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1.
Int J Nanomedicine ; 16: 2965-2981, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33935496

RESUMEN

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a meager prognosis due to its chemotherapy resistance. A new treatment method may be magnetic fluid hyperthermia (MFH). Magnetoliposomes (ML), consisting of superparamagnetic iron oxide nanoparticles (SPION) stabilized with a phospholipid-bilayer, are exposed to an alternating magnetic field (AMF) to generate heat. To optimize this therapy, we investigated the effects of MFH on human PDAC cell lines and 3D organoid cultures. Material and Methods: ML cytotoxicity was tested on Mia PaCa-2 and PANC-1 cells and on PDAC 3D organoid cultures, generated from resected tissue of patients. The MFH was achieved by AMF application with an amplitude of 40-47 kA/m and a frequency of 270 kHz. The MFH effect on the cell viability of the cell lines and the organoid cultures was investigated at two different time points. Clonogenic assays evaluated the impairment of colony formation. Altering ML set-ups addressed differences arising from intra- vs extracellular ML locations. Results: Mia PaCa-2 and PANC-1 cells showed no cytotoxic effects at ML concentrations up to 300 µg(Fe)/mL and 225 µg(Fe)/mL, respectively. ML at a concentration of 225 µg(Fe)/mL were also non-toxic for PDAC organoid cultures. MFH treatment using exclusively extracellular ML presented the highest impact on cell viability. Clonogenic assays demonstrated remarkable impairment as long-term outcome in MFH-treated PDAC cell lines. Additionally, we successfully treated PDAC organoids with extracellular ML-derived MFH, resulting in notably reduced cell viabilities 2h and 24 h post treatment. Still, PDAC organoids seem to partly recover from MFH after 24 h as opposed to conventional 2D-cultures. Conclusion: Treatment with MFH strongly diminished pancreatic cancer cell viability in vitro, making it a promising treatment strategy. As organoids resemble the more advanced in vivo conditions better than conventional 2D cell lines, our organoid model holds great potential for further investigations.


Asunto(s)
Hipertermia Inducida , Fenómenos Magnéticos , Organoides/patología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Adenocarcinoma/patología , Adenocarcinoma/terapia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Muerte Celular , Línea Celular Tumoral , Supervivencia Celular , Células Clonales , Humanos , Pronóstico
2.
Anticancer Res ; 41(5): 2543-2552, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33952482

RESUMEN

BACKGROUND/AIM: Maspin is a tumor-suppressor protein expressed in >90% of pancreatic ductal adenocarcinoma (PDAC) cases. We aimed to assess the prognostic value of subcellular localization of maspin. PATIENTS AND METHODS: Ninety-two resected PDAC specimens were immunohistochemically analyzed. Cytoplasmic-only expression observed in >10% of the tumor was defined as maspin-positive. RESULTS: The maspin-positive status (21.7%) was inversely correlated with well-differentiated histological type and indicated a shorter recurrence-free survival (RFS) and overall survival (OS). Cox's multivariate analysis showed that maspin-positive status was an independent factor for shorter RFS and OS. Maspin was localized to cytoplasm in AsPC-1 cells, but to both nucleus and cytoplasm in BxPC-3 cells. In AsPC-1 cells, cell invasion was significantly reduced in response to maspin suppression via transfection with siRNA targeting maspin, whereas no reduction was observed in BxPC-3 cells. CONCLUSION: Cytoplasmic-only expression of maspin could be an independent unfavorable prognostic indicator for patients with PDAC.


