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1.
J Thorac Dis ; 13(10): 5691-5700, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34795919

RESUMO

Background: Lung cancer is associated with a high morbidity and mortality rate worldwide; however, no reliable and independent prognostic predictor for non-small cell lung cancer (NSCLC) after curative surgery is available. Glucose metabolism is correlated with cancer cell proliferation. Pyruvate dehydrogenase E1α (PDH-E1α) catalyzes the conversion of pyruvate to acetyl-CoA and promotes aerobic glucose metabolism. In this study, we examined the relationship between PDH-E1α expression and clinicopathological factors associated with NSCLC to identify a reliable prognostic predictor of NSCLC after curative surgery. Methods: A total of 445 patients with NSCLC who underwent curative resection were enrolled in this study. PDH-E1α expression was evaluated via immunohistochemistry. We analyzed the correlation between PDH-E1α expression and clinicopathological features of the patients. Results: In total, 248 (56%) of the 445 patients with NSCLC were PDH-E1α-positive, and 197 patients were PDH-E1α-negative. PDH-E1α positivity was significantly correlated with the presence of adenocarcinoma (P<0.001) compared to the PDH-E1α-negative group. Patients with NSCLC showing PDH-E1α-negative expression had a significantly poorer overall survival rate (P=0.007) than those showing PDH-E1α-positive expression, especially at stage II. Patients with PDH-E1α negative expression also showed a poorer disease-free survival rate (P=0.02). Multivariate analysis revealed that PDH-E1α negativity (P=0.037) and male sex (P<0.001) were significantly correlated with a poor overall survival. Conclusions: PDH-E1α may represent a reliable prognostic predictor for NSCLC in patients that have recently undergone curative resection, especially at stage II.

2.
Anticancer Res ; 41(11): 5461-5468, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34732415

RESUMO

BACKGROUND/AIM: This study aimed to assess the effects of telmisartan (TEL), a potential antitumor agent, and its mechanism of action in the regulation of apoptosis, autophagy, and cell cycle in scirrhous gastric cancer (SGC). MATERIALS AND METHODS: The effect of TEL on the viability and chromatin condensation of OCUM-2M and OCUM-12 cells was assessed. Protein expression and the cell cycle were analysed using western blotting and flow cytometry, respectively. RESULTS: TEL inhibited cell proliferation in a dose-dependent manner and increased chromatin condensation and autophagy marker LC3-II levels in OCUM-12 cells. TEL also increased the proportion of cells in the G0/G1 phase transition. CONCLUSION: Apoptosis and autophagy are partially involved in the inhibitory effect of TEL on cell proliferation. Additionally, TEL caused G0/G1 cell cycle arrest. Therefore, TEL could be a promising treatment for SGC.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Telmisartan/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
3.
Cancer Lett ; 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34775002

RESUMO

Diffuse-type gastric carcinoma (DGC) has a poor prognosis due to its rapid diffusive infiltration and frequent peritoneal dissemination. DGC is associated with massive fibrosis caused by aberrant proliferation of cancer-associated fibroblasts (CAFs). Previously, we reported that direct heterocellular interaction between cancer cells and CAFs is important for the peritoneal dissemination of DGC. In this study, we aimed to identify and target the molecules that mediate such heterocellular interactions. Monoclonal antibodies (mAbs) against intact DGC cells were generated and subjected to high-throughput screening to obtain several mAbs that inhibit the adhesion of DGC cells to CAFs. Immunoprecipitation and mass spectrometry revealed that all mAbs recognized integrin α5 complexed with integrin ß1. Blocking integrin α5 in DGC cells or fibronectin, a ligand of integrin α5ß1, deposited on CAFs abrogated the heterocellular interaction. Administration of mAbs or knockout of integrin α5 in DGC cells suppressed their invasion led by CAFs in vitro and peritoneal dissemination in a mouse xenograft model. Altogether, these findings demonstrate that integrin α5 mediates the heterotypic cancer cell-fibroblast interaction during peritoneal dissemination of DGC and may thus be a therapeutic target.

