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Androgen deprivation therapy is given to suppress prostate cancer growth; however, some cells continue to grow hormone-independently as castration-resistant prostate cancer (CRPC). Sulfated glycosaminoglycans promote ligand binding to receptors as co-receptors, but their role in CRPC remains unknown. Using the human prostate cancer cell line C4-2, which can proliferate in hormone-dependent and hormone-independent conditions, we found that epidermal growth factor (EGF)-activated EGFR-ERK1/2 signaling via 3-O-sulfated heparan sulfate (HS) produced by HS 3-O-sulfotransferase 1 (HS3ST1) is activated in C4-2 cells under hormone depletion. Knockdown of HS3ST1 in C4-2 cells suppressed hormone-independent growth, and inhibited both EGF binding to the cell surface and activation of EGFR-ERK1/2 signaling. Gefitinib, an EGFR inhibitor, significantly suppressed C4-2 cell proliferation and growth of a xenografted C4-2 tumor in castrated mouse. Collectively, our study has revealed a mechanism by which cancer cells switch to hormone-independent growth and identified the key regulator as 3-O-sulfated HS.
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Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Animais , Camundongos , Neoplasias de Próstata Resistentes à Castração/patologia , Fator de Crescimento Epidérmico , Antagonistas de Androgênios/farmacologia , Receptores Androgênicos/metabolismo , Sulfatos , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Heparitina SulfatoRESUMO
Glycosaminoglycan (GAG) is a polysaccharide present on the cell surface as an extracellular matrix component, and is composed of repeating disaccharide units consisting of an amino sugar and uronic acid except in the case of the keratan sulfate. Sulfated GAGs, such as heparan sulfate, heparin, and chondroitin sulfate mediate signal transduction of growth factors, and their functions vary with the type and degree of sulfated modification. We have previously identified human and mouse cochlins as proteins that bind to sulfated GAGs. Here, we prepared a recombinant cochlin fused to human IgG-Fc or Protein A at the C-terminus as a detection and purification tag and investigated the ligand specificity of cochlin. We found that cochlin can be used as a specific probe for highly sulfated heparan sulfate and chondroitin sulfate E. We then used mutant analysis to identify the mechanism by which cochlin recognizes GAGs and developed a GAG detection system using cochlin. Interestingly, a mutant lacking the vWA2 domain bound to various types of GAGs. The N-terminal amino acid residues of cochlin contributed to its binding to heparin. Pathological specimens from human myocarditis patients were stained with a cochlin-Fc mutant. The results showed that both tryptase-positive and tryptase-negative mast cells were stained with this mutant. The identification of detailed modification patterns of GAGs is an important method to elucidate the molecular mechanisms of various diseases. The method developed for evaluating the expression of highly sulfated GAGs will help understand the biological and pathological importance of sulfated GAGs in the future.
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Sulfatos de Condroitina , Proteínas da Matriz Extracelular , Heparitina Sulfato , Animais , Humanos , Camundongos , Biomarcadores Tumorais/química , Proteínas de Ligação ao Cálcio/química , Sulfatos de Condroitina/análise , Heparitina Sulfato/análise , Imuno-Histoquímica/métodos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Triptases/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas da Matriz Extracelular/química , Proteínas da Matriz Extracelular/genéticaRESUMO
In bronchial asthma patients, mucous cell metaplasia (MCM) and fibrosis occur in the bronchial epithelium and interstitium, respectively. The mucus and collagen fibers are identified by Periodic acid-Schiff stain (PAS) or Sirius red stain on optical microscopy. On a scanning electron microscope (SEM) observation, formalin-fixed-paraffin-embedded specimens have high insulation, thereby attenuating the scattered electron signals leading to insufficient contrast. Moreover, there were no staining methods for SEM observation, which characterizes the changes in epithelium and interstitium by enhancing the scattered electrons. In this study, we established a method of coating osmium thin film on pathological tissue specimens using plasma chemical vapor deposition technology. This method ensured the intensity of scattered electron signals and enabled SEM observation. Furthermore, we found that morphological changes in MCM and interstitial fibrosis could be characterized by Grocott stain, which we optimized to evaluate pathological remodeling in bronchial asthma. Using these techniques, we compared asthma-induced mice with Amphiregulin (Areg) knockout mice, and found that Areg induce MCM, but the production of Grocott-stain-positive substrate in the interstitium is Areg-independent. The method developed in this study provides an understanding of the pathological spatial information linked to the ultrastructural changes in cells and interstitium due to disease-related signaling abnormalities.