Asunto(s)
Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Carcinoma Ductal Pancreático/genética , Serpinas/genética , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Anciano , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular/genética , Citoplasma/efectos de los fármacos , Citoplasma/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/inmunología , Serpinas/inmunología
3.
World J Surg Oncol ; 19(1): 126, 2021 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-33866970

RESUMEN

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis. Radical surgery is the best option for cure and, nowadays, it is performed by many surgeons also in cases of vascular infiltration. Whether this aggressive approach to a locally advanced PDAC produces a survival benefit is under debate. Most data in the literature come from retrospective comparative studies; therefore, it is still unclear if such an extensive surgery for an advanced cancer is justified. METHODS: A retrospective review of patients with PDAC treated at our institution over a 12-year period was performed. Data concerning patients' characteristics, operative details, postoperative course, and long-term survival were retrieved from prospective databases and analysed. Factors associated with poor survival were assessed via Cox regression analysis. RESULTS: A total of 173 patients with PDAC were included in the analysis, 41 subjects underwent pancreatectomy with vascular resection for locally advanced disease, and in 132 patients, only a pancreatic resection was undertaken. Demographics, major comorbidities, and tumour characteristics were similar between the two groups. Length of surgery (P=0.0006), intraoperative blood transfusions (P<0.0001), and overall complications (P<0.0001) were significantly higher in the vascular resection group. Length of hospital stay (P=0.684) and 90-day mortality (P=0.575) were comparable between groups. Overall median survival (P= 0.717) and survival rates at 1, 3, and 5 years (P=0.964, P=0.500, and P=0.445, respectively) did not differ significantly between groups. Age ≥70 years and postoperative complications were independent predictors of lower survival. CONCLUSIONS: Our study confirms that pancreatectomy with vascular resection for a locally advanced PDAC is a complex operation associated with a significant longer operating time that may increase morbidity; however, in selected patients, R0 margins can be obtained with an acceptable long-term survival rate. Older patients are less likely to benefit from surgery.


Asunto(s)
Carcinoma Ductal Pancreático/cirugía , Pancreatectomía/métodos , Neoplasias Pancreáticas/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pancreatectomía/mortalidad , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Complicaciones Posoperatorias , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Tasa de Supervivencia , Sobrevivientes
4.
Anticancer Res ; 41(4): 1733-1744, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813377

RESUMEN

BACKGROUND/AIM: We sought to identify the mechanisms of perineural invasion in pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: We utilized in vitro cancer cell-nerve co-culture models comprising human PDAC cell lines (MIA Paca2 and PANC-1) and a dorsal root ganglion (DRG) isolated from neonatal mice. We compared gene expression profiles between cell lines with/without DRG conditioned medium (DRG-CM) using RNA-sequencing (RNA-seq). RESULTS: Migration, invasion, and neurotropism were significantly enhanced in MIA Paca2 but not in PANC-1 cells co-cultured with DRGs. Among 285 genes which showed significant differences in expression levels between cell lines in RNA-seq, we focused on Ephrin receptor A4 (EPHA4), which was upregulated in MIA Paca2 cells treated with DRG-CM. The abilities of migration, invasion, and neurotropism enhanced by DRG co-culture were abolished when EPHA4 was knocked down by siRNA in MIA Paca2 cells. CONCLUSION: EPHA4 can be a potential target gene to regulate perineural invasion in PDAC cells.


Asunto(s)
Carcinoma Ductal Pancreático/metabolismo , Movimiento Celular , Ganglios Espinales/metabolismo , Neoplasias Pancreáticas/metabolismo , Comunicación Paracrina , Receptor EphA4/metabolismo , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Técnicas de Cocultivo , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Endogámicos ICR , Invasividad Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Receptor EphA4/genética , Transducción de Señal
5.
BMC Cancer ; 21(1): 385, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33836674

