RESUMO
Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-xL , Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-xL and Mcl-1. Expression of Bcl-xL , Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-xL and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatment with specific small molecule inhibitors of Bcl-xL (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-xL induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-xL and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-xL in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-xL as a key protein in cell death resistance of CCA and may pave the way for clinical application.
Assuntos
Colangiocarcinoma , Proteína bcl-X , Humanos , Proteína bcl-X/genética , Proteína bcl-X/metabolismo , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ductos Biliares Intra-Hepáticos , Linhagem Celular Tumoral , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/tratamento farmacológico , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genéticaRESUMO
BACKGROUND AND OBJECTIVES: In treatment of colorectal liver metastases (CRC-LM), liver surgery combined with systemic therapies and local ablation (LAT) allows improved survival. This study aims at the outcomes of patients with complex bilobar CRC-LM who were intended to undergo multimodal therapy with liver resection and LAT. METHODS: Forty-three CRC-LM patients with recommendation for multimodal treament were extracted from 5878 tumor board decisions between 2014 and 2017. Outcome variables included patient survival, as well as completion of hepatic clearance. Prognostic factors were identified by correlation and a Cox proportional hazards model. RESULTS: Out of 43 patients only 23 achieved complete clearance of CRC-LM. One- and 3-year overall survival of patients with cleared liver disease was 100% and 91.7%, respectively, as compared to 83.8% and 12.1%. Incomplete hepatic clearance was the strongest independent risk factor for overall survival (hazards ratio [HR], 5.86; p = .009). Risk factors for incomplete clearance were higher age (r = .34; p = .026), comorbidities (r = .40; p = .008), major complications (r = .34; p = .024), and prolonged intensive care unit stay (r = .41; p = .017). CONCLUSION: Completion of hepatic clearance is crucial to achieve long-term survival in patients with complex bilobar CRC-LM. Careful patient selection and treatment planning should avoid treatment failure before completing the intended therapy plan when multimodal treatments are planned.
Assuntos
Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Técnicas de Ablação/métodos , Idoso , Quimioterapia Adjuvante , Estudos de Coortes , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/cirurgia , Feminino , Hepatectomia/métodos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Intervalo Livre de Progressão , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
Aim: To survey European physicians managing patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and understand differences in baseline characteristics, diagnostic methods, symptoms and co-morbidities. Materials & methods: Patient record inclusion criteria were: ≥18 years old, metastatic PDAC diagnosis and completion of first-line treatment between July 2014 and January 2016. Records were grouped by patient age, gender and primary tumor location. Results: Records (n = 2565) were collected from nine countries. Baseline characteristics varied between subgroups. Computed tomography was the most frequently used diagnostic technique. Symptoms at diagnosis included abdominal and/or mid-back pain (72% of patients) and weight loss (61.5%). Co-morbidities varied with patient age. Conclusion: Greater awareness of symptoms, diagnostic methods and co-morbidities present at PDAC diagnosis may support better patient management decisions.
Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Competência Clínica/estatística & dados numéricos , Neoplasias Pancreáticas/diagnóstico , Padrões de Prática Médica/estatística & dados numéricos , Idoso , Carcinoma Ductal Pancreático/epidemiologia , Carcinoma Ductal Pancreático/terapia , Tomada de Decisão Clínica , Comorbidade , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/terapia , Estudos Retrospectivos , Inquéritos e Questionários/estatística & dados numéricos , Tomografia Computadorizada por Raios X/estatística & dados numéricosRESUMO
BACKGROUND: Mutations in the KRAS gene can be detected in about 70-90% of pancreatic cancer (PC) cases. Whether these mutations have a prognostic or predictive value remains elusive. Furthermore, the clinical relevance of the extended RAS (KRAS+NRAS) mutational status is unclear in PC. METHODS: We prospectively defined a PC patient population who received erlotinib-free chemotherapy regimens. A statistically significant difference between KRAS wild-type and KRAS mutated tumours in at least 160 patients in this population would support the assumption of a rather prognostic role of KRAS. RESULTS: One hundred and seventy-eight tumour samples were collected from prospective clinical studies and successfully analysed for the extended RAS status: 37 tumours were KRAS wild-type (21%), whereas 141 (79%) carried a KRAS mutation; 132 of these mutations were found in KRAS exon 2 (74%), whereas only 9 mutations (5%) were detected in KRAS exon 3. Within KRAS exon 4 and NRAS exons 2-4, no mutations were apparent. There was no significant difference in overall survival for KRAS wild-type vs mutant patients (9.9 vs 8.3 months, P=0.70). CONCLUSIONS: Together with the results of the AIO-PK-0104-trial, the present analysis supports the notion that KRAS mutation status is rather predictive than prognostic in advanced PC.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma/secundário , Antígeno CA-19-9/sangue , Capecitabina/administração & dosagem , Cisplatino/administração & dosagem , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Análise Mutacional de DNA , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/uso terapêutico , Éxons , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Neoplasias Pancreáticas/patologia , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida , GencitabinaRESUMO
OBJECTIVE: Progastrin is the incompletely cleaved precursor of gastrin that is secreted by G-cells in the gastric antrum. Both gastrin and progastrin bind to the CCK2 receptor (Cckbr or CCK2R) expressed on a subset of gastric epithelial cells. Little is known about how gastrin peptides and CCK2R regulate gastric stem cells and carcinogenesis. Interconversion among progenitors in the intestine is documented, but the mechanisms by which this occurs are poorly defined. DESIGN: We generated CCK2R-CreERT mice and performed inducible lineage tracing experiments. CCK2R+ antral cells and Lgr5+ antral stem cells were cultured in a three-dimensional in vitro system. We crossed progastrin-overexpressing mice with Lgr5-GFP-CreERT mice and examined the role of progastrin and CCK2R in Lgr5+ stem cells during MNU-induced carcinogenesis. RESULTS: Through lineage tracing experiments, we found that CCK2R defines antral stem cells at position +4, which overlapped with an Lgr5(neg or low) cell population but was distinct from typical antral Lgr5(high) stem cells. Treatment with progastrin interconverts Lgr5(neg or low) CCK2R+ cells into Lgr5(high) cells, increases CCK2R+ cell numbers and promotes gland fission and carcinogenesis in response to the chemical carcinogen MNU. Pharmacological inhibition or genetic ablation of CCK2R attenuated progastrin-dependent stem cell expansion and carcinogenesis. CONCLUSIONS: CCK2R labels +4 antral stem cells that can be activated and expanded by progastrin, thus identifying one hormonal trigger for gastric stem cell interconversion and a potential target for gastric cancer chemoprevention and therapy.
Assuntos
Carcinogênese , Antro Pilórico/citologia , Receptor de Colecistocinina B/fisiologia , Células-Tronco/fisiologia , Animais , Células Cultivadas , Gastrinas/fisiologia , Camundongos , Precursores de Proteínas/fisiologiaRESUMO
BACKGROUND: Pseudoprogression (PsPD) is a rare response pattern to immune checkpoint inhibitor (ICI) therapy in oncology. This study aims to reveal imaging features of PsPD, and their association to other relevant findings. METHODS: Patients with PsPD who had at least three consecutive cross-sectional imaging studies at our comprehensive cancer center were retrospectively analyzed. Treatment response was assessed according to immune Response Evaluation Criteria in Solid Tumors (iRECIST). PsPD was defined as the occurrence of immune unconfirmed progressive disease (iUPD) without follow-up confirmation. Target lesions (TL), non-target lesions (NTL), new lesions (NL) were analyzed over time. Tumor markers and immune-related adverse events (irAE) were correlated. RESULTS: Thirty-two patients were included (mean age: 66.7 ± 13.6 years, 21.9% female) with mean baseline STL of 69.7 mm ± 55.6 mm. PsPD was observed in twenty-six patients (81.3%) at FU1, and no cases occurred after FU4. Patients with iUPD exhibited the following: TL increase in twelve patients, (37.5%), NTL increase in seven patients (21.9%), NL appearance in six patients (18.8%), and combinations thereof in four patients (12.5%). The mean and maximum increase for first iUPD in sum of TL was 19.8 and 96.8 mm (+ 700.8%). The mean and maximum decrease in sum of TL between iUPD and consecutive follow-up was - 19.1 mm and - 114.8 mm (-60.9%) respectively. The mean and maximum sum of new TL at first iUPD timepoint were 7.6 and 82.0 mm respectively. In two patients (10.5%), tumor-specific serologic markers were elevated at first iUPD, while the rest were stable or decreased among the other PsPD cases (89.5%). In fourteen patients (43.8%), irAE were observed. CONCLUSIONS: PsPD occurred most frequently at FU1 after initiation of ICI treatment. The two most prevalent reasons for PsPD were TL und NTL progression, with an increase in TL diameter commonly below + 100%. In few cases, PsPD was observed even if tumor markers were rising compared to baseline. Our findings also suggest a correlation between PsPD and irAE. These findings may guide decision-making of ICI continuation in suspected PsPD.
Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Masculino , Inibidores de Checkpoint Imunológico/uso terapêutico , Estudos Retrospectivos , Progressão da Doença , Neoplasias/tratamento farmacológico , Biomarcadores TumoraisRESUMO
IL-1ß is believed to play a pathogenic role in the development of pancreatitis. Expression of human IL-1ß in pancreatic acinar cells produces chronic pancreatitis, characterized by extensive intrapancreatic inflammation, atrophy, and fibrosis. To determine if activation of trypsinogen is important in the pathogenesis of chronic pancreatitis in this model, we crossed IL-1ß transgenic [Tg(IL1ß)] mice with mice expressing a trypsin inhibitor that is normally produced in rat pancreatic acinar cells [pancreatic secretory trypsin inhibitor (PTSI) I]. We previously demonstrated that transgenic expression of PSTI-I [Tg(Psti1)] increased pancreatic trypsin inhibitor activity by 190%. Tg(IL1ß) mice were found to have marked pancreatic inflammation, characterized by histological changes, including acinar cell loss, inflammatory cell infiltration, and fibrosis, as well as elevated myeloperoxidase activity and elevated pancreatic trypsin activity, as early as 6 wk of age. In contrast to Tg(IL1ß) mice, pancreatitis was significantly less severe in dual-transgenic [Tg(IL1ß)-Tg(Psti1)] mice expressing IL-1ß and PSTI-I in pancreatic acinar cells. These findings indicate that overexpression of PSTI-I reduces the severity of pancreatitis and that pancreatic trypsin activity contributes to the pathogenesis of an inflammatory model of chronic pancreatitis.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Interleucina-1beta/biossíntese , Pâncreas/metabolismo , Pancreatite Crônica/prevenção & controle , Actinas/biossíntese , Amilases/metabolismo , Animais , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Masculino , Camundongos , Pâncreas/patologia , Pancreatite/patologia , Pancreatite Crônica/patologia , Ratos , Tripsina/metabolismo , Inibidor da Tripsina Pancreática de Kazal , Inibidores da Tripsina/biossíntese , Inibidores da Tripsina/fisiologiaRESUMO
AIM OF THE STUDY: Next-generation sequencing (NGS) might represent a valuable diagnostic tool to identify somatic alterations and enable personalised medicine in uro-oncology. We aim to determine feasibility and impact of routine NGS in clinical practice. METHODS: Tumours from patients with genitourinary cancers were subjected to NGS. Results were discussed in a dedicated molecular tumour board. Statistical analyses included chi-square test and Mann-Whitney U test. RESULTS: Between 2017 and 2020, 65 patients with advanced genitourinary cancers were consecutively enrolled. Number of tests increased (28 tests in 2020) and diagnostic turnaround time for generating output decreased (17.5 days [range 13-35]). Median patient's age was 62 years (range 33-84), and most NGS assays were performed upon start of systemic treatment (range 0-6 of treatment lines). 62/66 sequenced samples generated a report. Fifty samples (80.6%) showed at least one molecular alteration. Most prevalent alterations were TP53 (32.3%), PIK3CA (14.5%) and TMPRSS2-ERG (9.7%). Sequencing revealed potentially druggable targets in 29 samples (46.8%). Based on NGS results, six patients underwent therapy change, whereas for three patients, coverage of recommended off-label therapy was denied by health insurances. CONCLUSIONS: NGS is increasingly feasible in clinical routine for patients with genitourinary cancers. Number of performed analyses is constantly growing, and turnaround time to therapy recommendation is decreasing. While the majority of tumours harbour clinically relevant mutations, alterations related to urologic cancers are underrepresented, thus treatment changes occurred only in a minority of patients. Further, access to target agents remains a considerable obstacle in the consequent implementation of precision uro-oncology.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Medicina de Precisão , Neoplasias Urológicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/genética , Adulto JovemRESUMO