Assuntos
Asma , Animais , Asma/patologia , Corantes , Fibrose , Humanos , Camundongos , Microscopia Eletrônica de Varredura , Inclusão em Parafina , Coloração e RotulagemRESUMO
We report the case of a 29-year-old man who underwent umbilical cord blood transplantation for chronic myelogenous leukemia 14 years previously. He was diagnosed with secondary pleuroparenchymal fibroelastosis (sPPFE) following treatment for hematologic malignancies (sPPFE after HM-Tx) 2.5 years ago. On computed tomography, pleural thickening in the upper lobe, lung volume loss, and recurrent bilateral pneumothorax were detected. Although he waited for cadaveric lung transplantation (LTx) for 1.5 years, his respiratory failure worsened, and he died. Pathological autopsy and clinical course indicated sPPFE. After diagnosing sPPFE after HM-Tx, the timing for deciding LTx is critical, especially when pneumothorax recurs.
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In addition to the symptoms of aging, the main symptoms in Werner syndrome (WS), a hereditary premature aging disease, include calcification of subcutaneous tissue with solid pain and refractory skin ulcers. However, the mechanism of calcification in WS remains unclear. In this study, the histological analysis of the skin around the ulcer with calcification revealed an accumulation of calcium phosphate in the lymphatic vessels. Moreover, the morphological comparison with the lymphatic vessels in PAD patients with chronic skin ulcers demonstrated the ongoing lymphatic remodeling in WS patients because of the narrow luminal cross-sectional area (LA) of the lymphatic vessels but the increment of lymphatic microvessels density (MLVD). Additionally, fluorescence immunohistochemical analysis presented the cytoplasmic distribution and the accumulation of WRN proteins in endothelial cells on remodeling lymphatic vessels. In summary, these results point out a relationship between calcification in lymphatic vessels and the remodeling of lymphatic vessels and suggest the significance of the accumulation of WRN mutant proteins as an age-related change in WS patients. Thus, cytoplasmic accumulation of WRN protein can be an indicator of the decreasing drainage function of the lymphatic vessels and the increased risk of skin ulcers and calcification in the lymphatic vessels.