RESUMEN

BACKGROUND: Herein, we investigate the relationship between pancreatic stem cell markers (PCSC markers), CD44, and epithelial-specific antigen (ESA), tumor stroma, and the impact on recurrence outcomes in pancreatic ductal adenocarcinoma (PDAC) patients. METHODS: PDAC patients who underwent surgical resection between 01/2012-06/2014 were identified. CD44 and ESA expression was assessed by immunohistochemistry. Stroma was classified as loose, moderate, and dense based on fibroblast content. Overall survival (OS) and relapse-free survival (RFS) were estimated using the Kaplan-Meier method and compared between subgroups by log-rank test. The association between PCSC markers and stroma type was assessed by Fisher's exact test. RESULTS: N = 93 PDAC patients were identified. The number of PDAC patients with dense, moderate density, and loose stroma was 11 (12%), 51 (54%), and 31 (33%) respectively. PDAC with CD44+/ESA- had highest rate of loose stroma (63%) followed by PDAC CD44+/ESA+ (50%), PDAC CD44-/ESA+ (35%), CD44-/ESA- (9%) (p = 0.0033). Conversely, lack of CD44 and ESA expression was associated with the highest rate of moderate and dense stroma (91% p = 0.0033). No local recurrence was observed in patients with dense stroma and 9 had distant recurrence. The highest rate of cumulative local recurrence was observed in patients with loose stroma. No statistically significant difference in RFS and OS was observed among subgroups (P = 0.089). CONCLUSIONS: These data indicate PCSCs may have an important role in stroma differentiation in PDAC. Our results further suggest that tumor stroma may influence the recurrence pattern in PDAC patients.


Asunto(s)
Fibroblastos Asociados al Cáncer/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Células Madre Neoplásicas/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Células del Estroma/metabolismo , Biomarcadores , Fibroblastos Asociados al Cáncer/patología , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/terapia , Terapia Combinada , Femenino , Humanos , Inmunohistoquímica , Masculino , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Células Madre Neoplásicas/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Pronóstico , Recurrencia , Células del Estroma/patología , Resultado del Tratamiento , Microambiente Tumoral
6.
Nat Commun ; 12(1): 2328, 2021 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-33879793

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) has a collagen-rich dense extracellular matrix (ECM) that promotes malignancy of cancer cells and presents a barrier for drug delivery. Data analysis of our published mass spectrometry (MS)-based studies on enriched ECM from samples of progressive PDAC stages reveal that the C-terminal prodomains of fibrillar collagens are partially uncleaved in PDAC ECM, suggesting reduced procollagen C-proteinase activity. We further show that the enzyme responsible for procollagen C-proteinase activity, bone morphogenetic protein1 (BMP1), selectively suppresses tumor growth and metastasis in cells expressing high levels of COL1A1. Although BMP1, as a secreted proteinase, promotes fibrillar collagen deposition from both cancer cells and stromal cells, only cancer-cell-derived procollagen cleavage and deposition suppresses tumor malignancy. These studies reveal a role for cancer-cell-derived fibrillar collagen in selectively restraining tumor growth and suggest stratification of patients based on their tumor epithelial collagen I expression when considering treatments related to perturbation of fibrillar collagens.


Asunto(s)
Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Colágenos Fibrilares/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Animales , Proteína Morfogenética Ósea 1/metabolismo , Carcinoma Ductal Pancreático/secundario , Línea Celular Tumoral , Colágeno Tipo I/química , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Progresión de la Enfermedad , Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Colágenos Fibrilares/química , Colágenos Fibrilares/genética , Humanos , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Mutagénesis , Neoplasias Pancreáticas/genética , Procolágeno/química , Procolágeno/genética , Procolágeno/metabolismo , Dominios Proteicos , ARN Mensajero/genética , ARN Mensajero/metabolismo
7.
Int J Mol Sci ; 22(8)2021 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-33921242

