RESUMO
The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is associated with the tumour heterogeneity. To explore intra- and inter-tumoural heterogeneity in PDAC, we analysed the multi-omics profiles of 61 PDAC lesion samples, along with the matched pancreatic normal tissue samples, from 19 PDAC patients. Haematoxylin and Eosin (H&E) staining revealed that diversely differentiated lesions coexisted both within and across individual tumours. Whole exome sequencing (WES) of samples from multi-region revealed diverse types of mutations in diverse genes between cancer cells within a tumour and between tumours from different individuals. The copy number variation (CNV) analysis also showed that PDAC exhibited intra- and inter-tumoural heterogeneity in CNV and that high average CNV burden was associated poor prognosis of the patients. Phylogenetic tree analysis and clonality/timing analysis of mutations displayed diverse evolutionary pathways and spatiotemporal characteristics of genomic alterations between different lesions from the same or different tumours. Hierarchical clustering analysis illustrated higher inter-tumoural heterogeneity than intra-tumoural heterogeneity of PDAC at the transcriptional levels as lesions from the same patients are grouped into a single cluster. Immune marker genes are differentially expressed in different regions and tumour samples as shown by tumour microenvironment (TME) analysis. TME appeared to be more heterogeneous than tumour cells in the same patient. Lesion-specific differentially methylated regions (DMRs) were identified by methylated DNA immunoprecipitation sequencing (MeDIP-seq). Furthermore, the integration analysis of multi-omics data showed that the mRNA levels of some genes, such as PLCB4, were significantly correlated with the gene copy numbers. The mRNA expressions of potential PDAC biomarkers ZNF521 and KDM6A were correlated with copy number alteration and methylation, respectively. Taken together, our results provide a comprehensive view of molecular heterogeneity and evolutionary trajectories of PDAC and may guide personalised treatment strategies in PDAC therapy.
Assuntos
Adenocarcinoma/fisiopatologia , Carcinoma Ductal Pancreático/fisiopatologia , Perfilação da Expressão Gênica/métodos , Adenocarcinoma/classificação , Carcinoma Ductal Pancreático/classificação , China , Feminino , Perfilação da Expressão Gênica/tendências , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: Up to 26% of patients with early-stage cervical cancer experience relapse after primary surgery. However, little is known about which factors influence prognosis following disease recurrence. Therefore, our aims were to determine post-recurrence disease-specific survival (PR-DSS) and to identify respective prognostic factors for PR-DSS. METHODS: Data from 528 patients with early-stage cervical cancer who relapsed after primary surgery performed between 2007 and 2016 were obtained from the SCANN study (Surveillance in Cervical CANcer). Factors related to the primary disease and recurrence were combined in a multivariable Cox proportional hazards model to predict PR-DSS. RESULTS: The 5-year PR-DSS was 39.1% (95% confidence interval [CI] 22.7%-44.5%), median disease-free interval between primary surgery and recurrence (DFI1) was 1.5 years, and median survival after recurrence was 2.5 years. Six significant variables were identified in the multivariable analysis and were used to construct the prognostic model. Two were related to primary treatment (largest tumour size and lymphovascular space invasion) and four to recurrence (DFI1, age at recurrence, presence of symptoms, and recurrence type). The C-statistic after 10-fold cross-validation of prognostic model reached 0.701 (95% CI 0.675-0.727). Three risk-groups with significantly differing prognoses were identified, with 5-year PR-DSS rates of 81.8%, 44.6%, and 12.7%. CONCLUSIONS: We developed the robust model of PR-DSS to stratify patients with relapsed cervical cancer according to risk profiles using six routinely recorded prognostic markers. The model can be utilised in clinical practice to aid decision-making on the strategy of recurrence management, and to better inform the patients.
