RESUMO
The glycans form a unique complex on the surface of cancer cells and play a pivotal role in tumor progression, impacting proliferation, invasion, and metastasis. TRA-1-60 is a glycan that was identified as a critical marker for the establishment of fully reprogrammed inducible pluripotent stem cells. Its expression has been detected in multiple cancer tissues, including embryonal carcinoma, prostate cancer, and pancreatic cancer, but the biological and pathological characterization of TRA-1-60-expressing tumor cells remains unclear within various types of malignancies. Here, we report the biological characteristics of TRA-1-60-expressing gastric cancer cells, especially those with its cell surface expression, and the therapeutic significance of targeting TRA-1-60. The cells with cell membrane expression of TRA-1-60 were mainly observed in the invasive area of patient gastric cancer tissues and correlated with advanced stages of the disease based on histopathological and clinicopathological analyses. In vitro analysis using a scirrhous gastric adenocarcinoma line, HSC-58, which highly expresses TRA-1-60 on its plasma membrane, revealed increased stress-resistant mechanisms, supported by the upregulation of glutathione synthetase and NCF-1 (p47phox) via lipid-ROS regulatory pathways, as detected by RNA-seq analysis followed by oxidative stress gene profiling. Our in vivo therapeutic study using the TRA-1-60-targeting antibody-drug conjugate, namely, Bstrongomab-conjugated monomethyl auristatin E, showed robust efficacy in a mouse model of peritoneal carcinomatosis induced by intraperitoneal xenograft of HSC-58, by markedly reducing massive tumor ascites. Thus, targeting the specific cell surface glycan, TRA-1-60, shows a significant therapeutic impact in advanced-stage gastric cancers.
Assuntos
Adenocarcinoma , Polissacarídeos , Neoplasias Gástricas , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Humanos , Animais , Linhagem Celular Tumoral , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Camundongos , Polissacarídeos/metabolismo , Masculino , Feminino , Camundongos NusRESUMO
Clinical findings on cartilage conduction hearing aids (CCHAs) have gradually become clear; however, few reports include a large number of cases. This study included 91 ears from 69 patients who underwent CCHA fitting in our hospital. Their ears were divided into six groups (i.e., bilateral aural atresia or severe canal stenosis, unilateral aural atresia or severe canal stenosis, chronic otitis media or chronic otitis externa with otorrhea, sensorineural hearing loss, mixed hearing loss, and conductive hearing loss) according to their clinical diagnosis and type of hearing loss. Most clinical diagnoses were aural atresia or meatal stenosis (bilateral, 21.8%; unilateral, 39.6%). The purchase rate of CCHAs was higher in the closed-ear group (bilateral, 77.3%; unilateral, 62.5%). In the bilateral closed-ear group, air conduction thresholds at 1000, 2000, and 4000 Hz and aided thresholds with CCHAs at 4000 Hz were significantly lower in the purchase group than the non-purchase group. No significant difference was observed between the purchase and non-purchase groups in the unilateral closed-ear group. In the bilateral closed-ear group, air conduction thresholds and aided thresholds were associated with the purchase rate of CCHAs. In the unilateral closed-ear group, factors other than hearing might have affected the purchase rate of CCHAs.
RESUMO
OGFOD1, a prolyl-hydroxylase, has been reported to translocate from the nucleus to the cytoplasm in response to cellular stress. Here, we demonstrate that OGFOD1 regulates the transcription and post-transcriptional stabilization of cell cycle-related genes. OGFOD1 knockdown in lung cancer cells induced cell cycle arrest through the specific depletion of cyclin-dependent kinase (CDK) 1, CDK2 and cyclin B1 (CCNB1) mRNAs and the nuclear accumulation of p21Cip1 . Analysis of the mRNA dynamics in these cells revealed that CDK1 decreased in a time-dependent manner, reflecting post-transcriptional regulation by OGFOD1 and the RNA-binding protein HuR. In contrast, the depletion of CDK2 and CCNB1 resulted from decreased transcription mediated by OGFOD1. These results indicate that OGFOD1 is required to maintain the function of specific cell cycle regulators during cancer cell proliferation.