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Present-day treatments have not shown real improvements in reducing the high mortality rate and the short survival of the disease. The average survival is less than 5% after 5 years. New innovative treatments are necessary to curtail the situation. The very dense pancreatic cancer stroma is a barrier that impedes the access of chemotherapeutic drugs and at the same time establishes a pro-proliferative symbiosis with the tumor, thus targeting the stroma has been suggested by many authors. No ideal drug or drug combination for this targeting has been found as yet. With this goal in mind, here we have explored a different complementary treatment based on abundant previous publications on repurposed drugs. The cell surface protein CD44 is the main receptor for hyaluronan binding. Many malignant tumors show over-expression/over-activity of both. This is particularly significant in pancreatic cancer. The independent inhibition of hyaluronan-producing cells, hyaluronan synthesis, and/or CD44 expression, has been found to decrease the tumor cell's proliferation, motility, invasion, and metastatic abilities. Targeting the hyaluronan-CD44 pathway seems to have been bypassed by conventional mainstream oncological practice. There are existing drugs that decrease the activity/expression of hyaluronan and CD44: 4-methylumbelliferone and bromelain respectively. Some drugs inhibit hyaluronan-producing cells such as pirfenidone. The association of these three drugs has never been tested either in the laboratory or in the clinical setting. We present a hypothesis, sustained by hard experimental evidence, suggesting that the simultaneous use of these nontoxic drugs can achieve synergistic or added effects in reducing invasion and metastatic potential, in PDAC. A non-toxic, low-cost scheme for inhibiting this pathway may offer an additional weapon for treating pancreatic cancer.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Receptores de Hialuranos/genética , Hialuronano Sintasas/genética , Ácido Hialurónico/genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Bromelaínas/uso terapéutico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Receptores de Hialuranos/antagonistas & inhibidores , Hialuronano Sintasas/antagonistas & inhibidores , Ácido Hialurónico/antagonistas & inhibidores , Himecromona/uso terapéutico , Terapia Molecular Dirigida , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia , Piridonas/farmacología , Piridonas/uso terapéutico , Transducción de Señal/efectos de los fármacos
8.
J Surg Oncol ; 123(6): 1475-1488, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33831245

RESUMEN

Metastatic pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related mortality in 2021. Cytotoxic therapies are the therapeutic mainstay for PDAC. The recent approval of olaparib as maintenance therapy for germline BRCA1/2-mutated PDAC and pembrolizumab for mismatch repair deficient PDAC represent molecularly targeted approaches for this disease. Investigational therapeutic strategies include targeting the stroma, metabolism, tumor microenvironment, and the immune system, and selected approaches are reviewed herein.


Asunto(s)
Carcinoma Ductal Pancreático/terapia , Neoplasias Pancreáticas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/patología , Ensayos Clínicos como Asunto , Humanos , Inmunoterapia , Metástasis de la Neoplasia , Neoplasias Pancreáticas/patología , Ensayos Clínicos Controlados Aleatorios como Asunto
9.
J Surg Oncol ; 123(6): 1395-1404, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33831247

RESUMEN

The annual incidence of pancreatic cancer is nearly 50,000 patients. The 5-year overall survival is only 9%, and there remains a great need for better therapy. A subset of these patients presents with locally advanced disease. Multidisciplinary therapy has evolved to include some combination of systemic chemotherapy, locoregional radiation, and surgery in select patients with excellent biology. This review will address the thoughtful evidence-based and individualized approach to these patients.


Asunto(s)
Carcinoma Ductal Pancreático/terapia , Neoplasias Pancreáticas/terapia , Albúminas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/cirugía , Quimioradioterapia , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Manejo de la Enfermedad , Medicina Basada en la Evidencia , Fluorouracilo/administración & dosificación , Humanos , Irinotecán/administración & dosificación , Leucovorina/administración & dosificación , Terapia Neoadyuvante , Oxaliplatino/administración & dosificación , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Medicina de Precisión
10.
Medicine (Baltimore) ; 100(16): e25466, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879679

RESUMEN

RATIONALE: Endoscopic ultrasonography-guided tissue acquisition (EUS-TA) has become the norm for the diagnosis of pancreatic solid lesions. EUS-TA is relatively safe, but various complications can occur. Infected pancreatic necrosis (IPN) is a rare but serious complication. The latest guidelines suggest that all invasive interventions in patients with IPN should be delayed until walled-off necrosis appears. PATIENT CONCERNS: A 73-year-old man was referred to our hospital with double primary cancers including gallbladder and pancreas. We performed EUS-TA on metastatic pancreatic tail cancer to confirm histologic diagnosis. Six days after the procedure, he developed abdominal pain and fever. DIAGNOSES: The patient's laboratory findings showed leukocytosis and C-reactive protein elevation. Fluid collection around pancreas tail and stomach was detected in computed tomography (CT) scan, and the patient was diagnosed with IPN. INTERVENTIONS AND OUTCOMES: EUS-guided endoscopic transmural drainage (EUS-TD) was performed for the treatment of IPN. Two days after the procedure with antibiotics, his CRP level decreased abruptly, and he received chemotherapy for the treatment of pancreatic ductal adenocarcinoma (PDAC) 5 days after the procedure. He was discharged from our hospital without complications 15 days after chemotherapy. LESSONS: In selected patients with PDAC, early endoscopic drainage may be recommended as treatment for IPN resulting from complications of EUS-TA.