Assuntos
Adenocarcinoma/mortalidade , Carcinoma Adenoescamoso/mortalidade , Carcinoma Neuroendócrino/mortalidade , Carcinoma de Células Escamosas/mortalidade , Recidiva Local de Neoplasia/mortalidade , Neoplasias do Colo do Útero/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/fisiopatologia , Adenocarcinoma/terapia , Adulto , Doenças Assintomáticas , Carcinoma Adenoescamoso/patologia , Carcinoma Adenoescamoso/fisiopatologia , Carcinoma Adenoescamoso/terapia , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/fisiopatologia , Carcinoma Neuroendócrino/terapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/fisiopatologia , Carcinoma de Células Escamosas/terapia , Quimioterapia Adjuvante , Feminino , Humanos , Histerectomia , Linfonodos/patologia , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/fisiopatologia , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Taxa de Sobrevida , Traquelectomia , Carga Tumoral , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/fisiopatologia , Neoplasias do Colo do Útero/terapiaRESUMO
Colon adenocarcinoma (COAD) is the most common type of gastrointestinal cancer and is still the third leading cause of cancer-related mortality worldwide. Accurate screening tools for early diagnosis and prediction of prognosis and precision treatment strategies are urgently required to accommodate the unmet medical needs of COAD management. We herein aimed to explore the significance of the microRNA (miR)-216a/growth differentiation factor 15 (GDF15) axis in terms of clinical value, tumor immunity, and potential mechanisms in COAD by using multi-omic analysis. The gene expression levels of miR-216a and GDF15 showed an increase in the COAD group compared to those of the normal group. The expression of miR-216a presented a negative correlation with GDF15 in COAD tumor tissue. The use of an in vitro luciferase reporter assay and bioinformatic prediction revealed that miR-216a-3p acted toward translational inhibition on GDF15 by targeting its 3'untranslated region (UTR) site. High miR-216a expression was associated with decreased overall survival (OS), while the high expression of GDF15 was associated with increased OS. Enriched type 1 T-helper (Th1), enriched regulatory T (Treg), enriched eosinophils, and decreased nature killer T-cells (NKTs) in COAD tumor tissue may play counteracting factors on the tumor-regulatory effects of miR-216a and GDF15. In addition, high GDF15 expression had associations with suppressed immunoinhibitory genes and negative correlations with the infiltration of macrophages and endothelial cells. The enrichment analysis revealed that GDF15 and its co-expression network may be implicated in mitochondrial organization, apoptosis signaling, and endoplasmic reticulum (ER) stress response. The Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal (CTRP) analysis identified that Gemcitabine acted as a precision treatment for COAD when GDF15 expression was low. This study supports the miR-216a/GDF15 axis as a diagnostic/prognostic panel for COAD, identifies Th1, Treg, eosinophils, and NKTs as counteracting factors, indicates potential relationships underlying immunomodulation, mitochondrial organization, apoptotic signaling, and ER stress and unveil Gemcitabine as a potential drug for the development of treatment strategy when combined with targeting GDF15.
Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais , Neoplasias do Colo/genética , Biologia Computacional , Desoxicitidina/análogos & derivados , Fator 15 de Diferenciação de Crescimento/genética , MicroRNAs/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/imunologia , Adenocarcinoma/fisiopatologia , Antimetabólitos Antineoplásicos/uso terapêutico , Apoptose , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/imunologia , Neoplasias do Colo/fisiopatologia , Desoxicitidina/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HEK293 , Humanos , Mitocôndrias , Medicina de Precisão , Prognóstico , GencitabinaRESUMO
Importance: The current TNM staging system provides limited information for prognosis prediction and adjuvant chemotherapy benefits for patients with gastric cancer (GC). Objective: To develop a tumor-associated collagen signature of GC (TACSGC) in the tumor microenvironment to predict prognosis and adjuvant chemotherapy benefits in patients with GC. Design, Setting, and Participants: This retrospective cohort study included a training cohort of 294 consecutive patients treated between January 1, 2012, and December 31, 2013, from Nanfang Hospital, Southern Medical University, People's Republic of China, and a validation cohort of 225 consecutive patients treated between October 1, 2010, and December 31, 2012, from Fujian Provincial Cancer Hospital, Fujian Medical University, People's Republic of China. In total, 146 collagen features in the tumor microenvironment were extracted with multiphoton imaging. A TACSGC was then constructed using the least absolute shrinkage and selection operator Cox proportional hazards regression model in the training cohort. Data analysis was conducted from October 1, 2020, to April 30, 2021. Main Outcomes and Measures: The association of TACSGC with disease-free survival (DFS) and overall survival (OS) was assessed. An independent external cohort was