Assuntos
Senilidade Prematura/patologia , Calcinose , Vasos Linfáticos/metabolismo , Úlcera Cutânea/patologia , Síndrome de Werner , Células Endoteliais/metabolismo , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pele/metabolismo , Pele/patologia , Síndrome de Werner/genética , Síndrome de Werner/patologia , Helicase da Síndrome de Werner/genéticaRESUMO
BACKGROUND: Patients with cancer benefit from treatment with immune checkpoint inhibitors (ICIs), and those with an inflamed tumor microenvironment (TME) and/or high tumor mutation burden (TMB), particularly, tend to respond to ICIs; however, some patients fail, whereas others acquire resistance after initial response despite the inflamed TME and/or high TMB. We assessed the detailed biological mechanisms of resistance to ICIs such as programmed death 1 and/or cytotoxic T-lymphocyte-associated protein 4 blockade therapies using clinical samples. METHODS: We established four pairs of autologous tumor cell lines and tumor-infiltrating lymphocytes (TILs) from patients with melanoma treated with ICIs. These tumor cell lines and TILs were subjected to comprehensive analyses and in vitro functional assays. We assessed tumor volume and TILs in vivo mouse models to validate identified mechanism. Furthermore, we analyzed additional clinical samples from another large melanoma cohort. RESULTS: Two patients were super-responders, and the others acquired resistance: the first patient had a non-inflamed TME and acquired resistance due to the loss of the beta-2 microglobulin gene, and the other acquired resistance despite having inflamed TME and extremely high TMB which are reportedly predictive biomarkers. Tumor cell line and paired TIL analyses showed high CD155, TIGIT ligand, and TIGIT expression in the tumor cell line and tumor-infiltrating T cells, respectively. TIGIT blockade or CD155-deletion activated T cells in a functional assay using an autologous cell line and paired TILs from this patient. CD155 expression increased in surviving tumor cells after coculturing with TILs from a responder, which suppressed TIGIT+ T-cell activation. Consistently, TIGIT blockade or CD155-deletion could aid in overcoming resistance to ICIs in vivo mouse models. In clinical samples, CD155 was related to resistance to ICIs in patients with melanoma with an inflamed TME, including both primary and acquired resistance. CONCLUSIONS: The TIGIT/CD155 axis mediates resistance to ICIs in patients with melanoma with an inflamed TME, promoting the development of TIGIT blockade therapies in such patients with cancer.
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Imunoterapia/métodos , Melanoma/tratamento farmacológico , Receptores Imunológicos/metabolismo , Receptores Virais/metabolismo , Idoso , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Microambiente TumoralRESUMO
BACKGROUND: Increased skin and subcutaneous tissue stiffness in patients with early-stage lymphedema has been reported. The purpose of this study was to examine the use of shear wave elastography (SWE) for evaluating lower extremity lymphedema (LEL). METHODS: For 10 lower extremities of normal controls and 72 limbs of patients with gynecological cancer whose lymphatic function was categorized into six stages based on the range of dermal backflow (DBF) observed in indocyanine green (ICG) lymphography, SWE was performed and shear wave velocity (SWV) of the dermis and three layers of subcutaneous tissue at the thigh and calf were recorded. Twenty-five patients underwent thigh tissue histological and dermal thickness examinations. RESULTS: The strongest correlation between the ICG DBF stage and SWV during SWE was observed on the dermal layer of the thigh (p < 0.01, R = 0.67). There was a significant correlation between the dermal thickness of the thigh and the ICG DBF stage (p < 0.01, R = 0.87) and also between the dermal thickness of the thigh and SWV (p < 0.01, R = 0.73). CONCLUSION: Noninvasive, objective evaluation of LEL severity using SWE was well correlated with lymphatic function as determined by ICG lymphography. The DBF changes in the dermis of the thigh best reflected the changes in lymphatic function. Dermal thickness variations may partially account for differences in SWV.
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Técnicas de Imagem por Elasticidade , Neoplasias dos Genitais Femininos/complicações , Extremidade Inferior/diagnóstico por imagem , Linfedema/diagnóstico por imagem , Linfedema/etiologia , Biópsia , Feminino , Humanos , Verde de Indocianina , Linfografia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
The 4F2 cell-surface antigen heavy chain (4F2hc) forms a heterodimeric complex with L-type amino acid transporter 1 (LAT1) and transports large neutral essential amino acids. However, in contrast to the traditional role of LAT1 in various cancers, the role of 4F2hc has largely remained unknown. The role of 4F2hc in prostate cancer was studied. Treatment of C4-2 cells with si4F2hc was found to suppress cellular growth, migratory and invasive abilities, with this effect occurring through the cell cycle, with a significant decrease in S phase and a significant increase in G0/G1 phase, suggesting cell cycle arrest. In addition, it was proven by RNA seq that the key to 4F2hc's impact on cancer is SKP2. si4F2hc upregulates the protein expression of cyclin-dependent kinase inhibitors (P21cip1, P27kip1) through the downstream target SKP2. Furthermore, the expression of 4F2hc and LAT1 in prostate cancer cells suggests the importance of 4F2hc. Multivariate analysis showed that high 4F2hc expression was an independent prognostic factor for progression-free survival (HR 11.54, p = 0.0357). High 4F2hc was related to the clinical tumour stage (p = 0.0255) and Gleason score (p = 0.0035). Collectively, 4F2hc contributed significantly to prostate cancer (PC) progression. 4F2hc may be a novel marker and therapeutic target in PC.