Asunto(s)
Carcinoma Ductal Pancreático/diagnóstico , Drenaje/métodos , Neoplasias Pancreáticas/diagnóstico , Pancreatitis Aguda Necrotizante/cirugía , Complicaciones Posoperatorias/cirugía , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia/efectos adversos , Biopsia/métodos , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Drenaje/instrumentación , Endosonografía/efectos adversos , Endosonografía/instrumentación , Endosonografía/métodos , Fluorouracilo/uso terapéutico , Humanos , Irinotecán/uso terapéutico , Leucovorina/uso terapéutico , Masculino , Oxaliplatino/uso terapéutico , Páncreas/diagnóstico por imagen , Páncreas/patología , Páncreas/cirugía , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Pancreatitis Aguda Necrotizante/diagnóstico , Pancreatitis Aguda Necrotizante/etiología , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Stents , Resultado del Tratamiento , Ultrasonografía Intervencional/efectos adversos , Ultrasonografía Intervencional/métodos
11.
Cancer Treat Rev ; 96: 102180, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33812339

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with a dismal prognosis. The lack of symptoms in the early phase of the disease makes early diagnosis challenging, and about 80-85% of the patients are diagnosed only after the disease is locally advanced or metastatic. The current front-line treatment landscape in local stages comprises surgical resection and adjuvant chemotherapy. In Switzerland, although both FOLFIRINOX and gemcitabine plus nab-paclitaxel regimens are feasible and comparable in the first-line setting, FOLFIRINOX is preferred in the treatment of fit (Eastern Cooperative Oncology Group [ECOG] performance status [PS]: 0-1), young (<65 years old) patients with few comorbidities and normal liver function, while gemcitabine plus nab-paclitaxel is used to treat less fit (ECOG PS: 1-2) and more vulnerable patients. In the second-line setting of advanced PDAC, there is currently only one approved regimen, based on the phase III NAPOLI-1 trial. Furthermore, the use of liposomal-irinotecan in the second line is supported by real-world data. Beyond the standard of care, various alternative treatment modalities are being explored in clinical studies. Immunotherapy has demonstrated only limited benefits until now, and only in cases of high microsatellite instability (MSI-H). However, data on the benefit of poly (ADP-ribose) polymerase (PARP) inhibition as maintenance therapy in patients with germline BRCA-mutated tumors might signal of an advance in targeted therapy. Currently, there is a lack of molecular and genetic biomarkers for optimal stratification of patients and in guiding treatment decisions. Thus, identification of predictive and prognostic biomarkers and evaluating novel treatment strategies are equally relevant for improving the prognosis of metastatic pancreatic cancer patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Albúminas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/cirugía , Ensayos Clínicos Fase III como Asunto , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Fluorouracilo/administración & dosificación , Humanos , Irinotecán/administración & dosificación , Leucovorina/administración & dosificación , Liposomas/administración & dosificación , Metástasis de la Neoplasia , Oxaliplatino/administración & dosificación , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Ensayos Clínicos Controlados Aleatorios como Asunto
12.
Molecules ; 26(9)2021 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-33923185