included to validate the results. Interactions between TACSGC and adjuvant chemotherapy were calculated. Results: This study included 519 patients (median age, 57 years [IQR, 49-65 years]; 360 [69.4%] male). A 9 feature-based TACSGC was built. A higher TACSGC level was significantly associated with worse DFS and OS in both the training (DFS: hazard ratio [HR], 3.57 [95% CI, 2.45-5.20]; OS: HR, 3.54 [95% CI, 2.41-5.20]) and validation (DFS: HR, 3.10 [95% CI, 2.26-4.27]; OS: HR, 3.24 [95% CI, 2.33-4.50]) cohorts (continuous variable, P < .001 for all comparisons). Multivariable analyses found that carbohydrate antigen 19-9, depth of invasion, lymph node metastasis, distant metastasis, and TACSGC were independent prognostic predictors of GC, and 2 integrated nomograms that included the 5 predictors were established for predicting DFS and OS. Compared with clinicopathological models that included only the 4 clinicopathological predictors, the integrated nomograms yielded an improved discrimination for prognosis prediction in a C index comparison (training cohort: DFS, 0.80 [95% CI, 0.73-0.88] vs 0.78 [95% CI, 0.71-0.85], P = .03; OS, 0.81 [95% CI, 0.75-0.88] vs 0.80 [95% CI, 0.73-0.86], P = .03; validation cohort: DFS, 0.78 [95% CI, 0.70-0.87] vs 0.76 [95% CI, 0.67-0.84], P = .006; OS, 0.78 [95% CI, 0.69-0.86] vs 0.75 [95% CI, 0.67-0.84], P = .002). Patients with stage II and III GC and low TACSGC levels rather than high TACSGC levels had a favorable response to adjuvant chemotherapy (DFS: HR, 0.65 [95% CI, 0.43-0.96]; P = .03; OS: HR, 0.55 [95% CI, 0.36-0.82]; P = .004; dichotomized variable, P < .001 for interaction for both comparisons). Conclusions and Relevance: The findings suggest that TACSGC provides additional prognostic information for patients with GC and may distinguish patients with stage II and III disease who are more likely to derive benefits from adjuvant chemotherapy.
Assuntos
Adenocarcinoma/tratamento farmacológico , Biomarcadores Tumorais/sangue , Quimioterapia Adjuvante , Colágeno/sangue , Colágeno/uso terapêutico , Intervalo Livre de Doença , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/fisiopatologia , Adenocarcinoma/cirurgia , Idoso , China , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/fisiopatologia , Neoplasias Gástricas/cirurgia , Resultado do TratamentoRESUMO
OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in Japan. Previous studies from other countries have reported venous thromboembolism prevalence rates of 12 to 36% in patients with pancreatic cancer. In this study, we aimed to determine the incidence of VTE in patients with PDAC in Japan and compare the characteristics of patients with and without VTE. METHODS: In this retrospective cohort study, clinicopathological characteristics of patients with and without concomitant VTE were compared. PATIENTS: Patients with PDAC treated at Fukui Prefectural Hospital, Japan from 2010 to 2019. RESULTS: The 1-year survival rate of all patients with pancreatic cancer was 40.7%. Among 432 patients with PDAC, 31 developed VTE. Seventeen (55%) patients received anticoagulant therapy. Compared with the non-VTE group, the VTE group had significantly more patients whose body mass index was >25 kg/m² (p = .035) and had a significantly higher rate of chemotherapy (p = .024). There was no significant difference in median survival time from PDAC diagnosis between the VTE and non-VTE groups. The 6-month mortality rate after VTE diagnosis was 54.8%. PDAC-related death was the most frequent cause of death, and thrombus-related death was not observed. CONCLUSION: Several baseline characteristics differed between patients with and without VTE. The incidence of VTE in patients with PDAC is high. However, because the prognosis of PDAC itself remains quite poor, VTE may not have a significant effect on prognosis.
Assuntos
Adenocarcinoma/etiologia , Carcinoma Ductal Pancreático/etiologia , Neoplasias Pancreáticas/complicações , Adenocarcinoma/mortalidade , Adenocarcinoma/fisiopatologia , Idoso , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/fisiopatologia , Feminino , Humanos , Japão , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Neoplasias PancreáticasRESUMO
BACKGROUND: Compared to conventional adenocarcinoma (CA), mucin-producing adenocarcinoma (MPA) is an uncommon histological subtype and is usually separated from other histological types and has been evaluated separately. The objective was to compare the clinicopathological characteristics and survivals of MPA with CA. METHODS: We retrospectively analyzed 1515 MPA patients in SEER database. Log-rank tests and KM survival curves were applied to determine the differences in overall survival (OS) and cancer specific survival (CSS) time. RESULTS: No significant differences were noted in OS and CSS time. The MPA patients who were treated with surgery and chemotherapy exhibited longer OS and CSS time periods than those without treatment. MPA patients treated with radiotherapy exhibited similar OS and CSS time with those without radiotherapy. MPA was not a prognostic factor of survival. CONCLUSIONS: MPA was a rare histological type of gastric cancer. Patients with MPA exhibited similar prognosis with those with CA. Surgery and chemotherapy were effective treatments for patients with MPA.