Assuntos
Neoplasias , Prolil Hidroxilases , Prolil Hidroxilases/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Proliferação de Células , Núcleo Celular/metabolismo , Ciclo CelularRESUMO
We previously reported that high expression of procollagenlysine 2oxoglutarate 5dioxygenase 2 (PLOD2) leads to stabilization and plasma membrane translocation of integrin ß1 to promote the invasion and metastasis of oral squamous cell carcinoma (SCC). The present study aimed to further understand the relationship between PLOD2integrin ß1 signaling and the tumor microenvironment. This study provided further advanced insights indicating that elevated interleukin (IL)6 in the tumor microenvironment acts as a key molecule that triggers PLOD2integrin ß1 axisderived acceleration of tumor invasion and metastasis. It was found using the dualluciferase reporter assay system that signal transducer and activator of transcription 3 (STAT3) activation by IL6 was essential for increasing the expression levels of PLOD2 through direct activation of the PLOD2 promoter in oral SCC, whereas IL6 stimulation did not contribute to integrin ß1 expression or the subsequent maturation process towards a functional form on the plasma membrane. Furthermore, the expression of IL6 in oral SCC tissues was mainly observed in the tumor stroma. Finally, with double immunofluorescence staining, it was found that IL6 expression occurred in CD163positive M2 macrophages distributed around the tumor nest. These results combined with our previous results indicate that as IL6 significantly increases STAT3mediated PLOD2 promoter activity, IL6 released by M2type tumorassociated macrophages is a crucial factor that promotes PLOD2integrin ß1 axisenhanced invasion and metastasis of oral SCC cells.
Assuntos
Integrina beta1/metabolismo , Interleucina-6/metabolismo , Neoplasias Bucais/genética , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Bucais/imunologia , Neoplasias Bucais/patologia , Invasividade Neoplásica/genética , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/metabolismo , Regiões Promotoras Genéticas/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismoRESUMO
Cell-penetrating peptides, such as antibodies, have gained great attention as tools for the development of specific delivery systems for payloads, which might be applied as non-invasive carriers in vivo. Among these, tumor-homing peptides recently have been studied for use in tumor medicine. Tumor-homing peptides are oligopeptides, usually consisting of 30 or fewer amino acids that are efficiently and specifically incorporated into tumor cells, suggesting their potential use in establishing novel non-invasive tumor imaging systems for diagnostic and therapeutic applications. Here, we briefly introduce the biological characteristics of our tumor-homing peptides, focusing especially on those developed using a random peptide library constructed using mRNA display technology. The advantage of the tumor-homing peptides is their biological safety, given that these molecules do not show significant cytotoxicity against non-neoplastic cells; lack serious antigenicity, which alternatively might evoke unfavorable immune responses and inflammation in vivo; and are rapidly incorporated into target cells/tissues, with rates exceeding those seen for antibodies. Given their small size, tumor-homing peptides also are easy to modify and redesign. Based on these merits, tumor-homing peptides are expected to find wide application in various aspects of tumor medicine, including imaging diagnostics (eg, with dye-conjugated probes for direct visualization of invasive/metastatic tumor lesions in vivo) and therapeutics (eg, using peptide-drug conjugates [PDCs] for tumor targeting). Although further evidence will be required to demonstrate their practical utility, tumor-homing peptides are expected to show great potential as a next-generation bio-tool contributing to precision medicine for cancer patients.