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a 5-year survival rate of <8%. Therefore, finding new treatment strategies against PDAC cells is an imperative issue. Betulinic acid (BA), a plant-derived natural compound, has shown great potential to combat cancer owing to its versatile physiological functions. In this study, we observed the impacts of BA on the cell viability and migratory ability of PDAC cell lines, and screened differentially expressed proteins (DEPs) by an LC-MS/MS-based proteomics analysis. Our results showed that BA significantly inhibited the viability and migratory ability of PDAC cells under a relatively low dosage without affecting normal pancreatic cells. Moreover, a functional analysis revealed that BA-induced downregulation of protein clusters that participate in mitochondrial complex 1 activity and oxidative phosphorylation, which was related to decreased expressions of RNA polymerase mitochondrial (POLRMT) and translational activator of cytochrome c oxidase (TACO1), suggesting that the influence on mitochondrial function explains the effect of BA on PDAC cell growth and migration. In addition, BA also dramatically increased Apolipoprotein A1 (APOA1) expression and decreased NLR family CARD domain-containing protein 4 (NLRC4) expression, which may be involved in the dampening of PDAC migration. Notably, altered expression patterns of APOA1 and NLRC4 indicated a favorable clinical prognosis of PDAC. Based on these findings, we identified potential proteins and pathways regulated by BA from a proteomics perspective, which provides a therapeutic window for PDAC.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Triterpenos Pentacíclicos/farmacología , Proteoma/genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Biomarcadores de Tumor/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Fosforilación Oxidativa/efectos de los fármacos , Proteoma/efectos de los fármacos , Proteómica/métodos , Espectrometría de Masas en Tándem
13.
Anticancer Res ; 41(3): 1401-1406, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788731

RESUMEN

BACKGROUND/AIM: Pancreatic ductal adenocarcinoma is one of the deadliest forms of human cancer. Since only a vast panel of cell lines can fully recapitulate disease heterogeneity, our aim was to establish a new pancreatic cancer cell line. MATERIALS AND METHODS: Newly established pancreatic ductal adenocarcinoma cell line Capan-26 was characterized by assessing growth rate, tumor and stem cell marker expression, colony forming efficiency, mutations of KRAS and TP53 genes, karyotype and sensitivity to drug treatment. RESULTS: Cell doubling time was 74 h. We detected CA19-9, CEACAM6, CD44, OCT4 and ZEB1 expression in Capan-26 cell line. Cells formed colonies in soft agar, have a deletion of KRAS exon 3 and a point mutation V172F in TP53 exon 5. They are a mixed aneuploid/polyploid population with high sensitivity to gemcitabine. CONCLUSION: Capan-26 is a unique cell line that may be used to study the mechanism of pancreatic cancer.


Asunto(s)
Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/patología , Anciano , Antígenos CD/genética , Antígenos CD/metabolismo , Antimetabolitos Antineoplásicos/farmacología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Femenino , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Cariotipificación , Mutación , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína p53 Supresora de Tumor/genética
14.
Anticancer Res ; 41(3): 1629-1639, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788759

RESUMEN

BACKGROUND/AIM: An association between the pathological response to neoadjuvant chemotherapy (NAC) and the efficacy of adjuvant chemotherapy (AC) in patients with pancreatic ductal adenocarcinoma (PDAC) remains unknown. PATIENTS AND METHODS: A total of 121 patients with PDAC who underwent a pancreatectomy between January 2013 and March 2020 were divided into two groups: an upfront surgery (UFS) group (n=42), and an NAC (gemcitabine plus S-1) group (n=79). In the NAC group, the pathological response was evaluated using the Evans classification. RESULTS: The overall survival was significantly higher in patients with an AC relative dose intensity (RDI) ≥80% than in patients with an AC RDI <80% in the UFS, NAC-Evans IIa, and NAC-Evans IIb+III groups. However, this difference was not observed in the NAC-Evans I group. CONCLUSION: AC is preferable for patients with NAC-Evans IIa or IIb+III, but more effective AC regimens may be needed for NAC-Evans I patients.


Asunto(s)
Carcinoma Ductal Pancreático/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Quimioterapia Adyuvante , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Estudios Retrospectivos
15.
Nat Commun ; 12(1): 1541, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750829

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked desmoplasia and drug resistance due, in part, to poor drug delivery to extravascular tumor tissue. Here, we report that carcinoma-associated fibroblasts (CAFs) induce ß5 integrin expression in tumor cells in a TGF-ß dependent manner, making them an efficient drug delivery target for the tumor-penetrating peptide iRGD. The capacity of iRGD to deliver conjugated and co-injected payloads is markedly suppressed when ß5 integrins are knocked out in the tumor cells. Of note, ß5 integrin knock-out in tumor cells leads to reduced disease burden and prolonged survival of the mice, demonstrating its contribution to PDAC progression. iRGD significantly potentiates co-injected chemotherapy in KPC mice with high ß5 integrin expression and may be a powerful strategy to target an aggressive PDAC subpopulation.