4.
Sci Rep ; 11(1): 20664, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34667215

RESUMO

Cancer stem cells (CSCs) play an important role in the progression of carcinoma and have a high potential for survival in stress environments. However, the mechanisms of survival potential of CSCs have been unclear. The aim of this study was to clarify the significance of autophagy systems of CSCs under stress environments. Four gastric cancer cell line were used. Side population (SP) cells were sorted from the parent cells, as CSC rich cells. The expression of stem cell markers was examined by RT-PCR. The viability of cancer cells under starvation and hypoxia was evaluated. The expression level of the autophagy molecule LC3B-II was examined by western blot. The numbers of autophagosomes and autolysosomes were counted by electron microscope. SP cells of OCUM-12 showed a higher expression of stem cell markers and higher viability in starvation and hypoxia. Western blot and electron microscope examinations indicated that the autophagy was more induced in SP cells than in parent cells. The autophagy inhibitor significantly decreased the viability under the stress environments. These findings suggested that Cancer stem cells of gastric cancer might maintain their viability via the autophagy system. Autophagy inhibitors might be a promising therapeutic agent for gastric cancer.

5.
BMC Surg ; 21(1): 348, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34548054

RESUMO

BACKGROUND: Postoperative anastomotic leakage (AL) is associated with not only prolonged hospital stay and increased medical costs, but also poor prognosis in esophageal cancer. Several studies have addressed the utility of various inflammation-based and/or nutritional markers as predictors for postoperative complications. However, none have been documented as specific predictors for AL in esophageal cancer. We aimed to identify predictors of AL after esophagectomy for thoracic esophageal cancer, focusing on preoperative inflammation-based and/or nutritional markers. METHODS: We retrospectively analyzed 295 patients who underwent radical esophagectomy for thoracic esophageal squamous cell carcinoma between June 2007 and July 2020. As inflammation-based and/or nutritional markers, Onodera prognostic nutritional index, C-reactive protein (CRP)-to-albumin ratio (CAR) and modified Glasgow prognostic score were investigated. Optimal cut-off values of inflammation-based and/or nutritional markers for AL were determined by receiver operating characteristic curves. Predictors for AL were analyzed by logistic regression modeling. RESULTS: AL was observed in 34 patients (11.5%). In univariate analyses, preoperative body mass index (≥ 22.1 kg/m2), serum albumin level (≤ 3.8 g/dL), serum CRP level (≥ 0.06 mg/dL), CAR (≥ 0.0139), operation time (> 565 min) and blood loss (≥ 480 mL) were identified as predictors of AL. Multivariate analyses revealed higher preoperative CAR (≥ 0.0139) as an independent predictor of AL (p = 0.048, odds ratio = 3.02, 95% confidence interval 1.01-9.06). CONCLUSION: Preoperative CAR may provide a useful predictor of AL after esophagectomy for thoracic esophageal squamous cell carcinoma.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Albuminas , Fístula Anastomótica/diagnóstico , Fístula Anastomótica/epidemiologia , Fístula Anastomótica/etiologia , Proteína C-Reativa , Neoplasias Esofágicas/cirurgia , Esofagectomia/efeitos adversos , Humanos , Prognóstico , Estudos Retrospectivos
6.
Cancer Lett ; 521: 169-177, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34474145

RESUMO

Peritoneal metastasis of gastric cancer (GC) results in extremely poor prognoses. The peritoneal cavity is covered by a monolayer of peritoneal mesothelial cells (PMCs). Interactions between GC cells and PMCs might play a pivotal role in peritoneal metastasis. Extracellular vesicles (EVs) correlate with intercellular communication. Although intercellular communication between cancer cells and PMCs might be associated with the peritoneal metastatic process, the role of EVs from PMCs remains unclear. We investigated the effects of EVs from PMCs on GC cells. Three GC cell lines (OCUM-12, NUGC-3, and MKN74) and four mesothelial cell lines were used. The effects of EVs derived from the PMCs on the invasion and migration of GC cells were evaluated by Matrigel invasion assay. Factors contained in the PMC EVs were analyzed; extra-cellular matrix metalloproteinase inducer (EMMPRIN) was detected in the EVs. The effects of an EMMPRIN inhibitor on the invasion-stimulating activity of EVs were examined. The EMMPRIN expressions of 110 GCs were evaluated by immunohistochemistry. PMC EVs significantly promoted the invasion of diffuse-type GC cells, i.e., OCUM-12 and NUGC-3 cells. EMMPRIN in the EVs stimulated the invasion of OCUM-12 and NUGC-3 cells. The invasion-stimulating activity of PMC EVs was inhibited by the EMMPRIN inhibitor. A high EMMPRIN expression in PMCs was significantly associated with worse cancer-specific survival and peritoneal-recurrence-free survival. EMMPRIN in EVs from PMCs might stimulate the malignant progression of diffuse-type GC. EMMPRIN might be a useful prognostic marker of recurrence in GC patients.