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Cadeia Pesada da Proteína-1 Reguladora de Fusão/metabolismo , Fase G1 , Proteínas de Neoplasias/metabolismo , Neoplasias da Próstata/metabolismo , Fase de Repouso do Ciclo Celular , Proteínas Quinases Associadas a Fase S/metabolismo , Linhagem Celular Tumoral , Cadeia Pesada da Proteína-1 Reguladora de Fusão/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Proteínas de Neoplasias/genética , Neoplasias da Próstata/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Proteínas Quinases Associadas a Fase S/genéticaRESUMO
L-type amino acid transporter 3 (LAT3, SLC43A1) is abundantly expressed in prostate cancer (PC) and is thought to play an essential role in PC progression through the cellular uptake of essential amino acids. Here, we analyzed the expression, function, and downstream target of LAT3 in PC. LAT3 was highly expressed in PC cells expressing androgen receptor (AR), and its expression was increased by dihydrotestosterone treatment and decreased by bicalutamide treatment. In chromatin immunoprecipitation sequencing of AR, binding of AR to the SLC43A1 region was increased by dihydrotestosterone stimulation. Knockdown of LAT3 inhibited cell proliferation, migration, and invasion, and the phosphorylation of p70S6K and 4EBP-1. Separase (ESPL1) was identified as a downstream target of LAT3 by RNA sequencing analysis. In addition, immunostaining of prostatectomy specimens was performed. In the multivariate analysis, high expression of LAT3 was an independent prognostic factor for recurrence-free survival (hazard ratio: 3.24; P = .0018). High LAT3 expression was correlated with the pathological T stage and a high International Society of Urological Pathology grade. In summary, our results suggest that LAT3 plays an important role in the progression of PC.
Assuntos
Sistema y+L de Transporte de Aminoácidos/metabolismo , Sistemas de Transporte de Aminoácidos Básicos/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Separase/metabolismo , Transdução de Sinais/genética , Idoso , Sistemas de Transporte de Aminoácidos Básicos/genética , Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Estudos de Coortes , Di-Hidrotestosterona/farmacologia , Progressão da Doença , Técnicas de Silenciamento de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Células PC-3 , Prognóstico , Prostatectomia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Ligação Proteica/efeitos dos fármacos , Receptores Androgênicos/genética , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , TransfecçãoRESUMO
BACKGROUND: To identify the real high-risk group among Japanese de novo metastatic prostate cancer patients who fit CHAARTED or LATITUDE criteria. METHODS: We retrospectively studied patients who fitted CHAARTED (292 patients) and LATITUDE (294 patients) criteria from Japanese multi-institutions. All patients received androgen deprivation therapy with bicalutamide as an initial treatment. Factors related to overall survival (OS) and progression-free survival were statistically analyzed. RESULTS: The median OS was 55.5 months and 60.0 months in patients who met the CHAARTED and the LATITUDE criteria, respectively. In patients who met CHAARTED criteria, lactate dehydrogenase (LDH) (hazard ratio (HR) 2.63, P < 0.0001) and C-reactive protein (CRP) (HR 1.65, P = 0.042) were independent risk factors for OS. In patients who met the LATITUDE criteria, Gleason score (GS) ≥9 (HR 1.77, P = 0.0326) and LDH (HR 2.62, P < 0.0001) were independent risk factors for OS. Modified CHAARTED criteria by adding LDH and CRP showed a significant difference in OS (HR 2.55, P < 0.0001) with a comparative median OS (31.8 months) to placebo of CHAARTED trial (32.2 months). Modified LATITUDE criteria by adding GS ≥9 and LDH showed a significant difference in OS (HR 2.66, P < 0.0001) with a comparative median OS (32.7 months) to placebo of LATITUDE trial (34.7 months). CONCLUSION: Modified criteria may potentially elucidate the true "high volume" and "high risk" patients in the Japanese cohort who require early intensive therapy.