Assuntos
Peptídeos Penetradores de Células/fisiologia , Peptídeos Penetradores de Células/uso terapêutico , Neoplasias/diagnóstico , Neoplasias/terapia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Peptídeos Penetradores de Células/química , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias/metabolismo , Oligopeptídeos/química , Oligopeptídeos/fisiologia , Oligopeptídeos/uso terapêutico , Biblioteca de Peptídeos , Medicina de Precisão , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: Because of the aging of the Japanese population, traumatic brain injuries (TBI) have increased in elderly adults. However, the effectiveness and prognosis of intensive treatment for geriatric TBI have not yet been determined. Thus, we used nationwide data from the Japan Neurotrauma Data Bank (JNTDB) projects to analyze prognostic factors for intensive and aggressive treatments. METHODS: We analyzed 1,879 geriatric TBI cases (age ≥65 years) registered in four JNTDB projects: Project 1998 (P1998) to Project 2015 (P2015). Clinical features, use of aggressive treatment, and 6-month outcomes on the Glasgow Outcome Scale (GOS) were compared among study projects. Logistic regression was used to identify prognostic factors in aggressively treated patients. RESULTS: The percentage of geriatric TBI cases significantly increased with time-P1998: 30.1%; Project 2004 (P2004): 34.6%; Project 2009 (P2009): 43.9%; P2015: 53.6%, p<0.0001). Use of aggressive treatment also significantly increased, from 67.0% in P1998 to 69.3% in P2015 (p<0.0001). Less invasive methods, such as trepanation and normothermic targeted temperature management, were more often chosen for geriatric patients. These efforts resulted in a significant decrease in the 6-month mortality rate, from 76.2% in P1998 to 63.1% in P2015 (p=0.0003), although the percentage of severely disabled patients increased, from 8.9% in P1998 to 11.1% in P2015 (p=0.0003). Intraventricular hemorrhage was the factor most strongly associated with unfavorable 6-month outcomes (OR 3.79, 95% CI 1.78-8.06, p<0.0001). CONCLUSIONS: Less invasive treatments reduced mortality in geriatric TBI but did not improve functional outcomes. Patient age was not the strongest prognostic factor; thus, physicians should consider characteristics other than age.
Assuntos
Lesões Encefálicas Traumáticas/terapia , Idoso , Idoso de 80 Anos ou mais , Lesões Encefálicas Traumáticas/diagnóstico , Lesões Encefálicas Traumáticas/epidemiologia , Estudos de Coortes , Feminino , Avaliação Geriátrica , Escala de Resultado de Glasgow , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
RNA detection permits early diagnosis of several infectious diseases and cancers, which prevent propagation of diseases and improve treatment efficacy. However, standard technique for RNA detection such as reverse transcription-quantitative polymerase chain reaction has complicated procedure and requires well-trained personnel and specialized lab equipment. These shortcomings limit the application for point-of-care analysis which is critical for rapid and effective disease management. The multicomponent nucleic acid enzymes (MNAzymes) are one of the promising biosensors for simple, isothermal and enzyme-free RNA detection. Herein, we demonstrate simple yet effective strategies that significantly enhance analytical performance of MNAzymes. The addition of the cationic copolymer and structural modification of MNAzyme significantly enhanced selectivity and activity of MNAzymes by 250 fold and 2,700 fold, respectively. The highly simplified RNA detection system achieved a detection limit of 73 fM target concentration without additional amplification. The robustness of MNAzyme in the presence of non-target RNA was also improved. Our finding opens up a route toward the development of an alternative rapid, sensitive, isothermal, and protein-free RNA diagnostic tool, which expected to be of great clinical significance.
Assuntos
Técnicas Biossensoriais , Ácidos Nucleicos , Cátions , Detecção Precoce de Câncer , Técnicas de Amplificação de Ácido Nucleico , RNA , RNA Viral , Sensibilidade e EspecificidadeRESUMO
DNAzymes are DNA molecules capable of catalytic activity. The catalytic core of DNAzymes can be separated and conjugated with target binding arms to create allosteric DNAzymes known as multi-component nucleic acid enzymes (MNAzymes). Two widely used DNAzymes are the 10-23 and the 8-17 DNAzymes. These DNAzymes differ in catalytic core structures, cleavage sites, and reactive metal ion cofactors. Previously we showed that the presence of a cationic comb-type polymer poly(l-lysine)-graft-dextran (PLL-g-Dex) improved activities of the 10-23 DNAzyme and MNAzyme by facilitating assembly of the catalytic complex. In this work, we demonstrate that PLL-g-Dex enhances activities of the 8-17 DNAzyme and MNAzyme; poly(allylamine)-graft-dextran and cationic homopolymers did not enhance activities. Metal ion and pH dependences were observed in the presence of PLL-g-Dex, suggesting that the cationic copolymer did not impede the interaction between the metal ion and the DNA-based enzymes. Thus, PLL-g-Dex has chaperone-like activity for DNAzymes and MNAzymes regardless of structures, cleavage sites, and cofactors.