7.
Mol Cell ; 81(21): 4509-4526.e10, 2021 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-34560002

RESUMO

The interferon (IFN) pathway is critical for cytotoxic T cell activation, which is central to tumor immunosurveillance and successful immunotherapy. We demonstrate here that PKCλ/ι inactivation results in the hyper-stimulation of the IFN cascade and the enhanced recruitment of CD8+ T cells that impaired the growth of intestinal tumors. PKCλ/ι directly phosphorylates and represses the activity of ULK2, promoting its degradation through an endosomal microautophagy-driven ubiquitin-dependent mechanism. Loss of PKCλ/ι results in increased levels of enzymatically active ULK2, which, by direct phosphorylation, activates TBK1 to foster the activation of the STING-mediated IFN response. PKCλ/ι inactivation also triggers autophagy, which prevents STING degradation by chaperone-mediated autophagy. Thus, PKCλ/ι is a hub regulating the IFN pathway and three autophagic mechanisms that serve to maintain its homeostatic control. Importantly, single-cell multiplex imaging and bioinformatics analysis demonstrated that low PKCλ/ι levels correlate with enhanced IFN signaling and good prognosis in colorectal cancer patients.

8.
Mol Oncol ; 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34379869

RESUMO

In some tumors, a small number of cancer cells are scattered in a large fibrotic stroma. Here, we demonstrate a novel mechanism for expansion of pro-tumor fibroblasts via cancer-associated fibroblast (CAF)-mediated education of normal fibroblasts (NFs). When NFs were incubated with conditioned medium from CAFs, the resulting CAF-educated fibroblasts (CEFs) generated reactive oxygen species, which induced NF-κB-mediated expression of inflammatory cytokines and the extracellular matrix protein asporin (ASPN), while expression of a common CAF marker gene, α-SMA, was not increased. ASPN further increased CEF expression of downstream molecules, including indoleamine 2,3-dioxygenase 1 (IDO-1), kynureninase (KYNU), and pregnancy-associated plasma protein-A (PAPP-A). These CEFs induce cytocidal effects against CD8+ T cells and IGF-I activation in cancer cells. CEFs were generated without cancer cells by the direct mixture of NFs and CAFs in mouse xenografts, and once CEFs were generated, they sequentially educated NFs, leading to continuous generation of CEFs. In diffuse-type gastric cancers, ASPNhigh /IDO-1high /KYNUhigh /α-SMA- CEFs were located at the distal invading front. These CEFs expanded in the fibrotic stroma and caused dissemination of cancer cells. ASPN may therefore be a key molecule in facilitating tumor spreading and T-cell suppression.

