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1.
Transl Oncol ; 47: 102044, 2024 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-38917592

RESUMEN

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis, wherefore targeted therapies have experienced increasing interest. Zolbetuximab is a novel targeted therapy under investigation in patients with PDAC and targets Claudin 18.2 (CLDN18.2), which is a component of tight junctions and is of significance in various solid tumors. As its role in PDAC is not definitively elucidated, this study aims to clarify the significance of CLDN18.2 expression in PDAC in a real-world setting. METHODS: All patients (n = 309) were recruited at one of the PANCALYZE study centers and received pancreatic resection with curative intention. Paraffin samples were analyzed using an antibody against CLDN18.2, which is known to be comparable to the antibody used by the SPOTLIGHT and GLOW studies. RESULTS: 94 PDACs are positive for CLDN18.2 (30.4 %). Positive CLDN 18.2 expression was associated with significantly better cancer differentiation (p < 0.001). Patients with positive CLDN18.2 expression showed significantly better overall survival when compared to patients with negative expression (median OS: 30 versus 18 months, p = 0.003). Additionally, in multivariable analyses, CLDN18.2 expression was identified as an independent factor for better survival in patients with PDAC (HR = 0.686, 95 %CI = 0.492-0.956, p = 0.026). CONCLUSION: Significant improvement in survival could be demonstrated by adding Zolbetuximab to known chemotherapy regimes in patients with gastro-esophageal junction adenocarcinoma with at least 75 % CLDN18.2 positive cancer cells. Our findings demonstrate, that 30.4 % of the included patients with PDAC would potentially be eligible for therapy with Zolbetuximab in a real-world patient cohort. Results of trials targeting Claudin 18.2 are pending in patients with PDAC.

2.
Surgery ; 2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-38944588

RESUMEN

BACKGROUND: Multimodal therapy regimens became the standard of care for patients with esophageal cancer, whereas surgical resection remains at the center of curative treatment modalities. Current guidelines provide no recommendations on the extent of the oral resection margin, especially in the era of neoadjuvant therapy. Therefore, this study aimed to evaluate the relationship between the oral tumor-free resection margin and overall survival. METHODS: Retrospective study with 382 1:1 propensity-matched patients out of 660 patients, operated between 2013 and 2019, with an Ivor-Lewis-esophagectomy for adenocarcinoma and squamous cell carcinoma of the esophagus or esophagogastric junction after neoadjuvant therapy. Independent pathologists measured the oral resection margin after formalin fixation. RESULTS: The mean oral tumor-free resection margin was 37.2 ± 0.6 mm. The ideal cut-off for survival differences was determined for 33 mm. Patients with an oral resection margin of more than 33 mm had a better median overall survival (≤33 mm: 45.0 months, 95% confidence interval: 22.4-67.6 months, >33 mm: not reached, P = .005). An oral resection margin of more than 33 mm proved to be an independent favorable prognostic factor for patients' overall survival in multivariate Cox regression analyses (P = .049). CONCLUSION: This study analyzed a patient cohort retrospectively after curative intended Ivor-Lewis-esophagectomy after neoadjuvant therapy. An oral resection margin of more than 33 mm is a factor for improved overall survival. Therefore, a minimum resection margin of 34 mm after fixation could be suggested.

3.
BJS Open ; 8(3)2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38814750

RESUMEN

BACKGROUND: In contrast to the well-established multimodal therapy for localized oesophageal cancer, the metastatic stage is commonly treated only with systemic therapy as current international guidelines recommend. However, evidence suggesting that multimodal therapy including surgery could benefit selected patients with metastasized oesophageal cancer is increasing. The aim of this study was to investigate the survival of patients diagnosed with metastatic oesophageal cancer after different treatment regimens. METHODS: This was a retrospective single-centre study of patients with adenocarcinoma or squamous cell carcinoma of the oesophagus with synchronous or metachronous metastases who underwent Ivor Lewis oesophagectomy between 2010 and 2021. Each patient received an individual treatment for their metastatic burden based on an interdisciplinary tumour board conference. Survival differences between different treatments were assessed using the Kaplan-Meier method, as well as univariable and multivariable Cox regression models. RESULTS: Out of 1791 patients undergoing Ivor Lewis oesophagectomy, 235 patients diagnosed with metastases were included. Of all of the included patients, 42 (17.9%) only underwent surgical resection of their metastatic disease, 37 (15.7%) underwent multimodal therapy including surgery, 78 (33.2%) received chemotherapy alone, 49 (20.9%) received other therapies, and 29 (12.3%) received best supportive care. Patients who underwent resection or multimodal therapy including surgery of their metastatic burden showed superior overall survival compared with chemotherapy alone (median overall survival of 19.0, 18.0, and 11.0 months respectively) (P < 0.001). This was confirmed in subcohorts of patients with metachronous solid-organ metastases and with a single metastasis. In multivariable analyses, resection with or without multimodal therapy was an independent factor for favourable survival. CONCLUSION: Surgical resection could be a feasible treatment option for metastasized oesophageal cancer, improving survival in selected patients. Further prospective randomized studies are needed to confirm these findings and define reliable selection criteria.