Assuntos
DNA Catalítico , Cátions , DNA , PolímerosRESUMO
We report a case of a 74-year-old man with a cluster of differentiation (CD) 7-positive diffuse large B-cell lymphoma (DLBCL) in the right nasal cavity. Flow cytometry analyses showed CD7 and CD20 positivity in tumor cells. The patient received 6 cycles of R-CHOP plus local radiation therapy because positron emission tomography-computed tomography after R-CHOP revealed an intranasal lesion. The patient achieved complete remission (CR) after radiation therapy. The frequency of CD7-positive DLBCL is rare, and only 11 cases with follow-up of clinical course have been reported thus far. CR or partial response was noted in 8 of 11 cases after receiving rituximab combined with chemotherapy. In total, 9 of 12 cases involved the development of extranodal lesions, which occurred as an intranasal tumor in 3 cases. It is important to examine the clinical features by accumulation of further cases.
RESUMO
Identifying the specific functional regulator of integrin family molecules in cancer cells is critical because they are directly involved in tumor invasion and metastasis. Here we report high expression of PLOD2 in oropharyngeal squamous cell carcinomas (SCCs) and its critical role as a stabilizer of integrin ß1, enabling integrin ß1 to initiate tumor invasion/metastasis. Integrin ß1 stabilized by PLOD2-mediated hydroxylation was recruited to the plasma membrane, its functional site, and accelerated tumor cell motility, leading to tumor metastasis in vivo, whereas loss of PLOD2 expression abrogated it. In accordance with molecular analysis, examination of oropharyngeal SCC tissues from patients corroborated PLOD2 expression associated with integrin ß1 at the invasive front of tumor nests. PLOD2 is thus implicated as the key regulator of integrin ß1 that prominently regulates tumor invasion and metastasis, and it provides important clues engendering novel therapeutics for these intractable cancers.
RESUMO
Pancreatic invasive ductal adenocarcinoma (PDAC) is a representative intractable malignancy under the current cancer therapies, and is considered a scirrhous carcinoma because it develops dense stroma. Both PODXL1, a member of CD34 family molecules, and C5aR, a critical cell motility inducer, have gained recent attention, as their expression was reported to correlate with poor prognosis for patients with diverse origins including PDAC; however, previous studies reported independently on their respective biological significance. Here we demonstrate that PODXL1 is essential for metastasis of PDAC cells through its specific interaction with C5aR. In vitro assay demonstrated that PODXL1 bound to C5aR, which stabilized C5aR protein and recruited it to cancer cell plasma membranes to receive C5a, an inflammatory chemoattractant factor. PODXL1 knockout in PDAC cells abrogated their metastatic property in vivo, emulating the liver metastatic mouse model treated with anti-C5a neutralizing antibody. In molecular studies, PODXL1 triggered EMT on PDAC cells in response to stimulation by C5a, corroborating PODXL1 involvement in PDAC cellular invasive properties via specific interaction with the C5aR/C5a axis. Confirming the molecular assays, histological examination showed coexpression of PODXL1 and C5aR at the invasive front of primary cancer nests as well as in liver metastatic foci of PDAC both in the mouse metastasis model and patient tissues. Hence, the novel direct interaction between PODXL1 and the C5aR/C5a axis may provide a better integrated understanding of PDAC biological characteristics including its tumor microenvironment factors.
Assuntos
Carcinoma Ductal Pancreático/etiologia , Carcinoma Ductal Pancreático/metabolismo , Complemento C5a/imunologia , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/metabolismo , Receptor da Anafilatoxina C5a/metabolismo , Sialoglicoproteínas/genética , Microambiente Tumoral , Animais , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Movimento Celular , Complemento C5a/metabolismo , Modelos Animais de Doenças , Imunofluorescência , Expressão Gênica , Técnicas de Inativação de Genes , Xenoenxertos , Humanos , Imuno-Histoquímica , Camundongos , Metástase Neoplásica , Neoplasias Pancreáticas/patologia , Ligação Proteica , Transporte Proteico , Receptores de Quimiocinas/metabolismo , Sialoglicoproteínas/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Neoplasias PancreáticasRESUMO
The cell polarity regulator Crumbs3 (Crb3) promotes colon cancer cell migration and metastasis. However, the underlying mechanism of cancer cell migration regulated by Crb3 has not been fully elucidated. Here, we demonstrated that Crb3 is associated with cell migration by regulating glycosphingolipid (GSL) expression in human colon cancer cells. Crb3-knockout (KO) cells showed a remarkable increase in ganglioside GM3 (GM3) on the cell surface. Reduced migration by Crb3-KO cells was restored by forced expression of both Crb3 and Neuraminidase3 (Neu3). Immunofluorescent staining revealed that most Crb3 is colocalized with the recycling endosome marker Rab11. These findings show that Crb3 may promote colon cancer cell migration by regulating the expression of GSLs on the cell surface.
