• TGF-β
• epithelial-mesenchymal transition
• esophageal adenocarcinoma
• hub gene signature
• predictive biomarkers

• Humans
• Esophageal Neoplasms/drug therapy
• Esophageal Neoplasms/metabolism
• Esophageal Neoplasms/genetics
• Adenocarcinoma/drug therapy
• Adenocarcinoma/metabolism
• Adenocarcinoma/genetics
• Transforming Growth Factor beta/metabolism
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition/drug effects
• Biomarkers, Tumor/metabolism
• Biomarkers, Tumor/genetics
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Drug Resistance, Neoplasm/drug effects
• Gene Expression Regulation, Neoplastic/drug effects

• mesenchymal migration
• oesophageal cancer
• cancer stem cells

• 10992 KWF Kankerbestrijding (Dutch Cancer Society)

• oesophageal cancer
• cancer metabolism

• Chemotherapy
• Neoadjuvant
• esophageal neoplasm
• immune system
• immunotherapy

• Humans
• Adenocarcinoma/drug therapy
• Adenocarcinoma/pathology
• Esophageal Neoplasms/drug therapy
• Leukocytes, Mononuclear
• Monitoring, Immunologic
• Neoadjuvant Therapy
• Treatment Outcome
• Immune Checkpoint Inhibitors/therapeutic use

• Cancer
• Cell Culture
• Health Sciences
• Microscopy
• Model Organisms

• Humans
• Mice
• Animals
• Neoplasms/radiotherapy
• Mice, SCID

• SPARC
• TGF-β1
• TGFBR2
• epithelial-to-mesenchymal transition
• sophageal adenocarcinoma

• clinical decision- making
• deep learning
• esophageal adenocarcinoma (EAC)
• prognosis
• prognosis carcinoma

• ESRRA
• chemoradiation
• esophageal cancer
• metabolic reprogramming
• oxidative phosphorylation
• radiation
• resistance

Non-melanoma skin cancer has recently seen an increase in prevalence, and it is estimated that this grow will continue in the coming years. In this sense, the importance of therapy effectiveness has increased, especially photodynamic therapy. Photodynamic therapy has attracted much attention as a minimally invasive, selective and repeatable approach for skin cancer treatment and prevention. Although its high efficiency, this strategy has also faced problems related to tumor resistance, where the tumor microenvironment has gained a well-deserved role in recent years. Tumor microenvironment denotes a wide variety of elements, such as cancer-associated fibroblasts, immune cells, endothelial cells or the extracellular matrix, where their interaction and the secretion of a wide diversity of cytokines. Therefore, the need of designing new strategies targeting elements of the tumor microenvironment to overcome the observed resistance has become evident. To this end, in this review we focus on the role of cancer-associated fibroblasts and tumor-associated macrophages in the resistance to photodynamic therapy. We are also exploring new approaches consisting in the combination of new and old drugs targeting these cells with photodynamic therapy to enhance treatment outcomes of non-melanoma skin cancer.

Platinum-based drugs (PBDs), including cisplatin, carboplatin, and oxaliplatin, have been widely used in clinical practice as mainstay treatments for various types of cancer. Although there is firm evidence of notable achievements with PBDs in the management of cancers, the acquisition of resistance to these agents is still a major challenge to efforts at cure. The introduction of the epithelial-mesenchymal transition (EMT) concept, a critical process during embryonic morphogenesis and carcinoma progression, has offered a mechanistic explanation for the phenotypic switch of cancer cells upon PBD exposure. Accumulating evidence has suggested that carcinoma cells can enter a resistant state via induction of the EMT. In this review, we discussed the underlying mechanism of PBD-induced EMT and the current understanding of its role in cancer drug resistance, with emphasis on how this novel knowledge can be exploited to overcome PBD resistance via EMT-targeted compounds, especially those under clinical trials.

Breast cancer (BC) is the most common cancer and among the leading causes of cancer death in women. It is a heterogeneous group of tumours with numerous morphological and molecular subtypes, making predictions of disease evolution and patient outcomes difficult. Therefore, biomarkers are needed to help clinicians choose the best treatment for each patient. For the last years, studies have increasingly focused on biomarkers obtainable by liquid biopsy. Circulating proteins (from serum or plasma) can be used for inexpensive and minimally invasive determination of disease risk, early diagnosis, treatment adjusting, prognostication and disease progression monitoring. We provide here a review of the main published studies on serum proteins in breast cancer and elaborate on the potential of circulating proteins to be predictive and/or prognostic biomarkers in breast cancer.

• Biomarker
• Breast cancer
• Liquid biopsy
• Plasma proteins
• Predictive
• Prognostic
• Serum proteins

Background: Although immunotherapy with immune checkpoint therapy has been used to treat head and neck squamous cell carcinoma (HNSCC), response rates and treatment sensitivity remain limited. Recent studies have indicated that transforming growth factor-β (TGF-β) may be an important target for novel cancer immunotherapies.