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BACKGROUND/AIM: To examine the dynamics of circulating tumour cells (CTCs) in pancreatic cancer (PC), new mouse CTC models from human PC xenografts were developed. MATERIALS AND METHODS: Orthotopic (pancreas) and heterotopic (subcutaneous) transplantation models using GFP-tagged SUIT-2 PC cells were prepared. Using a cytology-based CTC detection platform, CTCs and metastasis were compared. RESULTS: The two types of orthotopic models, including the surgical transplantation model and the intraperitoneal injection model, showed a similar pattern of initial pancreatic tumour formation and subsequent development of peritoneal and hematogenous lung metastases. In the heterotopic model, only hematogenous lung metastasis was observed, and the number of CTCs and lung metastases was higher than that of the orthotopic model. Furthermore, KRAS mutation (G12D) was detected in CTCs. CONCLUSION: These orthotopic and heterotopic models clearly differ in terms of the pattern of metastasis and CTCs and therefore, would be useful PC models to investigate the effect of drug-therapy on CTCs and the role of KRAS mutation.
Assuntos
Citodiagnóstico , Mutação/genética , Células Neoplásicas Circulantes/patologia , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Background: It is not always possible to detect nonpalpable small lymph nodes (LNs) surrounded by adipose tissue under the wavelength of visible light. A newly developed near-infrared camera with InGaAs element was able to capture photographs using light at >1000-nm wavelength, at which the difference in absorbance between water and lipids is large. This study investigated the ability to detect nonvisible small LNs using light at 1300-nm wavelength. Methods and Results: Following retrieval of LNs through axillary LN dissection from 20 patients with breast cancer, residual specimens were simultaneously photographed using light at 970-, 1070-, 1200-, 1300-, 1450-, and 1600-nm wavelengths. A total of 45 specimens were observed pathologically at the selected portions in which the 1300-nm light was absorbed (high absorbance group [HA group], n = 25) and those in which the 970-nm light was absorbed instead (low absorbance group [LA group], n = 20). All specimens categorized in the HA group detected the LNs, whereas none of those categorized in the LA group detected an LN. The sensitivity and specificity in the identification of an LN were 1.0. The LNs detected using this camera were significantly smaller than those detected by surgeons (3.00 ± 2.93 mm vs. 5.90 ± 3.91 mm, p < 0.01). Discussion: The light at 1300-nm wavelength was absorbed by axillary LNs. This camera detected LNs that were undetectable by surgeons. This novel technology may be applied to lymphatic microsurgery and contribute to the development of a minimally invasive LN dissection method.
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Tecido Adiposo , Neoplasias da Mama , Linfonodos , Tecido Adiposo/patologia , Axila/patologia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Excisão de Linfonodo , Linfonodos/patologia , Metástase Linfática , Estadiamento de NeoplasiasRESUMO
L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids including leucine, which regulates the mTOR signaling pathway. Here, we studied the expression profile and functional role of LAT1 in bladder cancer. Furthermore, the pharmacological activity of JPH203, a specific inhibitor of LAT1, was studied in bladder cancer. LAT1 expression in bladder cancer cells was higher than that in normal cells. SiLAT1 and JPH203 suppressed cell proliferative and migratory and invasive abilities in bladder cancer cells. JPH203 inhibited leucine uptake by > 90%. RNA-seq analysis identified insulin-like growth factor-binding protein-5 (IGFBP-5) as a downstream target of JPH203. JPH203 inhibited phosphorylation of MAPK / Erk, AKT, p70S6K and 4EBP-1. Multivariate analysis revealed that high LAT1 expression was found as an independent prognostic factor for overall survival (HR3.46 P = 0.0204). Patients with high LAT1 and IGFBP-5 expression had significantly shorter overall survival periods than those with low expression (P = 0.0005). High LAT1 was related to the high Grade, pathological T stage, LDH, and NLR. Collectively, LAT1 significantly contributed to bladder cancer progression. Targeting LAT1 by JPH203 may represent a novel therapeutic option in bladder cancer treatment.