Asunto(s)
Cadenas beta de Integrinas/genética , Cadenas beta de Integrinas/metabolismo , Neoplasias Pancreáticas/metabolismo , Animales , Fibroblastos Asociados al Cáncer , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Sistemas de Liberación de Medicamentos , Quimioterapia , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos C57BL , Oligopéptidos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Microambiente Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto
16.
BMC Cancer ; 21(1): 237, 2021 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-33676427

RESUMEN

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal cancers, is driven by oncogenic KRAS mutations. Farnesyl thiosalicylic acid (FTS), also known as salirasib, is a RAS inhibitor that selectively dislodges active RAS proteins from cell membrane, inhibiting downstream signaling. FTS has demonstrated limited therapeutic efficacy in PDAC patients despite being well tolerated. METHODS: To improve the efficacy of FTS in PDAC, we performed a genome-wide CRISPR synthetic lethality screen to identify genetic targets that synergize with FTS treatment. Among the top candidates, multiple genes in the endoplasmic reticulum-associated protein degradation (ERAD) pathway were identified. The role of ERAD inhibition in enhancing the therapeutic efficacy of FTS was further investigated in pancreatic cancer cells using pharmaceutical and genetic approaches. RESULTS: In murine and human PDAC cells, FTS induced unfolded protein response (UPR), which was further augmented upon treatment with a chemical inhibitor of ERAD, Eeyarestatin I (EerI). Combined treatment with FTS and EerI significantly upregulated the expression of UPR marker genes and induced apoptosis in pancreatic cancer cells. Furthermore, CRISPR-based genetic ablation of the key ERAD components, HRD1 and SEL1L, sensitized PDAC cells to FTS treatment. CONCLUSION: Our study reveals a critical role for ERAD in therapeutic response of FTS and points to the modulation of UPR as a novel approach to improve the efficacy of FTS in PDAC treatment.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Degradación Asociada con el Retículo Endoplásmico/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Sistemas CRISPR-Cas/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Degradación Asociada con el Retículo Endoplásmico/genética , Farnesol/análogos & derivados , Farnesol/farmacología , Farnesol/uso terapéutico , Técnicas de Inactivación de Genes , Humanos , Hidrazonas/farmacología , Hidrazonas/uso terapéutico , Hidroxiurea/análogos & derivados , Hidroxiurea/farmacología , Hidroxiurea/uso terapéutico , Ratones , Neoplasias Pancreáticas/patología , Proteínas/genética , Salicilatos/farmacología , Salicilatos/uso terapéutico , Mutaciones Letales Sintéticas , Ubiquitina-Proteína Ligasas/genética , Respuesta de Proteína Desplegada/efectos de los fármacos
17.
Nat Commun ; 12(1): 1482, 2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33674596

RESUMEN

Immune evasion is a hallmark of KRAS-driven cancers, but the underlying causes remain unresolved. Here, we use a mouse model of pancreatic ductal adenocarcinoma to inactivate KRAS by CRISPR-mediated genome editing. We demonstrate that at an advanced tumor stage, dependence on KRAS for tumor growth is reduced and is manifested in the suppression of antitumor immunity. KRAS-deficient cells retain the ability to form tumors in immunodeficient mice. However, they fail to evade the host immune system in syngeneic wild-type mice, triggering strong antitumor response. We uncover changes both in tumor cells and host immune cells attributable to oncogenic KRAS expression. We identify BRAF and MYC as key mediators of KRAS-driven tumor immune suppression and show that loss of BRAF effectively blocks tumor growth in mice. Applying our results to human PDAC we show that lowering KRAS activity is likewise associated with a more vigorous immune environment.