Assuntos
Adenocarcinoma/mortalidade , Adenocarcinoma/fisiopatologia , Mucinas Gástricas/metabolismo , Programa de SEER/normas , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do TratamentoRESUMO
Metastasis is the leading cause of cancer-related deaths and enables cancer cells to compromise organ function by expanding in secondary sites. Since primary tumours and metastases often share the same constellation of driver mutations, the mechanisms that drive their distinct phenotypes are unclear. Here we show that inactivation of the frequently mutated tumour suppressor gene LKB1 (encoding liver kinase B1) has evolving effects throughout the progression of lung cancer, which leads to the differential epigenetic re-programming of early-stage primary tumours compared with late-stage metastases. By integrating genome-scale CRISPR-Cas9 screening with bulk and single-cell multi-omic analyses, we unexpectedly identify LKB1 as a master regulator of chromatin accessibility in lung adenocarcinoma primary tumours. Using an in vivo model of metastatic progression, we further show that loss of LKB1 activates the early endoderm transcription factor SOX17 in metastases and a metastatic-like sub-population of cancer cells within primary tumours. The expression of SOX17 is necessary and sufficient to drive a second wave of epigenetic changes in LKB1-deficient cells that enhances metastatic ability. Overall, our study demonstrates how the downstream effects of an individual driver mutation can change throughout cancer development, with implications for stage-specific therapeutic resistance mechanisms and the gene regulatory underpinnings of metastatic evolution.
Assuntos
Adenocarcinoma/genética , Cromatina/metabolismo , Neoplasias Pulmonares/genética , Metástase Neoplásica/genética , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Quinases Ativadas por AMP , Adenocarcinoma/fisiopatologia , Animais , Linhagem Celular Tumoral , Feminino , Proteínas HMGB/metabolismo , Humanos , Neoplasias Pulmonares/fisiopatologia , Masculino , Camundongos , Mutação , Proteínas Serina-Treonina Quinases/genética , Fatores de Transcrição SOXF/metabolismoAssuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aptidão Cardiorrespiratória , Neoplasias Esofágicas/tratamento farmacológico , Terapia Neoadjuvante , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/fisiopatologia , Adenocarcinoma/cirurgia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Esofágicas/fisiopatologia , Neoplasias Esofágicas/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Projetos Piloto , Estudos Prospectivos , Neoplasias Gástricas/fisiopatologia , Neoplasias Gástricas/cirurgiaRESUMO
BACKGROUND: Stomach adenocarcinoma (STAD) is one of the most prevalent malignances and ranks fifth in incidence and third in cancer-related death among all malignances. The prognosis of STAD is poor. The circadian clock is regulated by interlocked transcriptional-translational feedback loops that orchestrate circadian rhythms in some biological processes, including the immune response and metabolism. However, the association between core circadian clock genes and STAD patient prognosis is unclear. MATERIALS AND METHODS: In our study, bioinformatics methods were performed to explore the expression and prognostic value of core circadian clock genes in STAD and their association with immune infiltration. RESULTS: The mRNA levels of CLOCK, CRY1 and NR1D1 were upregulated, while the mRNA levels of CRY2, PER1, PER3 and RORA were downregulated in STAD tissues compared with normal tissues. Core circadian clock genes exert promoting or inhibiting effects on certain cancer-related hallmark pathways, including the DNA damage response, cell cycle, apoptosis and RAS/MAPK pathways. Moreover, core circadian clock genes were linked to drug sensitivity or drug resistance. Prognosis analysis revealed that high expression of PER1 and NR1D1 was associated with poor overall survival, progression-free survival, and disease-free survival rates in STAD patients. Validation analysis further confirmed our result. Immune infiltration analysis demonstrated that the expression of ICOSLG and CD70 was significantly correlated with immune cells, immune biomarkers, chemokines and their receptors. CONCLUSIONS: Our results suggest that NR1D1 and PER1 are prognostic biomarkers and are associated with immune infiltration in STAD.
