplasias Gástricas
11.
Proc Natl Acad Sci U S A ; 116(49): 24881-24891, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31754034

RESUMO

Dependence on the 26S proteasome is an Achilles' heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic target for both MM and TNBC. Genome editing or small-molecule mediated inhibition of DYRK2 significantly reduces 26S proteasome activity, bypasses bortezomib resistance, and dramatically delays in vivo tumor growth in MM and TNBC thereby promoting survival. We further characterized the ability of LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor burden in vivo. The drug docks into the active site of DYRK2 and partially inhibits all 3 core peptidase activities of the proteasome. Our results suggest that targeting 26S proteasome regulators will pave the way for therapeutic strategies in MM and TNBC.


Assuntos
Bortezomib/farmacologia , Processos Neoplásicos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , TYK2 Quinase/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , ATPases Associadas a Diversas Atividades Celulares/genética , Animais , Linhagem Celular Tumoral , Feminino , Edição de Genes , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mieloma Múltiplo , Fosforilação , Complexo de Endopeptidases do Proteassoma/genética , Inibidores de Proteassoma/farmacologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Neoplasias de Mama Triplo Negativas/patologia
12.
PLoS Comput Biol ; 15(11): e1007493, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31738747

RESUMO

A tumour grows when the total division (birth) rate of its cells exceeds their total mortality (death) rate. The capability for uncontrolled growth within the host tissue is acquired via the accumulation of driver mutations which enable the tumour to progress through various hallmarks of cancer. We present a mathematical model of the penultimate stage in such a progression. We assume the tumour has reached the limit of its present growth potential due to cell competition that either results in total birth rate reduction or death rate increase. The tumour can then progress to the final stage by either seeding a metastasis or acquiring a driver mutation. We influence the ensuing evolutionary dynamics by cytotoxic (increasing death rate) or cytostatic (decreasing birth rate) therapy while keeping the effect of the therapy on net growth reduction constant. Comparing the treatments head to head we derive conditions for choosing optimal therapy. We quantify how the choice and the related gain of optimal therapy depends on driver mutation, metastasis, intrinsic cell birth and death rates, and the details of cell competition. We show that detailed understanding of the cell population dynamics could be exploited in choosing the right mode of treatment with substantial therapy gains.


Assuntos
Citostáticos/farmacologia , Citotoxinas/farmacologia , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Evolução Biológica , Progressão da Doença , Humanos , Modelos Biológicos , Modelos Teóricos , Mutação , Processos Neoplásicos
13.
FEBS Open Bio ; 9(12): 2159-2169, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31705785

RESUMO

Platelets are implicated in the pathophysiology of breast and other cancers through their role in exchanging biomolecules with tumor cells in the tumor microenvironment. Such exchange results in tumor-educated platelets with altered RNA expression profiles. Multiple lines of evidence indicate that platelet RNA profiles may be suitable as diagnostic biomarkers for cancer-related biological processes. In this study, we characterized the gene expression signatures of platelets in breast cancer (BC) by high-throughput sequencing and quantitative real-time RT-PCR. Our results indicate that the expression of TPM3 (tropomyosin 3) mRNA is significantly elevated in platelets from patients with BC compared with age-matched healthy control subjects. Furthermore, up-regulation of TPM3 mRNA in platelets was found to be significantly correlated with metastasis in patients with BC. Finally, we report that platelet TPM3 mRNA is delivered into BC cells through microvesicles and leads to enhanced migrative phenotype of BC cells. In summary, our findings suggest that the transfer of platelet TPM3 mRNA into cancer cells via microvesicles promotes cancer cell migration, and thus platelet-derived TPM3 mRNA may be a suitable biomarker for early diagnosis of metastatic BC.


Assuntos
Neoplasias da Mama/genética , Micropartículas Derivadas de Células/genética , Tropomiosina/metabolismo , Adulto , Idoso , Biomarcadores Tumorais , Plaquetas/fisiologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Movimento Celular , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Metástase Neoplásica/fisiopatologia , Processos Neoplásicos , RNA Mensageiro/genética , Transcriptoma/genética , Tropomiosina/fisiologia , Microambiente Tumoral/fisiologia
14.
PLoS Comput Biol ; 15(8): e1007246, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31374072