Assuntos
Membrana Celular/metabolismo , Movimento Celular , Neoplasias do Colo/metabolismo , Glicoesfingolipídeos/biossíntese , Glicoproteínas de Membrana/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Humanos , Glicoproteínas de Membrana/deficiênciaRESUMO
The ATP-binding cassette transporter ABCG2 is expressed in various organs, such as the small intestine, liver, and kidney, and influences the pharmacokinetics of drugs that are its substrates. ABCG2 is also expressed by cancer cells and mediates resistance to anticancer agents by promoting the efflux of these drugs. In the present study, we investigated the interactions between epidermal growth factor receptor tyrosine kinase inhibitors and ABCG2 by MTT assay, intracellular drug accumulation assay, and FACS. This study showed that four epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) (gefitinib, erlotinib, lapatinib, and afatinib) were transported from tumor cells as substrates of ABCG2. Q141K is a common single-nucleotide polymorphism of ABCG2 in Asians. We demonstrated that the extracellular efflux of gefitinib, erlotinib, and lapatinib was reduced by Q141K, whereas afatinib transport was not affected. In addition, all four EGFR TKIs inhibited the transport of other substrates by both wild-type and variant ABCG2 at 0.1 µM concentrations. Accordingly, epidermal growth factor receptor tyrosine kinase inhibitors may induce interactions with other drugs that are substrates of ABCG2, and single-nucleotide polymorphisms of ABCG2 may influence both the pharmacokinetics and efficacy of these anticancer agents.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Antineoplásicos/farmacologia , Proteínas de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transporte Biológico , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Células HEK293 , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11-RAGE-TPL2-COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.
Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , MAP Quinase Quinase Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas S100/genética , Adenocarcinoma/sangue , Adenocarcinoma/patologia , Antígenos de Neoplasias/genética , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Técnicas de Cocultura , Ciclo-Oxigenase 2/genética , Dinoprostona/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Células Neoplásicas Circulantes/metabolismo , Proteínas S100/sangueRESUMO
Metastatic breast cancer is the leading cause of cancer-associated death in women. The progression of this fatal disease is associated with inflammatory responses that promote cancer cell growth and dissemination, eventually leading to a reduction of overall survival. However, the mechanism(s) of the inflammation-boosted cancer progression remains unclear. In this study, we found for the first time that an extracellular cytokine, S100A8/A9, accelerates breast cancer growth and metastasis upon binding to a cell surface receptor, melanoma cell adhesion molecule (MCAM). Our molecular analyses revealed an important role of ETS translocation variant 4 (ETV4), which is significantly activated in the region downstream of MCAM upon S100A8/A9 stimulation, in breast cancer progression in vitro as well as in vivo. The MCAM-mediated activation of ETV4 induced a mobile phenotype called epithelial-mesenchymal transition (EMT) in cells, since we found that ETV4 transcriptionally upregulates ZEB1, a strong EMT inducer, at a very high level. In contrast, downregulation of either MCAM or ETV4 repressed EMT, resulting in greatly weakened tumor growth and lung metastasis. Overall, our results revealed that ETV4 is a novel transcription factor regulated by the S100A8/A9-MCAM axis, which leads to EMT through ZEB1 and thereby to metastasis in breast cancer cells. Thus, therapeutic strategies based on our findings might improve patient outcomes.