Assuntos
Adenocarcinoma/imunologia , Adenocarcinoma/fisiopatologia , Relógios Circadianos/fisiologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/fisiopatologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Relógios Circadianos/efeitos dos fármacos , Relógios Circadianos/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Mutação/genética , Prognóstico , Reprodutibilidade dos Testes , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Análise de SobrevidaRESUMO
Here we present the case of a 73-year-old male with rectal adenocarcinoma with heterotopic ossification (HO). Cancer-associated HO in the digestive system is rare. Thus, the precise mechanism and clinicopathological significance of HO have not yet been defined. To clarify the molecular mechanisms of HO, we analyzed the expression levels of signaling molecules related to epithelial-mesenchymal transition (EMT) that lead to ossification in the tumor cells discriminating the ossified area (HO-area) and non-ossified area (non-HO area). Expression levels of BMP4 were elevated in both areas, whereas BMP2 was specifically increased in the HO-area by qPCR. EMT-related molecules such as Snail and Slug were especially higher in the HO-area. By immunohistochemistry, the expression of Smad4, nuclear staining of ß-catenin, and the phosphorylated form of GSK-3ß were detectable in both areas, and GSK-3ß was highly phosphorylated in the HO-area. The tumor growth rate was extremely high, with the Ki-67 labeling index at 90%. In the HO-area, osteoblasts with alkaline phosphatase expression were distributed surrounding the tumor cells. This is the first demonstration of the involvement of EMT in HO of colon cancer through BMP/SMAD and WNT/ß-catenin signaling pathways, which are especially prominent in the HO-area leading to the osteogenic property.
Assuntos
Proteína Morfogenética Óssea 2/genética , Transição Epitelial-Mesenquimal/fisiologia , Ossificação Heterotópica/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/fisiopatologia , Idoso , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/metabolismo , Colo/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/fisiopatologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Masculino , Osteoblastos/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
New therapies to treat pancreatic cancer are direly needed. However, efficacious interventions lack a strong preclinical model that can recapitulate patients' anatomy and physiology. Likewise, the availability of human primary malignant tissue for ex vivo studies is limited. These are significant limitations in the biomedical device field. We have developed RAG2/IL2RG deficient pigs using CRISPR/Cas9 as a large animal model with the novel application of cancer xenograft studies of human pancreatic adenocarcinoma. In this proof-of-concept study, these pigs were successfully generated using on-demand genetic modifications in embryos, circumventing the need for breeding and husbandry. Human Panc01 cells injected subcutaneously into the ears of RAG2/IL2RG deficient pigs demonstrated 100% engraftment with growth rates similar to those typically observed in mouse models. Histopathology revealed no immune cell infiltration and tumor morphology was highly consistent with the mouse models. The electrical properties and response to irreversible electroporation of the tumor tissue were found to be similar to excised human pancreatic cancer tumors. The ample tumor tissue produced enabled improved accuracy and modeling of the electrical properties of tumor tissue. Together, this suggests that this model will be useful and capable of bridging the gap of translating therapies from the bench to clinical application.
Assuntos
Adenocarcinoma/terapia , Eletroporação/métodos , Neoplasias Pancreáticas/terapia , Adenocarcinoma/patologia , Adenocarcinoma/fisiopatologia , Animais , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Condutividade Elétrica , Feminino , Técnicas de Inativação de Genes , Humanos , Hospedeiro Imunocomprometido , Subunidade gama Comum de Receptores de Interleucina/deficiência , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/imunologia , Masculino , Camundongos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/fisiopatologia , Estudo de Prova de Conceito , Suínos , Pesquisa Translacional Biomédica , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: miR-301b-3p is reported in various human cancers for its abnormal expression, while the role and molecular mechanisms in lung adenocarcinoma (LUAD) remain unclear, and this is the focus of the present study. MATERIALS AND METHODS: TCGA database was consulted to know gene expression in LUAD tissue. CCK-8, colony formation assay and Transwell assay were applied to identify the role of target genes in regulating LUAD cell biological properties. Bioinformatics analysis plus dual-luciferase assay were performed to validate the potential connection between genes. RESULTS: miR-301b-3p and DLC1 were the target genes of this study and respectively differentially up-regulated and down-regulated in LUAD. Functional experiments indicated that miR-301b-3p contributed to cancer cell proliferation, migration and invasion, while this effect was reversed with overexpressed DLC1 which was identified as a direct target of and regulated by miR-301b-3p. CONCLUSIONS: Collectively, miR-301b-3p was identified to actively function on LUAD malignant progression by suppressing DLC1 expression. This discovery provides a novel therapeutic strategy for LUAD patients, which helps improve the survival of patients.