RESUMO

Successful prediction of the likely paths of tumor progression is valuable for diagnostic, prognostic, and treatment purposes. Cancer progression models (CPMs) use cross-sectional samples to identify restrictions in the order of accumulation of driver mutations and thus CPMs encode the paths of tumor progression. Here we analyze the performance of four CPMs to examine whether they can be used to predict the true distribution of paths of tumor progression and to estimate evolutionary unpredictability. Employing simulations we show that if fitness landscapes are single peaked (have a single fitness maximum) there is good agreement between true and predicted distributions of paths of tumor progression when sample sizes are large, but performance is poor with the currently common much smaller sample sizes. Under multi-peaked fitness landscapes (i.e., those with multiple fitness maxima), performance is poor and improves only slightly with sample size. In all cases, detection regime (when tumors are sampled) is a key determinant of performance. Estimates of evolutionary unpredictability from the best performing CPM, among the four examined, tend to overestimate the true unpredictability and the bias is affected by detection regime; CPMs could be useful for estimating upper bounds to the true evolutionary unpredictability. Analysis of twenty-two cancer data sets shows low evolutionary unpredictability for several of the data sets. But most of the predictions of paths of tumor progression are very unreliable, and unreliability increases with the number of features analyzed. Our results indicate that CPMs could be valuable tools for predicting cancer progression but that, currently, obtaining useful predictions of paths of tumor progression from CPMs is dubious, and emphasize the need for methodological work that can account for the probably multi-peaked fitness landscapes in cancer.


Assuntos
Modelos Biológicos , Neoplasias/genética , Neoplasias/patologia , Teorema de Bayes , Biologia Computacional , Simulação por Computador , Estudos Transversais , Bases de Dados Factuais , Progressão da Doença , Evolução Molecular , Aptidão Genética , Genótipo , Humanos , Modelos Genéticos , Mutação , Processos Neoplásicos , Prognóstico
17.
Artigo em Chinês | MEDLINE | ID: mdl-31315361

RESUMO

Objective: To compare the carcinogenic abilities of CD133(+)CD44(+) laryngeal cancer stem cells and general laryngeal cancer stem cells and to identify the mechanism underlying the action of miRNAs. Methods: Solid tumor-derived laryngeal carcinoma stem cells and Hep-2-derived laryngeal carcinoma stem cells were cultured, and CD133(+)CD44(+) laryngeal cancer stem cells were sorted by flow cytometry. Boden chamber invasion assay, cell migration assay and tumor formation assay were then performed to compare the invasion, migration and tumorigenic abilities of CD133(+)CD44(+) laryngeal cancer stem cells and general laryngeal cancer stem cells. And then, miRNAs isolated from two laryngeal cancer stem cells were detected and analysed with miRNA chip. Results: (1)In Boyden chamber invasion assay, the cell invasion rate of CD133(+)CD44(+) laryngeal cancer stem cells was obviously higher (80.2%±2.3% vs. 63.9%±3.2%, t=5.011, P=0.027); (2)CD133(+)CD44(+) laryngeal cancer stem cells also had higher mobility in cell migration assay (82.9%±1.1% vs. 70.9%±0.6%, t=4.514, P=0.031); (3)In tumor formation assay, the tumor formation rate of CD133(+)CD44(+) laryngeal cancer stem cells was also higher (80% vs. 50%). What's more, we identified 15 miRNAs that were significantly upregulated in CD133(+)CD44(+) laryngeal cancer stem cells and 3 miRNAs that were significantly downregulated in CD133(+)CD44(+) laryngeal cancer stem cells, compared with normal laryngeal cancer stem cells. Conclusions: CD133(+)CD44(+) laryngeal cancer stem cells have stronger invasion, migration and tumorigenic abilities compared with normal laryngeal cancer stem cells, and the difference of miRNAs' expression is one of the possible causes.


Assuntos
Neoplasias Laríngeas/fisiopatologia , MicroRNAs/biossíntese , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Antígeno AC133/biossíntese , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Humanos , Receptores de Hialuronatos/biossíntese , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/patologia , Laringe/metabolismo , Laringe/patologia , Laringe/fisiopatologia , Invasividade Neoplásica/fisiopatologia , Processos Neoplásicos
18.
Rev. Eugenio Espejo ; 13(1): 53-61, Ene-Jul. 2019.
Artigo em Espanhol | LILACS | ID: biblio-1006782

RESUMO

Caso clínico: paciente masculino de 81 años de edad, con cuadro de 24 horas de evolución secundario a caída, caracterizado por somnolencia, desorientación en persona, tiempo y espacio, incontinencia urinaria y dificultad para la deambulación, motivo por el cual se le efectúa una tomografía simple de cráneo encontrándose hematomas subdurales bilaterales, presenta episodios de sangrado recurrente y leucocitosis sostenida , en frotis de sangre periférica se observó 28% de blastos por lo que se realiza una biopsia de medula ósea descubriéndose un cariotipo medular compatible con leucemia mieloide aguda, debido a sus características clínicas y a su mala evolución fue catalogado como paciente paliativo. Conclusiones: la leucemia mieloide aguda es una patología hematológica cuya evolución al no ser detectada genera un alto grado de mortalidad, sobre todo en el adulto mayor comórbido.