BACKGROUND: Molecular biomarkers and primary tumour sidedness guide treatment decisions in metastatic colorectal cancer. Comprehensive molecular profiling aims to identify targetable alterations and measure tumour mutational burden (TMB) to enable precision oncology. MATERIAL AND METHODS: FoundationOne® next-generation sequencing identified single-nucleotide variants (SNVs), copy number alterations, high TMB (TMB-H) and high-grade microsatellite instability (MSI-H) in patients treated in the FIRE-3 trial. Data were correlated with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: Three hundred seventy-three (49.6%) of 752 patients provided material for this analysis. Frequent SNVs included TP53, APC, KRAS, PIK3CA, BRAF, SMAD4 and FBXW7. KRAS, BRAF V600E and SMAD4 mutations were confirmed as prognostic biomarkers by logistic penalised regression for ORR. OS was significantly longer in patients with SMAD4 wild-type (WT) tumours than in those with SMAD4-mutated tumours (hazard ratio = 0.59 [95% confidence interval {CI} = 0.34-1.01], p = 0.05), with a higher probability of ORR [odds ratio, SMAD4 SNV versus WT = 0.32 [95% CI = 0.10-0.98], p = 0.05] when treated with cetuximab. MSI-H (30.0%, p = 0.03) and TMB-H (17.3%, p = 0.003) tumours were enriched by FBXW7 mutations. Numerically lower ORR, OS and PFS were observed in MSI-H tumours. CONCLUSIONS: RAS, BRAF V600E and SMAD4 mutations were identified as poor prognostic biomarkers in patients of the FIRE-3 trial, whereas improved outcome was observed for BRAF non-V600E mutation. SMAD4 mutation might provide predictive relevance for cetuximab efficacy. MSI-H tumours showed numerically lower ORR, OS and PFS.
Assuntos
Neoplasias Colorretais/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Polimorfismo de Nucleotídeo Único/genética , Carga Tumoral/genética , Adulto , Idoso , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos RetrospectivosRESUMO
PURPOSE: A prolonged time to treatment initiation (TTI) correlates with an adverse prognosis in different cancer types including resectable pancreatic cancer (PC). Only limited evidence on the correlation between TTI and prognosis in advanced PC exists. METHODS: Consecutive PC patients (n = 368) who were diagnosed or treated at our high-volume comprehensive cancer center were included in a prospectively maintained database. We retrospectively analyzed time from first imaging showing advanced PC to initiation of palliative first-line chemotherapy. Lead time bias and waiting time paradox were addressed by landmark analysis and correlation of tumor burden with TTI. RESULTS: Two hundred and ninety-seven patients met the pre-specified in- and exclusion criteria of our study. Median TTI was 29 days (range: 1-124 days). Most common reasons for prolonged TTI (> 21 days) were referral from an external treatment center (39%) and a second biopsy (31%). A TTI above the median-, 75th or 90th percentile (43 or 60 days, respectively) had no impact on overall survival. Furthermore, no correlation between levels of carbohydrate antigen 19-9 (CA 19-9) at time of treatment initiation and TTI was observed. CONCLUSION: While a timely work-up of advanced PC patients remains important, delays in treatment initiation due to repeated biopsies, inclusion in a clinical study or transfer to a specialized cancer center appear to be justified in light of the absence of a strong adverse effect of prolonged TTI on prognosis in advanced PC patients.
Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Tempo para o Tratamento , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno CA-19-9/sangue , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/mortalidade , Estudos de Coortes , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , GencitabinaRESUMO
Within the gastrointestinal stem cell niche, nerves help to regulate both normal and neoplastic stem cell dynamics. Here, we reveal the mechanisms underlying the cancer-nerve partnership. We find that Dclk1+ tuft cells and nerves are the main sources of acetylcholine (ACh) within the gastric mucosa. Cholinergic stimulation of the gastric epithelium induced nerve growth factor (NGF) expression, and in turn NGF overexpression within gastric epithelium expanded enteric nerves and promoted carcinogenesis. Ablation of Dclk1+ cells or blockade of NGF/Trk signaling inhibited epithelial proliferation and tumorigenesis in an ACh muscarinic receptor-3 (M3R)-dependent manner, in part through suppression of yes-associated protein (YAP) function. This feedforward ACh-NGF axis activates the gastric cancer niche and offers a compelling target for tumor treatment and prevention.
Assuntos
Acetilcolina/fisiologia , Fator de Crescimento Neural/fisiologia , Transdução de Sinais/fisiologia , Neoplasias Gástricas/etiologia , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Animais , Proteínas de Ciclo Celular , Quinases Semelhantes a Duplacortina , Mucosa Gástrica/inervação , Camundongos , Camundongos Endogâmicos C57BL , Fosfoproteínas/fisiologia , Proteínas Serina-Treonina Quinases/análise , Receptor Muscarínico M3/fisiologia , Proteínas de Sinalização YAPRESUMO
Epithelium of the colon and intestine are renewed every 3 days. In the intestine there are at least two principal stem cell pools. The first contains rapid cycling crypt-based columnar (CBC) Lgr5(+) cells, and the second is composed of slower cycling Bmi1-expressing cells at the +4 position above the crypt base. In the colon, however, the identification of Lgr5(-) stem cell pools has proven more challenging. Here, we demonstrate that the intermediate filament keratin-19 (Krt19) marks long-lived, radiation-resistant cells above the crypt base that generate Lgr5(+) CBCs in the colon and intestine. In colorectal cancer models, Krt19(+) cancer-initiating cells are also radioresistant, while Lgr5(+) stem cells are radiosensitive. Moreover, Lgr5(+) stem cells are dispensable in both the normal and neoplastic colonic epithelium, as ablation of Lgr5(+) stem cells results in their regeneration from Krt19-expressing cells. Thus, Krt19(+) stem cells are a discrete target relevant for cancer therapy.
Assuntos
Colo/patologia , Intestinos/patologia , Queratina-19/metabolismo , Células-Tronco Neoplásicas/metabolismo , Tolerância a Radiação , Receptores Acoplados a Proteínas G/metabolismo , Animais , Queratina-19/genética , Camundongos Transgênicos , Células-Tronco Neoplásicas/patologia , Transporte de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
The regulation and stem cell origin of normal and neoplastic gastric glands are uncertain. Here, we show that Mist1 expression marks quiescent stem cells in the gastric corpus isthmus. Mist1(+) stem cells serve as a cell-of-origin for intestinal-type cancer with the combination of Kras and Apc mutation and for diffuse-type cancer with the loss of E-cadherin. Diffuse-type cancer development is dependent on inflammation mediated by Cxcl12(+) endothelial cells and Cxcr4(+) gastric innate lymphoid cells (ILCs). These cells form the perivascular gastric stem cell niche, and Wnt5a produced from ILCs activates RhoA to inhibit anoikis in the E-cadherin-depleted cells. Targeting Cxcr4, ILCs, or Wnt5a inhibits diffuse-type gastric carcinogenesis, providing targets within the neoplastic gastric stem cell niche.