Assuntos
Adenocarcinoma/genética , Proteínas Ativadoras de GTPase/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Proteínas Supressoras de Tumor/genética , Adenocarcinoma/patologia , Adenocarcinoma/fisiopatologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Biologia Computacional , Bases de Dados Genéticas , Regulação para Baixo , Proteínas Ativadoras de GTPase/metabolismo , Expressão Gênica , Humanos , Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , MicroRNAs/metabolismo , Invasividade Neoplásica/genética , Proteínas Supressoras de Tumor/metabolismo , Regulação para CimaRESUMO
OBJECTIVE: The endpoint of the present study was to evaluate the outcomes of short-course radiotherapy (SCRT) and SCRT with delayed surgery (SCRT-DS) on a selected subgroup of frail patients with locally advanced middle/low rectal adenocarcinoma. METHODS: From January 2008 to December 2018, a total of 128 frail patients with locally advanced middle-low rectal adenocarcinoma underwent SCRT and subsequent restaging for eventual delayed surgery. Rates of complete pathological response, down-staging, disease free survival (DFS) and overall survival (OS) were analyzed. RESULTS: 128 patients completed 5 × 5 Gy pelvic radiotherapy. 69 of these were unfit for surgery; 59 underwent surgery 8 weeks (average time: 61 days) after radiotherapy. Downstaging of T occurred in 64% and down-staging of N in 50%. The median overall survival (OS) of SCRT alone was 19.5 months. The 1-year, 2-year, 3-year and 5-year OS was 48%, 22%, 14% and 0% respectively. In the surgical group, the median disease-free survival (DFS) and median OS were, respectively, 67 months (95% CI 49.8-83.1 months) and 72.1 months (95% CI 57.5-86.7 months). The 1, 2, 3, 5-year OS was 88%, 75%, 51%, 46%, respectively. Post-operative morbidity was 22%, mortality was 3.4%. CONCLUSIONS: Frail patients with advanced rectal cancer are often "unfit" for long-term neoadjuvant chemoradiation. A SCRT may be considered a valid option for this group of patients. Once radiotherapy is completed, patients can be re-evaluated for surgery. If feasible, SCRT and delayed surgery is the best option for frail patients.
Assuntos
Adenocarcinoma/terapia , Fragilidade/complicações , Protectomia/métodos , Radioterapia Conformacional/métodos , Neoplasias Retais/terapia , Abscesso/epidemiologia , Adenocarcinoma/complicações , Adenocarcinoma/patologia , Adenocarcinoma/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Dor do Câncer/etiologia , Dor do Câncer/fisiopatologia , Colectomia , Fístula do Sistema Digestório/epidemiologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Complicações Pós-Operatórias/epidemiologia , Neoplasias Retais/complicações , Neoplasias Retais/patologia , Neoplasias Retais/fisiopatologia , Estudos Retrospectivos , Infecção da Ferida Cirúrgica/epidemiologia , Taxa de SobrevidaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Although rigorous efforts identified the presence of 'cancer stem cells (CSCs)' in PDAC and molecular markers for them, stem cell dynamics in vivo have not been clearly demonstrated. Here we focused on Doublecortin-like kinase 1 (Dclk1), known as a CSC marker of PDAC. Using genetic lineage tracing with a dual-recombinase system and live imaging, we showed that Dclk1+ tumor cells continuously provided progeny cells within pancreatic intraepithelial neoplasia, primary and metastatic PDAC, and PDAC-derived spheroids in vivo and in vitro. Furthermore, genes associated with CSC and epithelial mesenchymal transition were enriched in mouse Dclk1+ and human DCLK1-high PDAC cells. Thus, we provided direct functional evidence for the stem cell activity of Dclk1+ cells in vivo, revealing the essential roles of Dclk1+ cells in expansion of pancreatic neoplasia in all progressive stages.