Assuntos
Regulação Neoplásica da Expressão Gênica , Transportador 1 de Aminoácidos Neutros Grandes/biossíntese , Sistema de Sinalização das MAP Quinases , Proteínas de Neoplasias/biossíntese , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/microbiologia , Benzoxazóis/farmacologia , Linhagem Celular Tumoral , Intervalo Livre de Doença , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Masculino , Proteínas de Neoplasias/antagonistas & inibidores , Taxa de Sobrevida , Serina-Treonina Quinases TOR/metabolismo , Tirosina/análogos & derivados , Tirosina/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologiaRESUMO
Large neutral amino acid transporter 1 (LAT1, SLC7A5) is abundantly expressed in various types of cancer, and it has been thought to assist cancer progression through its activity for uptake of neutral amino acids. However, the roles of LAT1 in renal cell carcinoma (RCC) prognosis and treatment remain uncharacterized. Therefore, we first retrospectively examined the LAT1 expression profile and its associations with clinical factors in RCC tissues (n = 92). The results of immunohistochemistry showed that most of the tissues examined (92%) had cancer-associated LAT1 expression. Furthermore, the overall survival (OS) and progression-free survival (PFS) were shorter in patients with high LAT1 expression levels than in those with low LAT1 expression levels (P = 0.018 and 0.014, respectively), and these associations were further strengthened by the results of univariate and multivariate analyses. Next, we tested the effects of JPH203, which is a selective LAT1 inhibitor, on RCC-derived Caki-1 and ACHN cells. It was found that JPH203 inhibited the growth of these cell types in a dose-dependent manner. Moreover, JPH203 clearly suppressed their migration and invasion activities. Thus, our results show that LAT1 has a great potential to become not only a prognosis biomarker but also a therapeutic target in RCC clinical settings.
Assuntos
Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Benzoxazóis/farmacologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Tirosina/análogos & derivados , Tirosina/farmacologiaRESUMO
Tube-forming growth is an essential histological feature of pancreatic duct adenocarcinoma (PDAC) and of the pancreatic duct epithelium; nevertheless, the nature of the signals that start to form the tubular structures remains unknown. Here, we showed the clonal growth of PDAC cell lines in a three-dimensional (3D) culture experiment that modeled the clonal growth of PDAC. At the beginning of this study, we isolated the sphere- and tube-forming clones from established mouse pancreatic cancer cell lines via limiting dilution culture using collagen gel. Compared with cells in spherical structures, the cells in the formed tubes exhibited a lower CK19 expression in 3D culture and in the tumor that grew in the abdominal cavity of nude mice. Conversely, the expression of the transforming growth factor ß (TGF-ß)-signaling target mRNAs was higher in the formed tube vs the spherical structures, suggesting that TGF-ß signaling is more active in the tube-forming process than the sphere-forming process. Treatment of sphere-forming clones with TGF-ß1 induced tube-forming growth, upregulated the TGF-ß-signaling target mRNAs, and yielded electron microscopic findings of a fading epithelial phenotype. In contrast, the elimination of TGF-ß-signaling activation by treatment with inhibitors diminished the tube-forming growth and suppressed the expression of the TGF-ß-signaling target mRNAs. Moreover, upregulation of the Fn1, Mmp2, and Snai1 mRNAs, which are hallmarks of tube-forming growth in PDAC, was demonstrated in a mouse model of carcinogenesis showing rapid progression because of the aggressive invasion of tube-forming cancer. Our study suggests that the tube-forming growth of PDAC relies on the activation of TGF-ß signaling and highlights the importance of the formation of tube structures.