Asunto(s)
Adenocarcinoma , Neoplasias Esofágicas , Esofagectomía , Humanos , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Terapia Combinada , Adenocarcinoma/terapia , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Adenocarcinoma/patología , Estimación de Kaplan-Meier , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/patología , Modelos de Riesgos Proporcionales
4.
World J Surg ; 48(6): 1414-1423, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38554145

RESUMEN

PURPOSE: Patients with local recurrence of esophageal cancer have a highly decreased overall survival. There is currently no standardized treatment algorithm for this group. This retrospective cohort study aimed to evaluate the survival of patients with local recurrence, despite receiving individualized treatment options. METHODS: 241 of 1791 patients were diagnosed with a local recurrence following Ivor-Lewis esophagectomy at the University Hospital of Cologne. 59 patients, who were diagnosed only with a local recurrence of adeno- or squamous cell carcinoma and received their individualized therapy regimes at our high-volume center, were included. RESULTS: The study included 52 patients with adenocarcinoma and 7 with squamous cell carcinoma. Among these, 6 patients underwent resection, 19 received solely chemotherapy, 29 received chemoradiotherapy, and 5 were provided with best supportive care. Patients who underwent resection showed a better survival outcome compared to patients without resection (median OS: not reached vs. 15.1 months, p = 0.012). Best supportive care and palliative care were found to be independent risk factors for shorter overall survival compared to curative intended treatment options like local resection or chemoradiotherapy. CONCLUSION: In this study, different treatment strategies for patients with local recurrence of esophageal cancer were depicted. Resection as well as chemoradiotherapy could play a role in selected patients. Further prospective studies are needed to improve the selection of eligible patients.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Esofagectomía , Hospitales de Alto Volumen , Recurrencia Local de Neoplasia , Humanos , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Esofagectomía/métodos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Hospitales de Alto Volumen/estadística & datos numéricos , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Adenocarcinoma/terapia , Adenocarcinoma/cirugía , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Quimioradioterapia/métodos , Resultado del Tratamiento , Adulto
5.
J Cancer Res Clin Oncol ; 150(3): 137, 2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38502354

RESUMEN

PURPOSE: Patients with pancreatic ductal adenocarcinoma (PDAC) have yet to experience significant benefits from targeted therapy. Olaparib is currently the only active substance in BRCA-mutated PDACs that successfully influences the DNA repair of carcinoma cells. H2AX belongs to the histone family and is known as a part of the DNA repair system. The inhibition of γ-H2AX could lead to the inhibition of mitotically active tumor cells. Therefore, we aimed to evaluate the predictive value of the γ-H2AX in patients with PDAC. METHODS: All included patients (n = 311) received a pancreatic resection with curative intention in one of our PANCALYZE study centers. Subsequently, they were enrolled in a standardized follow-up protocol. Immunohistochemical stainings for γ-H2AX were conducted on tissue microarrays. RESULTS: Patients exhibiting high levels of γ-H2AX expression experience more frequent R1 resections, indicating advanced tumor stages in this subgroup. Additionally, patients with high γ-H2AX expression demonstrated significantly poorer survival compared to those with low expression (median OS: 15 vs. 25 months, p < 0.001). In multivariate analyses, high γ-H2AX expression could be identified as an independent risk factor for worse patient survival. Moreover, high γ-H2AX expression could be more frequently observed in the more aggressive basal-like subtype. CONCLUSION: γ-H2AX can be characterized as a predictive biomarker for poorer patient survival. Consequently, upcoming clinical trials focused on the efficacy of targeted therapies influencing the DNA repair system and radiotherapy should evaluate γ-H2AX as a potential biomarker for therapy response. Furthermore, γ-H2AX may serve as a viable target for treatment in the future.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Histonas/genética , Histonas/metabolismo , Regulación hacia Arriba , Pronóstico , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/patología , Biomarcadores
6.
Front Cell Dev Biol ; 12: 1337361, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38328551