9.
PLoS One ; 16(7): e0253702, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34255789

RESUMO

BACKGROUND: Gastric cancer (GC) patients frequently develop peritoneal metastasis. Recently, it has been reported that peritoneal mesothelial cells (PMCs) activated by GC cells acquire a migratory capacity and promote GC cell invasion. The invasiveness of PMCs reportedly depends on the activity of Tks5, an adaptor protein required for invadopodia formation. However, the relationship between clinicopathologic features and Tks5 expression in PMCs has been poorly documented. In this study, we evaluated the clinicopathologic significance of the Tks5 expression of PMCs in GC patients. MATERIALS AND METHODS: A total of 110 GC patients who underwent gastrectomy were enrolled in this study. Tks5 expressions in PMCs from the greater omentum, lesser omentum and retroperitoneum were evaluated by immunohistochemistry. We analyzed the correlation between Tks5 expressions in PMCs and the patients' clinicopathologic features. RESULTS: Tks5 expression was found in 71 (64.5%) of the 110 patients, while 39 (35.5%) were Tks5-negative. Tks5 positivity was significantly (p = 0.038) associated with a greater tumor depth (i.e., T3/4 compared with T1/T2). Peritoneal recurrence was found in 12 of 98 cases within 3 years of surgery. The 3-year peritoneal recurrence-free survival (PRFS) rate in Tks5-positive cases was significantly poorer than that in Tks5-negative cases (80.1% vs 97.4%, p = 0.024). Multivariate analysis revealed that Tks5 positivity and lymph node metastasis were independent factors for PRFS. CONCLUSION: Tks5 is frequently expressed in PMCs in advanced-stage gastric cancer. Tks5 might be a useful predictor for peritoneal recurrence in GC patients.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Peritoneais/epidemiologia , Peritônio/patologia , Neoplasias Gástricas/patologia , Proteínas Adaptadoras de Transporte Vesicular/análise , Idoso , Biomarcadores Tumorais/análise , Intervalo Livre de Doença , Células Epiteliais/patologia , Feminino , Seguimentos , Gastrectomia , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Neoplasias Peritoneais/secundário , Peritônio/citologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/cirurgia
10.
Cancer Genomics Proteomics ; 18(4): 521-529, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34183385

RESUMO

BACKGROUND/AIM: Peritoneal dissemination (PD) occurs frequently in gastric cancer (GC) and is fatal. The interactions between tumor cells and stromal cells are critical for cancer progression. Our aim was to identify a novel PD-associated gene derived from stromal cells in GC. MATERIALS AND METHODS: Among the candidate PD-associated genes identified in our previous study, we focused on spondin-2 (SPON2), an extracellular matrix-secreted protein. Clinicopathological and prognostic analyses of SPON2 mRNA expression were performed using GC datasets. Localization of SPON2 expression was assessed by immunohistochemistry. In vitro migration assay and immunofluorescence staining were also conducted using GC cell lines. RESULTS: SPON2 was expressed in and secreted from cancer-associated fibroblasts in GC. High expression of SPON2 in tumor tissues was correlated with PD, tumor size and poor prognosis in GC. The motility of GC cells was increased by treatment with a SPON2 recombinant protein in vitro. CONCLUSION: Cancer-associated fibroblast-derived SPON2 may promote PD, in part, by facilitating GC cell motility and serve as a predictive marker for PD in GC.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Movimento Celular , Proteínas da Matriz Extracelular/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Bases de Dados Genéticas , Humanos , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/metabolismo , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Carga Tumoral , Regulação para Cima
11.
World J Gastrointest Oncol ; 13(5): 366-390, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34040699

RESUMO

Gastrointestinal (GI) cancer remains the deadliest cancer in the world. The current standard treatment for GI cancer focuses on 5-fluorouracil-based chemotherapeutic regimens and surgery, and molecular-targeted therapy is expected to be a more effective and less toxic therapeutic strategy for GI cancer. There is well-established evidence for the use of epidermal growth factor receptor-targeted and vascular endothelial growth factor-targeted antibodies, which should routinely be incorporated into treatment strategies for GI cancer. Other potential therapeutic targets involve the PI3K/AKT pathway, tumor growth factor-ß pathway, mesenchymal-epithelial transition pathway, WNT pathway, poly (ADP-ribose) polymerase, and immune checkpoints. Many clinical trials assessing the agents of targeted therapy are underway and have presented promising and thought-provoking results. With the development of molecular biology techniques, we can identify more targetable molecular alterations in larger patient populations with GI cancer. Targeting these molecules will allow us to reach the goal of precision medicine and improve the outcomes of patients with GI cancer.