It was presented a clinical case of a male patient of 81 years of age, with a 24-hour of secondary evolution to a fall. It was characterized by drowsiness, disorientation in person, time and space, urinary incontinence and difficulty in walking, that was why a simple skull tomography was performed, in which bilateral subdural hematomas were found. The patient presented episodes of recurrent bleeding and sustained leukocytosis. Peripheral blood smear showed 28% of blasts, so a bone marrow biopsy was performed, revealing a medullary karyotype compatible with acute myeloid leukemia. The patient was classified as palliative due to its clinical characteristics and evolution. The hematological pathology above was potentially fatal. If this one was not detected early, it would generate an accelerated unfavorable evolution, especially in the elderly comorbid, as occurred in the case presented.


Assuntos
Humanos , Masculino , Idoso de 80 Anos ou mais , Neoplasias Hematológicas , Doenças Hematológicas , Doenças Sanguíneas e Linfáticas , Síndromes Paraneoplásicas , Neoplasias , Processos Neoplásicos
19.
Pathol Res Pract ; 215(8): 152454, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31146977

RESUMO

Alpha-fetoprotein (AFP)-producing gastric cancer (AFPGC) is regarded as a rare but highly malignant gastric adenocarcinoma subtype and its clinic pathological presentation mimics hepatocellular carcinoma. However, the underlying mechanism of this disease remains elusive. The level of ANGPTL6 in AFPGC cell lines is much higher than that of common types of gastric cancer cells. A high level of ANGPTL6 confers a poor prognosis and is correlated with the expression of CD34 (an endothelial cell marker). ANGPTL6 promotes endothelial cell migration and tube formation, Moreover, ANGPTL6 knockdown inhibits cancer cell apoptosis and invasiveness. Mechanistically, ANGPTL6 activates the ERK1/2 and AKT pathways. Treatment of ERK1/2 or AKT inhibitor can attenuated cell migration and tube formation. ANGPTL6 loss results in tumor growth in vivo. Our study revealed that ANGPTL6 is an important driver gene of angiogenesis in AFPGC development. These findings provide not only an effective biomarker for diagnosis but also an attractive therapeutic target for use in AFPGC patients.


Assuntos
Proteínas Semelhantes a Angiopoietina/metabolismo , Neovascularização Patológica/patologia , Neoplasias Gástricas/patologia , alfa-Fetoproteínas/metabolismo , Proteínas Semelhantes a Angiopoietina/genética , Progressão da Doença , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Processos Neoplásicos , Neovascularização Patológica/genética , Estômago/patologia , Neoplasias Gástricas/genética , alfa-Fetoproteínas/genética
20.
Proc Natl Acad Sci U S A ; 116(24): 11754-11763, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31138683

RESUMO

Human homolog of mouse double minute 2 (HDM2) is an oncogene frequently overexpressed in cancers with poor prognosis, but mechanisms of controlling its abundance remain elusive. In an unbiased biochemical search, we discovered Skp1-Cullin 1-FBXO22-ROC1 (SCFFBXO22) as the most dominating HDM2 E3 ubiquitin ligase from human proteome. The results of protein decay rate analysis, ubiquitination, siRNA-mediated silencing, and coimmunoprecipitation experiments support a hypothesis that FBXO22 targets cellular HDM2 for ubiquitin-dependent degradation. In human breast cancer cells, FBXO22 knockdown (KD) increased cell invasiveness, which was driven by elevated levels of HDM2. Moreover, mouse 4T1 breast tumor model studies revealed that FBXO22 KD led to a significant increase of breast tumor cell metastasis to the lung. Finally, low FBXO22 expression is correlated with worse survival and high HDM2 expression in human breast cancer. Altogether, these findings suggest that SCFFBXO22 targets HDM2 for degradation and possesses inhibitory effects against breast cancer tumor cell invasion and metastasis.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Movimento Celular/fisiologia , Proteínas F-Box/metabolismo , Invasividade Neoplásica/patologia , Metástase Neoplásica/patologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Células HCT116 , Células HeLa , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Processos Neoplásicos , RNA Interferente Pequeno/metabolismo , Transfecção/métodos , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/fisiologia
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