Assuntos
Neoplasias da Mama/genética , Transição Epitelial-Mesenquimal/genética , Proteínas Proto-Oncogênicas c-ets/genética , Animais , Neoplasias da Mama/patologia , Antígeno CD146/genética , Calgranulina A/genética , Calgranulina B/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genéticaRESUMO
Epithelial cell polarity regulator Crumbs3 (Crb3), a mammalian homolog within the Drosophila Crb gene family, was initially identified as an essential embryonic development factor. It is recently implicated in tumor suppression, though its specific functions are controversial. We here demonstrate that Crb3 strongly promotes tumor invasion and metastasis of human colon adenocarcinoma cells. Crb3 centrality to tumor migration was supported by strong expression at invasive front and metastatic foci of colonic adenocarcinoma of the patient tissues. Accordingly, two different Crb3-knockout (KO) lines, Crb3-KO (Crb3 -/-) DLD-1 and Crb3-KO WiDr from human colonic adenocarcinomas, were generated by the CRISPR-Cas9 system. Crb3-KO DLD-1 cells exhibited loss of cellular mobility in vitro and dramatic suppression of liver metastases in vivo in contrast to the wild type of DLD-1. Unlike DLD-1, Crb3-KO WiDr mobility and metastasis were unaffected, which were similar to wild-type WiDr. Proteome analysis of Crb3-coimmunopreciptated proteins identified different respective fibroblast growth factor receptor (FGFR) isotypes specifically bound to Crb3 isoform a through their intracellular domain. In DLD-1, Crb3 showed membranous localization of FGFR1 leading to its functional activation, whereas Crb3 bound to cytoplasmic FGFR4 in WiDr without FGFR1 expression, leading to cellular growth. Correlative expression between Crb3 and FGFR1 was consistently detected in primary and metastatic colorectal cancer patient tissues. Taking these together, Crb3 critically accelerates cell migration, namely invasion and metastasis of human colon cancers, through specific interaction to FGFR1 on colon cancer cells.
Assuntos
Adenocarcinoma/patologia , Neoplasias do Colo/patologia , Neoplasias Hepáticas/patologia , Glicoproteínas de Membrana/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Adenocarcinoma/secundário , Animais , Linhagem Celular Tumoral , Movimento Celular , Colo/patologia , Técnicas de Inativação de Genes , Humanos , Fígado/patologia , Neoplasias Hepáticas/secundário , Glicoproteínas de Membrana/genética , Camundongos , Invasividade Neoplásica/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The fertile stroma in pancreatic ductal adenocarcinomas (PDACs) has been suspected to greatly contribute to PDAC progression. Since the main cell constituents of the stroma are fibroblasts, there is crosstalking(s) between PDAC cells and surrounding fibroblasts in the stroma, which induces a fibroblast proliferation burst. We have reported that several malignant cancer cells including PDAC cells secrete a pronounced level of S100A11, which in turn stimulates proliferation of cancer cells via the receptor for advanced glycation end products (RAGE) in an autocrine manner. Owing to the RAGE+ expression in fibroblasts, the extracellular abundant S100A11 will affect adjacent fibroblasts. In this study, we investigated the significance of the paracrine axis of S100A11-RAGE in fibroblasts for their proliferation activity. In in vitro settings, extracellular S100A11 induced upregulation of fibroblast proliferation. Our mechanistic studies revealed that the induction is through RAGE-MyD88-mTOR-p70 S6 kinase upon S100A11 stimulation. The paracrine effect on fibroblasts is linked mainly to triggering growth but not cellular motility. Thus, the identified pathway might become a potential therapeutic target to suppress PDAC progression through preventing PDAC-associated fibroblast proliferation.
Assuntos
Fibroblastos/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas S100/metabolismo , Animais , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Espaço Extracelular/metabolismo , Fibroblastos/patologia , Humanos , Imuno-Histoquímica , Camundongos , Modelos Biológicos , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Microambiente TumoralRESUMO
INTRODUCTION: Most transitional cell carcinomas (TCCs) occur in the urinary tract. There are no reports of TCC originating in the colon. This report presents a very rare case of TCC that primarily occurred in the colon. PRESENTATION OF CASE: A 78-year-old female presented with adenocarcinoma of the rectum and TCC of the ascending colon. She was screened for urologic and gynecologic carcinomas because the TCC was considered a metastatic lesion; however, cytodiagnosis of urine, the cervix and corpus uteri revealed no abnormal findings. An operation was performed, and histological examination revealed adenocarcinoma of the rectum and TCC of the ascending colon. Immunohistochemical stained specimens of the ascending colon revealed tumor cells of cytokeratin (CK) 7-/CK20+ pattern. Eleven months post-operation, a metastatic TCC was found in the liver. The patient was treated with chemotherapy; however, she died 19 months after the operation. DISCUSSION: Our case was clinically considered that the TCC primarily occurred in the colon after analyzing the results of several examinations. Immunohistochemical staining of CK7 and CK20 expression pattern also suggested that the TCC of the ascending colon originated in the colon. CONCLUSION: To the best of our knowledge, this is the first literature report of TCC that originated in the colon. TCC that primarily occurs in the colon may rapidly progress, as in the case presented. Therefore, it is necessary to establish more appropriate treatment for similar cases.