12.
Mol Clin Oncol ; 14(5): 105, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33815794

RESUMO

Trophoblast cell-surface antigen 2 (TROP2) is a transmembrane glycoprotein expressed in epithelial cells. Increased TROP2 expression has been reported to be associated with malignant progression in most carcinomas; however, TROP2 has a tumor-suppressive function in certain types of cancer. Since the function of TROP2 is controversial, the present study subsequently aimed to clarify the clinicopathologic significance of TROP2 and pTROP2 expression in human gastric cancer (GC). The cases of 704 patients with GC who underwent gastrectomy were retrospectively analyzed. The expression levels of TROP2 and pTROP2 in each tumor were evaluated by immunohistochemistry. The association between the clinicopathologic features of patients with GC and the levels of TROP2 and pTROP2 in their tumors was analyzed. Increased TROP2 and pTROP2 expression was identified in 330 (46.9%) and 306 (43.5%) of the 704 patients with GC, respectively. Increased TROP2 expression was associated with the histological intestinal type, high tumor invasion depth (T3/T4), lymph node metastasis, lymphatic invasion and venous invasion. By contrast, increased pTROP2 expression was associated with intestinal type, low tumor invasion depth (T1/2), no lymph node metastasis and no lymphatic invasion. Increased TROP2 expression was associated with poorer overall survival (OS) (P<0.01; log rank test), whereas increased pTROP2 expression was significantly associated with improved OS (P<0.01; log rank test). In conclusion, increased expression levels of TROP2, but not pTROP2, may be associated with the metastatic ability of GC, resulting in poor prognosis of patients with GC.

13.
Eur Surg Res ; 62(1): 53-60, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33882483

RESUMO

BACKGROUND: Asporin (ASPN), a member of the proteoglycan family, has been shown to have a close correlation with cancer progression. It is not known whether ASPN is an oncogenic driver or a tumor suppressor in human gastric cancer. We sought herein to determine the relationship between ASPN expression and clinicopathological features of gastric cancer. PATIENTS AND METHODS: A total of 296 gastric cancer patients (diffuse type, n = 144; intestinal type, n = 152) were enrolled. The ASPN expression level in each case was analyzed by immunohistochemistry. RESULTS: ASPN was mainly found on stromal cells, especially on fibroblasts in tumor stroma, i.e., cancer-associated fibroblasts. The ASPN expression on either cancer cells or stromal cells was significantly high in macroscopic scirrhous-type tumors (p < 0.001) and histologically abundant stroma-type tumors (p < 0.001). Interestingly, a Kaplan-Meier survival curve of the 144 cases of diffuse-type gastric cancer revealed a significantly poorer prognosis in patients with ASPN-positive expression (p = 0.043; log rank) compared to those with ASPN-negative expression, but the prognoses were not significantly different in these subgroups of the 152 cases of intestinal-type gastric cancer. A multivariate analysis with respect to overall survival showed that ASPN expression on stromal cells and/or cancer cells was significantly correlated with overall survival in patients with diffuse-type gastric cancer (p = 0.041). CONCLUSION: In gastric cancer, ASPN was expressed mainly on stromal cells and partially on cancer cells. ASPN expression on stromal cells and/or cancer cells might be a useful prognostic marker in patients with diffuse-type gastric cancer.

14.
PLoS One ; 16(2): e0247090, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33635883

RESUMO

BACKGROUND: Clinical sequencing using a panel of genes has recently been applied worldwide for patients with refractory solid tumors, but the significance of clinical sequencing using gene panel testing remains uncertain. Here we sought to clarify the feasibility and utility of clinical sequencing in the treatment of refractory tumors at our hospital. METHODS: A total of 39 patients with advanced solid tumors treated at our hospital between 2018 and 2020 were enrolled in the clinical sequencing. Among them, we identified 36 patients whose tissue samples were of suitable quality for clinical sequencing, and we analyzed the genomic profiles of these tumors. RESULTS: Pathogenic alterations were detected in 28 (78%) of the 36 patients. The most common mutation was TP53 (55%), followed by KRAS (22%), and the highest frequency of gene amplification was ERBB2 (17%). Nine of the 36 patients were identified as candidates for novel molecular-targeted therapy based on their actionable gene alterations, but only one case ended up receiving novel targeted therapy following the genetic tests. CONCLUSIONS: Our current results suggested that clinical sequencing might be useful for the detection of pathogenic alterations and the management of additional cancer treatment. However, molecular target based on actionable genomic alteration does not always bridge to subsequent therapy due to clinical deterioration, refusal for unapproved drug, and complexity of clinical trial access. Both improved optimal timing of clinical sequencing and a consensus about its off-label use might help patients receive greater benefit from clinical sequencing.