Assuntos
Carcinogênese/patologia , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/patologia , Esferoides Celulares/ultraestrutura , Fator de Crescimento Transformador beta1/metabolismo , Animais , Benzamidas/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinoma Ductal Pancreático/genética , Técnicas de Cultura de Células , Linhagem Celular Tumoral/transplante , Dioxóis/farmacologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Neoplasias Pancreáticas/genética , Pirazóis/farmacologia , Pirróis/farmacologia , RNA-Seq , Proteínas Recombinantes/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/antagonistas & inibidoresRESUMO
BACKGROUND: We retrospectively assessed the clinical significance of the Prostate Imaging Reporting and Data System (PI-RADS), version 2, criteria based on biparametric magnetic resonance imaging (bp-MRI), together with the International Society of Urological Pathology (ISUP) grade, for predicting biochemical recurrence (BCR) after radical prostatectomy. MATERIALS AND METHODS: The data from 126 patients who had undergone radical prostatectomy were retrospectively analyzed. The prognostic significance of the PI-RADS v2 score based on bp-MRI was assessed with other clinical factors, including the ISUP grade. We defined a positive PI-RADS and ISUP score as ≥ 4 and ≥ 3, respectively. Statistical analysis was performed using Cox proportional hazard models, logistic regression analysis, and the Kaplan-Meier method. RESULTS: The median age and median prostate-specific antigen level were 66 years and 7.96 ng/mL, respectively. The number of positive PI-RADS scores was 106 (84.1%) and the number of positive ISUP grade scores was 71 (56.3%). PI-RADS ≥ 4 (P = .0031) and ISUP ≥ 3 (P = .070) were the 2 independent prognostic factors predictive of BCR. A positive PI-RADS score was related to tumor volume (P = .014), and a positive ISUP score was related to prostate-specific antigen level (P = .043), extraprostatic extension (P = .029), and Gleason upgrading (P < .0001). After stratifying patients into risk groups according to PI-RADS and ISUP positivity, the poor-risk group (PI-RADS and ISUP grade positive) showed significantly worse BCR-free survival compared with that of the favorable- and intermediate-risk groups (P < .0001), with a median survival difference of 21 months. CONCLUSION: Biparametric PI-RADS v2 and ISUP grade criteria predicted for BCR after radical prostatectomy. PI-RADS v2 combined with the ISUP grade might be helpful in choosing the treatment modality of patients with localized prostate cancer.
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Recidiva Local de Neoplasia/diagnóstico , Antígeno Prostático Específico/metabolismo , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Idoso , Sistemas de Dados , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/metabolismo , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias da Próstata/metabolismo , Estudos RetrospectivosRESUMO
Medical non-thermal plasma (NTP) treatments for various types of cancers have been reported. Cells with tumorigenic potential (cancer-initiating cells; CICs) are few in number in many types of tumors. CICs efficiently eliminate anti-cancer chemicals and exhibit high-level aldehyde dehydrogenase (ALDH) activity. We previously examined the effects of direct irradiation via NTP on cancer cells; even though we targeted CICs expressing high levels of ALDH, such treatment affected both non-CICs and CICs. Recent studies have shown that plasma-activated medium (PAM) (culture medium irradiated by NTP) selectively induces apoptotic death of cancer but not normal cells. Therefore, we explored the anti-cancer effects of PAM on CICs among endometrioid carcinoma and gastric cancer cells. PAM reduced the viability of cells expressing both low and high levels of ALDH. Combined PAM/cisplatin appeared to kill cancer cells more efficiently than did PAM or cisplatin alone. In a mouse tumor xenograft model, PAM exerted an anti-cancer effect on CICs. Thus, our results suggest that PAM effectively kills both non-CICs and CICs, as does NTP. Therefore, PAM may be a useful new anti-cancer therapy, targeting various cancer cells including CICs.