RESUMEN

Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rapidly increasing in high income countries due to its association with persistent high-risk human papilloma virus (HPV) infection. Recent scientific advances have highlighted the importance of the tumor microenvironment in OPSCC. In this study, including 216 OPSCC patients, we analyze the composition of four established markers of cancer associated fibroblasts (CAFs) in the context of intratumoral CD8 T-cell infiltration. Methods: Immunohistochemical staining for fibroblast activation protein (FAP), platelet-derived growth factor receptor beta (PDGFRb), periostin, alpha smooth muscle actin (α-SMA) and CD8 were analyzed digitally and their association with survival, tumor- and patient characteristics was assessed. Results: Co-expression of CAF markers was frequent but not associated with HPV status. FAPhigh and PDGFRbhigh expression were associated with increased CD8 T-cell infiltration. Low expression of PDGFRb improved patient survival in female patients but not in male patients. We identified PDGFRblow periostinlow α-SMAlow status as an independent predictor of improved survival (hazard ratio 0.377, p = 0.006). Conclusion: These findings elucidate the co-expression of four established CAF markers in OPSCC and underscore their association with T-cell infiltration and patient survival. Future analyses of CAF subgroups in OPSCC may enable the development of individualized therapies.

7.
Sci Rep ; 13(1): 17699, 2023 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-37848472

RESUMEN

Esophageal adenocarcinoma exhibits one of the highest mortality rates among all cancer entities. Multimodal therapy strategies have improved patients' survival significantly. However, patients in early stages are currently limited to receiving only local therapies, even though some patients within this group showcase short survival periods. Until now, there has been no widely established clinically used biomarker to detect these high-risk patients. Telomerase reverse transcriptase (TERT), a gene encoding a crucial subunit of the telomerase enzyme, plays a significant role in establishing cancer cell immortality and is under suspicion for its potential contribution to tumor progression. Therefore, we aimed to evaluate the clinical relevance of the TERT amplification status. We included 643 patients with esophageal adenocarcinoma, who underwent Ivor-Lewis esophagectomy at the University Hospital of Cologne. The TERT amplification status was characterized using fluorescence in situ hybridization. Clinicopathological values and patients' overall survival were compared between patients with and without TERT amplification. Further sub-cohort analyses were conducted for patients with pT1N0-3 tumor stage. Eighty-One patients (12.6%) exhibited TERT amplification. Patients with amplified TERT showed significantly worse overall survival (median OS: 22.6 vs. 36.8 months, p = 0.009). Interestingly, TERT amplification could be characterized as an independent risk factor for worse overall survival in multivariate analysis in patients with pT1N0-3 tumor stage (HR = 2.440, 95% CI 1.095-5.440, p = 0.029). In this study, we describe the TERT amplification status as an independent risk factor for worse survival in patients diagnosed with esophageal adenocarcinoma at pT1N0-3 tumor stage, encompassing cases involving tumor infiltration of the lamina propria, muscularis mucosae, and/or submucosa. Based on our findings, we put forth the proposition that evaluating the TERT amplification status may serve as a valuable tool in identifying a specific subgroup of patients, namely those with TERT amplification and pT1N0-3 tumor-stage esophageal adenocarcinoma. The patients of this subgroup could potentially benefit from enhanced follow-up protocols, more aggressive treatment approaches, or possible targeted TERT inhibition therapies, all aimed at improving their overall clinical outcomes.


Asunto(s)
Adenocarcinoma , Neoplasias Esofágicas , Telomerasa , Humanos , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Biomarcadores de Tumor/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Esofagectomía , Hibridación Fluorescente in Situ , Pronóstico , Telomerasa/genética , Telomerasa/metabolismo
8.
Int J Mol Sci ; 24(17)2023 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-37686288