Assuntos
Testes Genéticos/normas , Neoplasias/diagnóstico , Análise de Sequência de DNA/normas , Idoso , Biomarcadores Tumorais/genética , Feminino , Testes Genéticos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor ErbB-2/genética , Análise de Sequência de DNA/métodos , Proteína Supressora de Tumor p53/genética
15.
Sci Rep ; 11(1): 4698, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33633310

RESUMO

Fibroblast growth factor receptor 2 (FGFR2) has two isoforms: IIIb type and IIIc type. Clinicopathologic significance of these two FGFR2 subtypes in gastric cancer remains to be known. This study aimed to clarify the clinicopathologic difference of FGFR2IIIb and/or FGFR2IIIc overexpression. A total of 562 patients who underwent gastrectomy was enrolled. The expressions of FGFR2IIIb and FGFR2IIIc were retrospectively examined by immunohistochemistry or fluorescence in situ hybridization (FISH) using the 562 gastric tumors. We evaluated the correlation between clinicopathologic features and FGFR2IIIb overexpression and/or FGFR2IIIc overexpression in gastric cancer. FGFR2IIIb overexpression was observed in 28 cases (4.9%), and FGFR2IIIc overexpression was observed in four cases (0.7%). All four FGFR2IIIc cases were also positive for FGFR2IIIb, but not in the same cancer cells. FGFR2IIIb and/or FGFR2IIIc overexpression was significantly correlated with lymph node metastasis and clinical stage. Both FGFR2IIIb and FGFR2IIIc were significantly associated with poor overall survival. A multivariate analysis showed that FGFR2IIIc expression was significantly correlated with overall survival. FISH analysis indicated that FGFR2 amplification was correlated with FGFR2IIIb and/or FGFR2IIIc overexpression. These findings suggested that gastric tumor overexpressed FGFR2IIIc and/or FGFR2IIIb at the frequency of 4.9%. FGFR2IIIc overexpression might be independent prognostic factor for patients with gastric cancer.

16.
Esophagus ; 18(3): 548-558, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33591543

RESUMO

BACKGROUND: We focused on the Systemic Inflammatory Response Syndrome (SIRS) duration after surgery for esophageal squamous cell carcinoma (ESCC) as the prognostic marker. METHODS: We enrolled a total of 222 patients with local ESCC, who underwent curative esophagectomy between 2005 and 2015. SIRS was diagnosed according to the criteria as a condition involving two or more of the following factors after surgery: (a) body temperature of > 38 °C or < 36 °C; (b) heart rate > 90 beats/min; (c) respiratory rate > 20 breaths/min (d) WBC count > 12,000 or < 4000 cells/mm3. We defined SIRS duration as the total sum of the days defined as SIRS conditions during 7 days after surgery. The SIRS duration was analyzed by Cox hazards modeling to determine the independent prognostic factors for overall survival (OS) and Cancer-specific survival (CSS). RESULTS: The cutoff point of SIRS duration was determined to be set at 5.0 days according to the receiver operating characteristic (ROC) curve, which was plotted using 5-year OS as the endpoint. Of the 222 patients, 165 (74.4%) and 57 (25.6%) were classified as having short (< 5.0) and long (≥ 5.0) SIRS, respectively. The long SIRS was significantly associated with postoperative pneumonia (Hazard Ratio (HR):9.07; P < 0.01), great amount of blood loss during surgery (HR: 2.20: P = 0.04), preoperative high CRP value (HR: 2.45: P = 0.04) and preoperative low albumin (HR: 2.79: P = 0.03) by logistic-regression multivariate analysis. Cox Hazard Multivariate analyses revealed that long SIRS was a worse prognostic factor for OS (HR: 2.36; 95% Confidence Interval (CI):1.34-4.20, P < 0.01) and CSS (HR: 2.07; 95% CI:1.06-4.06, P = 0.03), while postoperative pneumonia and postoperative high CRP value were not worse prognostic factors for OS and CSS. CONCLUSION: SIRS duration is a more reliable prognostic marker than the development of pneumonia and high postoperative CRP value after surgery for ESCC. The surgeons should aim to reduce the SIRS duration to improve the prognosis of ESCC patients.