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Meios de Cultivo Condicionados/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Gases em Plasma/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Secretogranin III (SgIII) is a member of the chromogranin/secretogranin family of neuroendocrine secretory proteins. Granins are expressed in endocrine and neuroendocrine cells and subsequently processed into bioactive hormones. Although granin-derived peptide expression is correlated with neuroendocrine carcinomas, little is known about SgIII. We previously identified SgIII by a comparative glycoproteomics approach for elucidation of glycobiomarker candidates in lung carcinoma. Here, we examined the expression, secretion, and glycosylation of SgIII to identify novel biomarkers of small cell lung carcinoma (SCLC). In comparative immunohistochemical analysis and secretion profiling, SgIII was observed in all types of lung cancer. However, low-molecular-weight SgIII (short-form SgIII) was specifically found in SCLC culture medium. Glycoproteomics analysis showed that a fucosylated glycan was attached to the first of three potential N-glycosylation sites and an unfucosylated glycan was detected on the second site; however, the third site was not glycosylated. Next, we performed lectin capture with a fucose-binding lectin and detected short-form SgIII specifically in the sera of patients with SCLC. The results suggested an association between the fucosylated glycoform of short-form SgIII and SCLC. Thus, fucosylated short-form SgIII may be a valuable biomarker for SCLC and could be used to monitor development of the disease. All MS data are available via ProteomeXchange and jPOST with identifiers PXD007626 and JPST000313, respectively.
Assuntos
Cromograninas/sangue , Carcinoma de Pequenas Células do Pulmão/sangue , Biomarcadores , Células Cultivadas , Cromograninas/química , Cromograninas/metabolismo , Glicoproteínas/análise , Glicosilação , Humanos , Espectrometria de Massas , Carcinoma de Pequenas Células do Pulmão/diagnósticoRESUMO
Nonequilibrium atmospheric pressure plasma (NEAPP) is a novel approach for blood coagulation, wound healing, and tumor elimination. NEAPP not only directly but also indirectly affects living cells via the medium exposed to NEAPP-yielding devises, called plasma-activated medium (PAM). The conservable and portable PAM serves as an alternative and advantageous approach over direct NEAPP. Here we examined the effect of PAM on lymphoplasmacytic lymphoma (LPL) cell lines. We found that PAM induced plasma cell differentiation and reduced tumorigenic population. PAM increased the expression level of PRDM1α, which is a transcription factor promoting plasma cell differentiation, suggesting that plasma cell differentiation of LPL might be mediated by PRDM1α. We previously reported that plasma cell component of LPL is vulnerable to apoptosis and less tumorigenic. These findings suggested that PAM treatment might become a novel therapy against LPL by inducing the transition from tumorigenic to non-tumorigenic population.
Assuntos
Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Gases em Plasma/farmacologia , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Antígenos CD20/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica , Humanos , Fenótipo , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Sindecana-1/metabolismo , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/metabolismo , Macroglobulinemia de Waldenstrom/patologiaRESUMO
Low temperature plasma (LTP) coagulation equipment, which avoids causing burn injuries to patients, has been introducing into minimally invasive surgery. The mechanism by which this equipment stops bleeding is to directly occupy the injury with the formed blood clots, and different from the mechanism of the common electrical hemostatic devices that cauterize the tissues around the bleeding to stem the blood flow. A noteworthy point is that LTP treatment with our equipment is not confined only to the blood coagulation system, but it has significant effects on the other blood components to form clots with or without hemolysis, and that there is a plasma current threshold that determines whether the treatment makes stable clots. In this review, we introduce the clinical benefits of LTP current and describe the clot formation it facilitates.