RESUMO
BACKGROUND: There is a need to stratify patients who may develop heart failure because of the current "heart failure pandemic". We hypothesized that noninvasive assessment of diastolic electromechanical coupling by electrocardiography and Doppler echocardiography may be clinically useful for risk stratification of hypertensive patients who may develop heart failure. METHODS: We measured the time from the peak to end of the T wave (TpTe) as an electrophysiological parameter, and peak early diastolic mitral flow (E) and lateral annular (e') velocities as mechanical parameters in 109 patients with hypertension. Relationships between these parameters and their association with the prognosis were evaluated. RESULTS: The e' was inversely correlated with TpTe (p < 0.001) and QTc (p < 0.014), whereas E/e' was positively correlated with TpTe (p < 0.001) and QTc (p < 0.001). The TpTe predicted patients with E/e' > 12. There were 24 cardiovascular events during follow-up (57 ± 20 months), and Kaplan-Meier analysis showed that outcome was worse (p = 0.003) in patients with higher E/e' than lower E/e'; however, there was no difference between patients with longer TpTe (â§72 ms) and shorter TpTe (< 72 ms). CONCLUSION: The correlation of TpTe with e' and E/e' in hypertensive patients suggests that these parameters reflect diastolic ventricular electromechanical coupling. The E/e' predicted outcome, and an elevated E/e' should be suspected when TpTe is prolonged (> 72 ms). Noninvasive evaluation of diastolic electromechanical coupling is clinically useful in patients with hypertension for predicting their outcome.
Assuntos
Ecocardiografia Doppler , Eletrocardiografia , Coração/diagnóstico por imagem , Hipertensão/diagnóstico por imagem , Idoso , Arritmias Cardíacas/epidemiologia , Doenças Cardiovasculares/mortalidade , Infarto Cerebral/epidemiologia , Diástole , Feminino , Seguimentos , Coração/fisiopatologia , Insuficiência Cardíaca/epidemiologia , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Intervenção Coronária PercutâneaRESUMO
Despite receiving rituximab-combined chemotherapy, follicular lymphoma (FL) patients often suffer tumor recurrence and understand that the cause of relapse in FL would thus significantly ameliorate the tumor therapeutics. In the present study, we show that TRA-1-60-expressing cells are a unique population in FL, converge to the conventional stem cell marker Oct3/4 and ALDH1-positive population, and resist current B-lymphoma agents. TRA-1-60 expression was observed in scattered lymphoma cells in FL tissues only as well as in resting B-lymphocytes inside germinal centers. Retrospective comparison between recurrent and cognate primary tissues showed that the number of TRA-1-60-positive cells from rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP)-treated FL had increased relative to primary tissue, a finding corroborated by assays on different rituximab-treated FL cell lines, FL-18 and DOHH2, wherein TRA-positive cell numbers increased over 10-fold compared to the untreated sample. Concordantly, scanty TRA-1-60-positive FL-18 cells implanted s.c. into mice evinced potent tumor-initiating capacity in vivo, where tumors were 12-fold larger in volume (P = 0.0021 < 0.005) and 13-fold heavier in weight (P = 0.0015 < 0.005) compared to those xenografted from TRA-negative cells. To explain these results, gene expression profiling and qPCR analysis indicated that TRA-1-60-positive cells defined a distinct population from that of TRA-negative cells, with upregulation of multiple drug transporters and therapeutic resistance genes. Hence, TRA-1-60-expressing cells in FL are considered to be vigorously intractable against conventional therapeutic agents, which may explain its refractory recurrence.