Assuntos
Adenocarcinoma/fisiopatologia , Carcinoma Ductal Pancreático/fisiopatologia , Linhagem da Célula/genética , Células-Tronco Neoplásicas/metabolismo , Neoplasias Pancreáticas/fisiopatologia , Adenocarcinoma/patologia , Animais , Carcinoma Ductal Pancreático/patologia , Humanos , Camundongos , Metástase Neoplásica , Neoplasias Pancreáticas/patologiaRESUMO
Multiple primary lung cancer (MPLC) refers to the simultaneous occurrence of two or more lung primary malignant tumors in one individual. The detection rate of MPLC has increased significantly in recent years, and the distinction between MPLC and lung metastasis has strong clinical significance. Whole exome sequencing (WES) can clearly identify the heterogeneity between MPLC nodules. Here, we report a case of a 50-year-old Asian female without a history of smoking. She underwent a lung computed tomography (CT) scan and three ground-glass nodules (GGNs) were found which were pathologically confirmed as atypical adenomatous hyperplasia (AAH), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA), respectively. We performed WES on the three pulmonary nodules and analyzed the sequencing results. We believe that this is the first published report of a case of "three phases" of lung adenocarcinoma analyzed by WES. Under the same genetic background and internal environment, these three nodules showed significant genetic differences and developed into "three phases" of lung adenocarcinoma. Analysis of the WES results supported the lung adenocarcinoma model from AAH to MIA and IA, and explored possible potential driver genes and therapeutic targets. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: We used WES to analyze the gene mutation status of three tumors in one individual. We found that even if under the same genetic background, AAH, MIA and IA showed significant genetic differences and developed into "three phases" of lung adenocarcinoma. WHAT THIS STUDY ADDS: Analysis of the WES results supported the lung adenocarcinoma model from AAH to MIA and IA, and explored possible potential driver genes and therapeutic targets.
Assuntos
Adenocarcinoma/fisiopatologia , Hiperplasia/fisiopatologia , Feminino , Humanos , Pessoa de Meia-Idade , MutaçãoRESUMO
Gastric cancer is the fifth most common cancer worldwide with a poor survival rate. Therefore, it is important to identify predictive and prognostic biomarkers of gastric cancer. Laminin subunit beta 1 (LAMB1) is involved in attachment, migration, and organization during development, and its elevated expression has been associated with several cancers. However, the role and mechanism of LAMB1 in gastric cancer remains unknown. Here, we determined that LAMB1 is upregulated in gastric cancer tissues and contributes to cell growth and motility. Using a public database, we showed that LAMB1 expression was significantly upregulated in gastric cancer compared to normal tissues. LAMB1 was also found to be associated with poor prognosis in patients with gastric cancer. Overexpression of LAMB1 elevated cell proliferation, invasion, and migration; however, knockdown of LAMB1 decreased these effects in gastric cancer cells. U0126, an extracellular signal-regulated kinase (ERK) inhibitor, regulated the expression of LAMB1 in gastric cancer cells. Additionally, we showed that c-Jun directly binds to the LAMB1 promoter as a transcription factor and regulates its gene expression via the ERK pathway in gastric cancer cells. Therefore, our study indicates that LAMB1 promotes cell growth and motility via the ERK/c-Jun axis and is a potential biomarker and therapeutic target of gastric cancer.
Assuntos
Adenocarcinoma/genética , Movimento Celular , Proliferação de Células , Laminina/genética , Neoplasias Gástricas/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Adenocarcinoma/fisiopatologia , Linhagem Celular Tumoral , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Laminina/metabolismo , Laminina/fisiologia , Sistema de Sinalização das MAP Quinases , Prognóstico , Proteínas Proto-Oncogênicas c-jun/metabolismo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/fisiopatologiaRESUMO
OBJECTIVE: To test the performance of free-breathing Dynamic Contrast-Enhanced MRI (DCE-MRI) using a radial volumetric interpolated breath-hold examination (VIBE) sequence combined with diffusion-weighted imaging (DWI) for quantitative solitary pulmonary nodule (SPN) assessment. METHODS: A total of 67 SPN cases receiving routine MRI routine scans, DWI, and dynamic-enhanced MRI in our hospital from May 2017 to November 2018 were collected. These cases were divided into a malignant group and a benign group according to the characteristics of the SPNs. The quantitative DCE-MRI parameters (Ktrans, Kep, Ve) and apparent diffusion coefficient (ADC) values of the nodules were measured. RESULTS: The Ktrans and Kep values in the malignant group were higher than those in the benign group, while the ADC values in the malignant group were lower than those in the benign group. Furthermore, the Ktrans value of adenocarcinoma was higher than that of squamous cell carcinoma and small cell carcinoma (P < 0.05). The Ve value was significantly different between non-small cell carcinoma and small cell carcinoma (P < 0.05). With an ADC value of 0.98 × 10-3 mm2/s as the threshold, the specificity and sensitivity to diagnose benign and malignant nodules was 90.6% and 80%, respectively. CONCLUSION: High-temporal-resolution DCE-MRI using the r-VIBE technique in combination with DWI could contribute to pulmonary nodule analysis and possibly serve as a potential alternative to distinguish malignant from benign nodules as well as differentiate different types of malignancies.