17.
Cancer Sci ; 112(3): 1251-1261, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33393151

RESUMO

Asporin (ASPN), a small leucine-rich proteoglycan expressed predominantly by cancer associated fibroblasts (CAFs), plays a pivotal role in tumor progression. ASPN is also expressed by some cancer cells, but its biological significance is unclear. Here, we investigated the effects of ASPN expression in gastric cancer cells. Overexpression of ASPN in 2 gastric cancer cell lines, HSC-43 and 44As3, led to increased migration and invasion capacity, accompanied by induction of CD44 expression and activation of Rac1 and MMP9. ASPN expression increased resistance of HSC-43 cells to oxidative stress by reducing the amount of mitochondrial reactive oxygen species. ASPN induced expression of the transcription factor HIF1α and upregulated lactate dehydrogenase A (LDHA) and PDH-E1α, suggesting that ASPN reprograms HSC-43 cells to undergo anaerobic glycolysis and suppresses ROS generation in mitochondria, which has been observed in another cell line HSC-44PE. By contrast, 44As3 cells expressed high levels of HIF1α in response to oxidant stress and escaped apoptosis regardless of ASPN expression. Examination of xenografts in the gastric wall of ASPN-/- mice revealed that growth of HSC-43 tumors with increased micro blood vessel density was significantly accelerated by ASPN; however, ASPN increased the invasion depth of both HSC-43 and 44As3 tumors. These results suggest that ASPN has 2 distinct effects on cancer cells: HIF1α-mediated resistance to oxidative stress via reprogramming of glucose metabolism, and activation of CD44-Rac1 and MMP9 to promote cell migration and invasion. Therefore, ASPN may be a new therapeutic target in tumor fibroblasts and cancer cells in some gastric carcinomas.


Assuntos
Carcinoma/patologia , Proteínas da Matriz Extracelular/metabolismo , Neoplasias Gástricas/patologia , Animais , Apoptose , Fibroblastos Associados a Câncer/citologia , Fibroblastos Associados a Câncer/patologia , Carcinoma/cirurgia , Linhagem Celular Tumoral , Movimento Celular , Proteínas da Matriz Extracelular/genética , Gastrectomia , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/patologia , Invasividade Neoplásica/patologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Estômago/patologia , Estômago/cirurgia , Neoplasias Gástricas/cirurgia , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas rac1 de Ligação ao GTP/metabolismo
18.
Anticancer Res ; 41(1): 203-210, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33419814

RESUMO

BACKGROUND: Meningioma is a common intracranial tumor originating from arachnoid cap cells. Meningiomas are generally benign tumors curable by one-time resection. However, some meningiomas regrow and invade into the dura mater, and thus frequently require additional treatment. A useful marker to predict the regrowth of meningioma is desired. This study aimed to clarify the significance of p53 and Ki67 for postoperative recurrence of meningioma. MATERIALS AND METHODS: The expression of p53 and Ki67 in 215 intracranial or intraspinal meningiomas was investigated by immunohistochemistry. RESULTS: Of the 215 meningiomas, 35 cases (16.3%) were p53-positive and 49 cases (22.8%) were Ki67-positive. Multivariate analysis revealed Ki67 and p53 status as being significantly correlated with recurrence. Positivity for either Ki67- or p53 was significantly associated with poor recurrence-free survival. CONCLUSION: Combined p53 and Ki67 status might represent a useful independent predictive marker for recurrence of meningioma.