RESUMEN

The tumor microenvironment comprises multiple cell types, like cancer cells, endothelial cells, fibroblasts, and immune cells. In recent years, there have been massive research efforts focusing not only on cancer cells, but also on other cell types of the tumor microenvironment, thereby aiming to expand and determine novel treatment options. Fibroblasts represent a heterogenous cell family consisting of numerous subtypes, which can alter immune cell fractions, facilitate or inhibit tumor growth, build pre-metastatic niches, or stabilize vessels. These effects can be achieved through cell-cell interactions, which form the extracellular matrix, or via the secretion of cytokines or chemokines. The pro- or antitumorigenic fibroblast phenotypes show variability not only among different cancer entities, but also among intraindividual sites, including primary tumors or metastatic lesions. Commonly prescribed for arterial hypertension, the inhibitors of the renin-angiotensin system have recently been described as having an inhibitory effect on fibroblasts. This inhibition leads to modified immune cell fractions and increased tissue stiffness, thereby contributing to overcoming therapy resistance and ultimately inhibiting tumor growth. However, it is important to note that the inhibition of fibroblasts can also have the opposite effect, potentially resulting in increased tumor growth. We aim to summarize the latest state of research regarding fibroblast heterogeneity and its intricate impact on the tumor microenvironment and extracellular matrix. Specifically, we focus on highlighting recent advancements in the comprehension of intraindividual heterogeneity and therapy options within this context.


Asunto(s)
Fibroblastos Asociados al Cáncer , Carcinogénesis , Neoplasias , Fibroblastos Asociados al Cáncer/clasificación , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Fibroblastos Asociados al Cáncer/fisiología , Humanos , Microambiente Tumoral , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antihipertensivos/farmacología , Proteínas de la Matriz Extracelular/metabolismo , Carcinogénesis/metabolismo , Carcinogénesis/patología
9.
BMC Cancer ; 23(1): 669, 2023 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-37461005

RESUMEN

BACKGROUND: Patients diagnosed with esophageal cancer demonstrate a low overall survival even despite the established multimodal therapy as the current standard of care. Therefore, further biomarkers for patients with high-risk and additional therapy options are needed. NANOG is a transcription factor, which can be found in stem cells and is known to support tumorigenesis. METHODS: Six hundred sixty patients with esophageal adenocarcinoma, who were operated at the University of Cologne with a curative intent, were included. Immunohistochemical stainings for NANOG were performed. The study population was divided into NANOG-positive and -negative subgroups. RESULTS: Positive NANOG expression correlates significantly with worse overall survival (p = 0.002) and could be confirmed as an independent risk factor for worse patient survival in multivariate analysis (HR = 1.40, 95%CI = 1.09-1.80, p = 0.006). This effect could be detected in the subgroup of primarily operated patients, but not in patients after neoadjuvant therapy. CONCLUSIONS: We describe a NANOG-positive subgroup of patients with esophageal cancer, who exhibit worse overall survival in a large patient cohort. This discovery suggests the potential use of NANOG as a biomarker for both intensified therapy and stricter follow-up regimes. Additionally, NANOG-positive stem cell-like cancer cells could be used as a new antitumoral treatment target if validated in mechanistic and clinical studies.


Asunto(s)
Adenocarcinoma , Neoplasias Esofágicas , Humanos , Adenocarcinoma/genética , Adenocarcinoma/terapia , Adenocarcinoma/metabolismo , Análisis Multivariante , Células Madre/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/terapia , Proteína Homeótica Nanog/genética , Proteína Homeótica Nanog/metabolismo , Pronóstico
10.
Cancers (Basel) ; 15(7)2023 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-37046710

RESUMEN

PURPOSE: The pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer entities. Effective therapy options are still lacking. The tumor microenvironment possibly bears further treatment possibilities. This study aimed to describe the expression patterns of four established carcinoma-associated fibroblast (CAFs) markers and their correlation in PDAC tissue samples. METHODS: This project included 321 patients with PDAC who underwent surgery with a curative intent in one of the PANCALYZE study centers. Immunohistochemical stainings for FAP, PDGFR, periostin, and SMA were performed. The expression patterns of each marker were divided into low- and high-expressing CAFs and correlated with patients' survival. RESULTS: Tumors showing SMAhigh-, PeriostinhighSMAhigh-, or PeriostinhighSMAlowPDGFRlowFAPhigh-positive CAFs demonstrated significantly worse survival. Additionally, a high expression of SMA in PDAC tissue samples was shown to be an independent risk factor for worse survival. CONCLUSION: This project identified three subgroups of PDAC with different expression patterns of CAF markers which showed significantly worse survival. This could be the base for the further characterization of the fibroblast subgroups in PDAC and contribute to the development of new targeted therapy options against CAFs.