Assuntos
Suspensão da Respiração , Imagem de Difusão por Ressonância Magnética , Processamento de Imagem Assistida por Computador , Nódulo Pulmonar Solitário/diagnóstico por imagem , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/fisiopatologia , Adulto , Idoso , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/fisiopatologia , Meios de Contraste , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Nódulo Pulmonar Solitário/fisiopatologiaAssuntos
Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/fisiopatologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Células Neoplásicas Circulantes/patologia , Microangiopatias Trombóticas/diagnóstico por imagem , Microangiopatias Trombóticas/patologia , Adenocarcinoma/mortalidade , Adulto , Evolução Fatal , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Microangiopatias Trombóticas/mortalidade , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: The objective of this study was to compare functional and surgical outcomes of patients undergoing ileocecal resection for Crohn's disease (CD) to patients undergoing oncological right colectomy. METHODS: Retrospective single-center cohort study including consecutive patients undergoing right colectomy for adenocarcinoma (oncological resection) or CD (mesentery-sparing resection) between July 2011 and November 2017. Outcome measures were pathological details (lymph node yield), postoperative recovery (pain levels, return to flatus and stool, intake of fluids, weight change, and mobilization), and early (30-day) outcomes (surgical/medical complications, hospital stay, readmissions). RESULTS: A total of 195 patients (153 [78%] with cancer and 42 [22%] with CD) were included. Overall compliance with the institutional enhanced recovery protocol was comparable between the 2 groups (compliance ≥70%: 60% in CD patients vs. 62% in cancer, p = 0.458). The adenocarcinoma group had a larger lymph node yield than the CD group (26 ± 13 vs. 2.4 ± 5, respectively, p < 0.001). While the CD group experienced significantly more pain (3.7 ± 1.9/10 vs. 2.8 ± 2.5/10, p = 0.007, patients requiring opioids: 65 vs. 28%, p = 0.001), return of flatus (2.3 ± 1.2 days vs. 2.4 ± 2.8 days, p = 0.642) and stool (4.1 ± 6.0 vs. 3.0 ± 1.8 days, p = 0.292) was no different in both groups. No difference was observed regarding postoperative complications, length of stay, and readmission rate. CONCLUSION: This study revealed no differences in both functional and surgical outcomes in CD and cancer patients undergoing mesentery-sparing or formal oncological right colectomy, respectively.
Assuntos
Adenocarcinoma/fisiopatologia , Adenocarcinoma/cirurgia , Colectomia , Neoplasias do Colo/fisiopatologia , Neoplasias do Colo/cirurgia , Doença de Crohn/fisiopatologia , Doença de Crohn/cirurgia , Adulto , Idoso , Recuperação Pós-Cirúrgica Melhorada , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The N-myc downstream regulated gene (NDRG) family members are dysregulated in several tumors. Functionally, NDRGs play an important role in the malignant progression of cancer cells. However, little is known about the potential implications of NDRG4 in pancreatic ductal adenocarcinoma (PDAC). The aim of the current study was to elucidate the expression pattern of NDRG4 in PDAC and evaluate its potential cellular biological effects. Here, we firstly report that epigenetic-mediated silencing of NDRG4 promotes PDAC by regulating mitochondrial function. Data mining demonstrated that NDRG4 was significantly down-regulated in PDAC tissues and cells. PDAC patients with low NDRG4 expression showed poor prognosis. Epigenetic regulation by DNA methylation was closely associated with NDRG4 down-regulation. NDRG4 overexpression dramatically suppressed PDAC cell growth and metastasis. Further functional analysis demonstrated that up-regulated NDRG4 in SW1990 and Canpan1 cells resulted in attenuated mitochondrial function, including reduced ATP production, decreased mitochondrial membrane potential, and increased fragmented mitochondria. However, opposite results were obtained for HPNE cells with NDRG4 knockdown. These results indicate that hypermethylation-driven silencing of NDRG4 can promote PDAC by regulating mitochondrial function and that NDRG4 could be as a potential biomarker for PDAC patients. [BMB Reports 2020; 53(12): 658-663].