Assuntos
Antígeno Ki-67/metabolismo , Meningioma/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Biomarcadores Tumorais , Feminino , Humanos , Antígeno Ki-67/genética , Masculino , Meningioma/diagnóstico , Meningioma/mortalidade , Meningioma/cirurgia , Prognóstico , Recidiva , Proteína Supressora de Tumor p53/genética
19.
Dev Cell ; 56(1): 95-110.e10, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33207226

RESUMO

Cancer-associated fibroblasts (CAFs) promote tumor malignancy, but the precise transcriptional mechanisms regulating the acquisition of the CAF phenotype are not well understood. We show that the upregulation of SOX2 is central to this process, which is repressed by protein kinase Cζ (PKCζ). PKCζ deficiency activates the reprogramming of colonic fibroblasts to generate a predominant SOX2-dependent CAF population expressing the WNT regulator Sfrp2 as its top biomarker. SOX2 directly binds the Sfrp1/2 promoters, and the inactivation of Sox2 or Sfrp1/2 in CAFs impaired the induction of migration and invasion of colon cancer cells, as well as their tumorigenicity in vivo. Importantly, recurrence-free and overall survival of colorectal cancer (CRC) patients negatively correlates with stromal PKCζ levels. Also, SOX2 expression in the stroma is associated with CRC T invasion and worse prognosis of recurrence-free survival. Therefore, the PKCζ-SOX2 axis emerges as a critical step in the control of CAF pro-tumorigenic potential.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Carcinogênese/metabolismo , Neoplasias Colorretais/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Proteína Quinase C/deficiência , Fatores de Transcrição SOXB1/metabolismo , Animais , Fibroblastos Associados a Câncer/patologia , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Invasividade Neoplásica/genética , Organoides/metabolismo , Organoides/patologia , Ligação Proteica , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , RNA-Seq , Recidiva , Fatores de Transcrição SOXB1/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Análise de Célula Única , Regulação para Cima , beta Catenina/genética , beta Catenina/metabolismo
20.
Cancer Med ; 10(2): 521-528, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33381922

RESUMO

It has been reported that circulating tumor cells (CTCs) are beneficial for predicting tumor stage or treatment response. Although epithelial cell adhesion molecules (EpCAMs) and cytokeratin (CK) have been often used for the identification of CTCs, other tumor markers have not been fully investigated as detecting tools for CTCs. Thus, this study aims to clarify the significance of carcinoembryonic antigen (CEA, CD66e)-positive CTCs in patients with gastric cancer. A total of 150 patients with gastric cancer were enrolled in this study. The mononuclear fraction of peripheral blood was enriched by Ficoll. The number of cells was enumerated depending on the positivity of EpCAM and CEA or CK by flow cytometry. The association of these cells with clinicopathologic characteristics was investigated. The mean age was 70 (range 28-92). The macroscopic type of gastric cancer was classified as 0/1/2/3/4/5 in 59/11/22/38/16/4 patients, respectively. Seventy-one patients (47.3%) were diagnosed with intestinal-type cancer, while 76 patients (50.7%) were diagnosed with the diffuse type. The mean numbers of cells with EpCAM-CK+, EpCAM+CK-, EpCAM+CK+, EpCAM-CEA+, EpCAM+CEA-, and EpCAM+CEA+ were 618, 237, 19.9, 1147, 291, and 7.41, respectively. The number of EpCAM-CEA+cells was significantly higher in patients with stage II-III and IV than in patients with stage I. The 3-year RFS rate in patients with a high number of EpCAM-CEA+cells (>=622) was 57.5%, while it was 79.3% in patients with a low number of EpCAM-CEA+cells (<622) (log-rank p = 0.0079). Thus, we conclude that CEA-positive CTCs will be a clinically beneficial biomarker in patients with gastric cancer.


Assuntos
Antígeno Carcinoembrionário/sangue , Molécula de Adesão da Célula Epitelial/sangue , Gastrectomia/mortalidade , Excisão de Linfonodo/mortalidade , Recidiva Local de Neoplasia/diagnóstico , Células Neoplásicas Circulantes/patologia , Neoplasias Gástricas/cirurgia , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Feminino , Seguimentos , Proteínas Ligadas por GPI/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/epidemiologia , Células Neoplásicas Circulantes/metabolismo , Prognóstico , Neoplasias Gástricas/patologia , Taxa de Sobrevida
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