11.
J Cancer Res Clin Oncol ; 149(10): 7539-7546, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36971797

RESUMEN

PURPOSE: Rising incidence of pancreatic ductal adenocarcinoma (PDAC) bind with insufficient therapy options showcases a great medical challenge. Further biomarkers are required to identify patients, who will benefit from more aggressive therapy. METHODS: 320 patients were included by the PANCALYZE study group. Cytokeratin 6 (CK6) immunohistochemical staining as a putative marker for the basal-like subtype of PDAC was performed. The correlation between CK6 expression patterns and survival data, as well as various markers of the (inflammatory) tumor microenvironment, were analyzed. RESULTS: We divided the study population based on the expression pattern of CK6. Patients with a high CK6 tumor expression had a significantly shorter survival (p = 0.013), confirmed in a multivariate cox regression model. CK6-expression is an independent marker for a decreased overall survival (HR = 1.655, 95% CI 1.158-2.365, p = 0.006). In addition, the CK6-positive tumors showed significantly less plasma cell infiltration and more cancer-associated fibroblasts (CAFs) expressing Periostin and SMA. CONCLUSIONS: CK6 could be considered as an independent biomarker for a shorter overall survival. CK6 is a clinically easily accessible biomarker for the identification of the basal-like subtype of PDAC. Therefore, it could be taken into consideration in deciding for the more aggressive therapy regimes. Prospectively, studies addressing the chemosensitive characteristics of this subtype are required.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Queratina-6 , Pronóstico , Biomarcadores de Tumor/metabolismo , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/patología , Microambiente Tumoral
12.
Chirurgie (Heidelb) ; 94(5): 400-405, 2023 May.
Artículo en Alemán | MEDLINE | ID: mdl-36700973

RESUMEN

Due to the increasing research into familial clustering of cancer entities, more and more genes are being identified in which mutations explain this clustering. Mutations in the cadherin 1 (CDH1) and catenin alpha 1 (CTNNA1) genes are considered to be causative for the occurrence of hereditary diffuse gastric cancer. Those affected show an incidence of gastric cancer of around 40% up to the age of 80 years and affected women show an incidence of 55% for the occurrence of lobular breast cancer. In 2020 updated international guidelines were published for the clinical management of patients with hereditary diffuse gastric cancer. When the specific test criteria are fulfilled, patients should undergo genetic testing for mutations in the CDH1 and CTNNA1 genes. In cases of the familial occurrence of diffuse gastric cancer and detection of a pathological mutation, a prophylactic total gastrectomy with D1 lymphadenectomy is recommended. Alternatively, or when pathological mutations are not detected, a gastroscopy should be performed annually with targeted and random biopsies. The occurrence of lobular breast cancer should be monitored annually by magnetic resonance imaging (MRI) from the age of 30 years onwards. A bilateral mastectomy for risk reduction should be discussed in a multidisciplinary setting.


Asunto(s)
Neoplasias Gástricas , Adulto , Anciano de 80 o más Años , Femenino , Humanos , Adenocarcinoma/cirugía , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/cirugía , Carcinoma Lobular/genética , Carcinoma Lobular/patología , Carcinoma Lobular/cirugía , Pruebas Genéticas , Mastectomía , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/genética
13.
J Cancer Res Clin Oncol ; 149(9): 5531-5538, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36472768

RESUMEN

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is currently one of the leading causes of cancer death worldwide. Therefore, building further subgroups as well as enabling individual patient therapy and diagnostics are needed. X-linked inhibitor of apoptosis protein (XIAP) is known to modulate apoptotic and inflammatory pathways. Its expression was found to correlate with patients' survival in other tumor entities. This study aims to examine the role of XIAP in patients with PDAC in relation to the inflammatory microenvironment. METHODS: The PANCALYZE multicenter study group included 257 patients with PDAC. Paraffin-embedded tumor samples were stained immunohistochemically for CD3, CD20, CD38, CD56, CD66b, CD117, and CD163 and XIAP. These stainings were further analyzed digitally with QuPath and survival analyses were done. RESULTS: XIAP-positive patients with T-cell, respectively, neutrophil enriched tumors survived significantly longer compared to XIAP-negative patients (CD3: 37.6 vs. 24.6 months, p = 0.028; CD66b: 34.1 vs. 14.9 months, p = 0.027). Additionally, XIAP-positive patients showed better survival in the lymph node-negative population (48.4 vs. 24.2 months, p = 0.019). Regarding the total population, our findings did not show a correlation between XIAP expression and survival. In multivariate cox regression analyzes XIAP proves to be an independent factor for better survival in the identified subgroups (CD3: p = 0.043; CD66b: p = 0.012, N0: p = 0.040). CONCLUSION: We found XIAP-positive subgroups with significantly better survival in patients with PDAC in T-cell-rich, neutrophil-rich, or lymph node-negative cohorts. This could lead to further individualized cancer treatment with less aggressive therapy protocols for XIAP-positive tumors or more intensive follow-up for XIAP-negative tumors.