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células Epiteliais/metabolismo , Mucosa Gástrica/metabolismo , Células-Tronco Neoplásicas/metabolismo , Nicho de Células-Tronco , Neoplasias Gástricas/metabolismo , Microambiente Tumoral , Animais , Anoikis , Antineoplásicos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Transplante de Medula Óssea , Caderinas/metabolismo , Comunicação Celular , Linhagem Celular Tumoral , Linhagem da Célula , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Senescência Celular , Quimiocina CXCL12/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Humanos , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Camundongos , Camundongos Transgênicos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Receptores CXCR4/metabolismo , Transdução de Sinais , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Fatores de Tempo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , Proteína Wnt-5a , Proteínas rho de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTPRESUMO
XMD8-92 is a kinase inhibitor with anti-cancer activity against lung and cervical cancers, but its effect on pancreatic ductal adenocarcinoma (PDAC) remains unknown. Doublecortin-like kinase1 (DCLK1) is upregulated in various cancers including PDAC. In this study, we showed that XMD8-92 inhibits AsPC-1 cancer cell proliferation and tumor xenograft growth. XMD8-92 treated tumors demonstrated significant downregulation of DCLK1 and several of its downstream targets (including c-MYC, KRAS, NOTCH1, ZEB1, ZEB2, SNAIL, SLUG, OCT4, SOX2, NANOG, KLF4, LIN28, VEGFR1, and VEGFR2) via upregulation of tumor suppressor miRNAs let-7a, miR-144, miR-200a-c, and miR-143/145; it did not however affect BMK1 downstream genes p21 and p53. These data taken together suggest that XMD8-92 treatment results in inhibition of DCLK1 and downstream oncogenic pathways (EMT, pluripotency, angiogenesis and anti-apoptotic), and is a promising chemotherapeutic agent against PDAC.
Assuntos
Antineoplásicos/farmacologia , Benzodiazepinonas/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Carcinoma Ductal Pancreático/enzimologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinases Semelhantes a Duplacortina , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fator 4 Semelhante a Kruppel , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
The nervous system plays an important role in the regulation of epithelial homeostasis and has also been postulated to play a role in tumorigenesis. We provide evidence that proper innervation is critical at all stages of gastric tumorigenesis. In three separate mouse models of gastric cancer, surgical or pharmacological denervation of the stomach (bilateral or unilateral truncal vagotomy, or local injection of botulinum toxin type A) markedly reduced tumor incidence and progression, but only in the denervated portion of the stomach. Vagotomy or botulinum toxin type A treatment also enhanced the therapeutic effects of systemic chemotherapy and prolonged survival. Denervation-induced suppression of tumorigenesis was associated with inhibition of Wnt signaling and suppression of stem cell expansion. In gastric organoid cultures, neurons stimulated growth in a Wnt-mediated fashion through cholinergic signaling. Furthermore, pharmacological inhibition or genetic knockout of the muscarinic acetylcholine M3 receptor suppressed gastric tumorigenesis. In gastric cancer patients, tumor stage correlated with neural density and activated Wnt signaling, whereas vagotomy reduced the risk of gastric cancer. Together, our findings suggest that vagal innervation contributes to gastric tumorigenesis via M3 receptor-mediated Wnt signaling in the stem cells, and that denervation might represent a feasible strategy for the control of gastric cancer.
Assuntos
Carcinogênese/patologia , Denervação , Neoplasias Gástricas/prevenção & controle , Animais , Biomarcadores Tumorais/metabolismo , Carcinogênese/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Inflamação/patologia , Camundongos , Células-Tronco Neoplásicas/patologia , Neurônios/metabolismo , Periferinas/metabolismo , Receptor Muscarínico M3/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Via de Sinalização WntRESUMO
Pancreatic cancer is a uniformly lethal disease characterized by a strong stromal reaction called desmoplasia. Organ fibrosis is also a feature of chronic pancreatitis a known risk factor for pancreatic cancer. Here we describe a transplantation approach to investigate bone marrow-derived cells in murine models of chronic pancreatitis and pancreatic cancer.