Asunto(s)
Evasión Inmune/fisiología , Modelos Genéticos , Neoplasias Pancreáticas/inmunología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Edición Génica , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Desnudos , Conductos Pancreáticos/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/inmunología , Transcriptoma
19.
Br J Surg ; 108(2): 119-127, 2021 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-33711148

RESUMEN

BACKGROUND: Preoperative chemo(radio)therapy is used increasingly in pancreatic cancer. Histological evaluation of the tumour response provides information on the efficacy of preoperative treatment and is used to determine prognosis and guide decisions on adjuvant treatment. This systematic review aimed to provide an overview of the current evidence on tumour response scoring systems in pancreatic cancer. METHODS: Studies reporting on the assessment of resected pancreatic ductal adenocarcinoma following neoadjuvant chemo(radio)therapy were searched using PubMed and EMBASE. All original studies reporting on histological tumour response in relation to clinical outcome (survival, recurrence-free survival) or interobserver agreement were eligible for inclusion. This systematic review followed the PRISMA guidelines. RESULTS: The literature search yielded 1453 studies of which 25 met the eligibility criteria, revealing 13 unique scoring systems. The most frequently investigated tumour response scoring systems were the College of American Pathologists system, Evans scoring system, and MD Anderson Cancer Center system, investigated 11, 9 and 5 times respectively. Although six studies reported a survival difference between the different grades of these three systems, the reported outcomes were often inconsistent. In addition, 12 of the 25 studies did not report on crucial aspects of pathological examination, such as the method of dissection, sampling approach, and amount of sampling. CONCLUSION: Numerous scoring systems for the evaluation of tumour response after preoperative chemo(radio)therapy in pancreatic cancer exist, but comparative studies are lacking. More comparative data are needed on the interobserver variability and prognostic significance of the various scoring systems before best practice can be established.


Asunto(s)
Carcinoma Ductal Pancreático/cirugía , Quimioradioterapia Adyuvante , Terapia Neoadyuvante , Neoplasias Pancreáticas/cirugía , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/terapia , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Resultado del Tratamiento
20.
Medicine (Baltimore) ; 100(12): e24957, 2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33761652

RESUMEN

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is 1 of the highly fatal and most aggressive types of malignancies and accounts for the vast majority of Pancreatic Cancer. Numerous studies have reported that the tumor microenvironment (TME) was significantly correlated with the oncogenesis, progress, and prognosis of various malignancies. Therefore, mining of TME-related genes is reasonably important to improve the overall survival of patients with PDAC.The Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data algorithm was applied to identify differential expressed genes. Functional and pathway enrichment analyses, protein-protein interaction network construction and module analysis, overall survival analysis and tumor immune estimation resource database analysis were then performed on differential expressed genes.Data analysis indicated that higher immune scores were correlated with better overall survival (P = 0.033). Differential expression analysis obtained 90 intersection genes influencing both stromal and immune scores. Among these intersection genes, CA9, EBI3, SPOCK2, WDFY4, CD1D, and CCL22 were significantly correlated with overall survival in PDAC patients. Moreover, multivariate Cox analysis revealed that CA9, SPOCK2, and CD1D were the most significant prognostic genes, and were closely correlated with immune infiltration in TCGA cohort. Further analysis indicated that CD1D were significantly related with immune cell biomarkers for PDAC patients.In summary, our findings provide a more comprehensive insight into TME and show a list of prognostic immune associated genes in PDAC. However, further studies on these genes need to be performed to gain additional understanding of the association between TME and prognosis in PDAC.


Asunto(s)
Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/inmunología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Algoritmos , Antígenos CD1d/genética , Antígenos de Neoplasias/genética , Biomarcadores de Tumor , Anhidrasa Carbónica IX/genética , Carcinoma Ductal Pancreático/patología , Regulación Neoplásica de la Expresión Génica , Marcadores Genéticos , Humanos , Estimación de Kaplan-Meier , Estadificación de Neoplasias , Neoplasias Pancreáticas/patología , Pronóstico , Modelos de Riesgos Proporcionales , Mapas de Interacción de Proteínas/genética , Proteoglicanos/genética
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