Asunto(s)
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Pronóstico , Adenocarcinoma/patología , Páncreas/metabolismo , Páncreas/patología , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/metabolismo , Biomarcadores de Tumor/metabolismo , Microambiente Tumoral , Neoplasias Pancreáticas
15.
Clin Cancer Res ; 25(18): 5674-5685, 2019 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-31239322

RESUMEN

PURPOSE: To investigate the clinical relevance of macrophages in liver metastasis of colorectal cancer and their influence on angiogenesis and patient survival. Moreover to evaluate specific blood monocytes as markers of disease recurrence.Experimental design: In a mouse model with spontaneous liver metastasis, the angiogenic characteristics of tumor- and metastasis (MAM)-associated macrophages were evaluated. Macrophages and the vasculature from 130 primary tumor (pTU) and 123 patients with liver metastasis were assessed. In vivo and in human samples, the clinical relevance of macrophage VEGFR1 expression was analyzed. Blood samples from patients (n = 157, 80 pTU and 77 liver metastasis) were analyzed for assessing VEGFR1-positive (VEGFR1+) cells as suitable biomarkers of disease recurrence. RESULTS: The number of macrophages positively correlated with vascularization in metastasis. Both in the murine model as well as in primary isolated human cells, a subpopulation of MAMs expressing VEGFR1 were found highly angiogenic. While VEGFR1 expression in pTU patients did not predict prognosis; high percentage of VEGFR1+ cells in liver metastasis was associated with worse patient outcome. Interestingly, VEGFR1+-circulating monocytes in blood samples from patients with liver metastasis not only predicted progression but also site of recurrence. CONCLUSIONS: Our findings identify a new subset of proangiogenic VEGFR1+ MAMs in colorectal cancer that support metastatic growth and may become a liquid biomarker to predict disease recurrence in the liver.


Asunto(s)
Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Macrófagos/metabolismo , Neovascularización Patológica/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Animales , Biomarcadores de Tumor , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/mortalidad , Modelos Animales de Enfermedad , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/secundario , Macrófagos/efectos de los fármacos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Pronóstico , Recurrencia , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Int J Cancer ; 145(9): 2509-2520, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31034094

RESUMEN

The immune microenvironment plays a crucial role in supporting tumor growth and metastasis. Tumor-associated macrophages (TAMs) and neutrophils (TANs) are essential components of this microenvironment and affect tumor growth and progression in almost all solid neoplasms. Furthermore, TAMs, TANs and tumor-infiltrating dendritic cells (TIDCs) are found to infiltrate specific distant organs to prepare them as a site for metastatic cell seeding, forming the pre-metastatic niche. The spleen was identified as a major reservoir and source of circulating and tumor infiltrating immune cells. However, discrepancies about its role in supporting tumor growth exist. Thus, here we investigated the role of splenectomy in primary tumor and metastatic growth, and in the formation of an inflammatory niche. In a murine 4T1 and E0771 breast and Panc02 pancreatic cancer model, our results show that while splenectomy reduces the number of infiltrating TAMs, TANs and TIDCs within primary tumors, it does not affect its growth. In line, fewer TAMs, TANs and TIDCs accumulate in the metastatic microenvironment after splenectomy. Interestingly though, this affected metastatic growth depending on the metastatic route/site. The number of hematogenous breast cancer lung metastases was reduced after splenectomy but no effect was observed in breast or pancreatic lymph node metastases. Moreover, we observed that the immune composition of the pre-metastatic niche in lungs of breast cancer bearing mice was altered, and that this could cause the reduction of metastases. Altogether, our results highlight that splenectomy affects the immune microenvironment not only of primary tumors but also of pre-metastatic and metastatic sites.


Asunto(s)
Inflamación/patología , Neoplasias Pulmonares/patología , Pulmón/patología , Metástasis Linfática/patología , Bazo/cirugía , Animales , Mama/patología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/fisiología , Progresión de la Enfermedad , Femenino , Ganglios Linfáticos/patología , Macrófagos/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neutrófilos/patología , Neoplasias Pancreáticas/patología , Bazo/patología , Esplenectomía/métodos , Microambiente Tumoral/fisiología
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