Materials and methods: We collected genomic profile data from The Cancer Genome Atlas and Gene Expression Omnibus. The least absolute shrinkage and selection operator method and Cox regression were used to establish a prognostic model. Gene set enrichment analysis was applied to explore biological functions. Tracking of indels by decomposition and subclass mapping algorithms were adopted to evaluate immunotherapy efficiency.

Result: We established a seven TGF-β pathway-associated gene signature with good prediction efficiency. The high-risk score subgroup mainly showed enrichment in tumor-associated signaling such as hypoxia and epithelial-mesenchymal transition (EMT) pathways; This subgroup was also associated with tumor progression. The low-risk score subgroup was more sensitive to immunotherapy and the high-risk score subgroup to cisplatin, erlotinib, paclitaxel, and crizotinib.

Conclusion: The TGF-β pathway signature gene model provides a novel perspective for evaluating effectiveness pre-immunotherapy and may guide further studies of precision immuno-oncology.

In this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (nCRT) resection; (ii) 66 EAC patients with resection and corresponding recurrence. Activity of six key cancer-related signaling pathways was inferred using the Bayesian inference method. When assessing pre- and post-nCRT samples, lower FOXO transcriptional activity was observed in poor nCRT responders compared to good nCRT responders (p = 0.0017). This poor responder profile was preserved in recurrences compared to matched resections (p = 0.0007). PI3K pathway activity, inversely linked with FOXO activity, was higher in CRT poor responder cell lines compared to CRT good responders. Poor CRT responder cell lines could be sensitized to CRT using PI3K inhibitors. To conclude, by using a novel method to measure signaling pathway activity on clinically available material, we identified an association of low FOXO transcriptional activity with poor response to nCRT. Targeting this pathway sensitized cells for nCRT, underlining its feasibility to select appropriate targeted therapies.

• Esophageal adenocarcinoma
• Neoadjuvant chemoradiation therapy
• Pathway analysis
• Predictive

Real-world data on treatment and outcomes in patients with synchronous metastatic disease compared with patients with metachronous metastatic disease in esophagogastric cancer have not been published before. The aim of our study was to explore treatment, overall survival (OS), and time to treatment fialure (TTF) in patients with synchronous and metachronous metastatic esophagogastric adenocarcinoma.

Patients with synchronous metastatic disease (2015–2017) and patients with metachronous metastatic disease initially treated with curative intent for nonmetastatic disease (2015–2016) were selected from the Netherlands Cancer Registry. OS and TTF were assessed from metastatic diagnosis for patients with synchronous, early metachronous (⩽6 months) or late metachronous (>6 months) metastatic disease using Kaplan–Meier curves with two-sided log-rank test.

Median OS was 4.2, 2.1, and 4.4 months in patients with synchronous, early metachronous, and late metachronous metastatic disease, respectively (p < 0.001). The proportion of patients receiving systemic treatment was 41.3%, 21.5%, and 32.5% for synchronous, early metachronous, and late metachronous metastatic disease, respectively (p = 0.001). Among patients receiving systemic treatment, median OS was 8.8, 4.5, and 9.1 months (p < 0.001) and median TTF was 6.1, 3.8, and 5.7 months (p < 0.001) in synchronous, early metachronous, and late metachronous metastatic disease, respectively.

Patients with early metachronous metastatic disease have a worse survival compared with patients with synchronous or late metachronous metastatic disease. These patients less often receive systemic treatment, and even when treated, survival is worse compared with patients with synchronous or late metachronous metastatic disease, suggesting a more aggressive tumor behavior.

• 5-Fluorouracil
• Chemoresistance
• Cisplatin
• Esophageal cancer
• Molecular mechanisms
• Paclitaxel

• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/antagonists & inhibitors
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Carboplatin/therapeutic use
• Cisplatin/therapeutic use
• Drug Resistance, Neoplasm/drug effects
• Drug Resistance, Neoplasm/genetics
• Esophageal Neoplasms/drug therapy
• Esophageal Neoplasms/genetics
• Esophageal Neoplasms/metabolism
• Fluorouracil/therapeutic use
• Humans
• Molecular Targeted Therapy/methods
• Mutation
• Paclitaxel/therapeutic use
• Tumor Microenvironment/drug effects
• Tumor Microenvironment/genetics

Gastrointestinal (GI) cancer, including esophageal, gastric, and colorectal cancer, is one of the most prevalent types of malignant carcinoma and the leading cause of cancer-related deaths. Despite significant advances in therapeutic strategies for GI cancers in recent decades, drug resistance with various mechanisms remains the prevailing cause of therapy failure in GI cancers. Accumulating evidence has demonstrated that the transforming growth factor (TGF)-β signaling pathway has crucial, complex roles in many cellular functions related to drug resistance. This review summarizes current knowledge regarding the role of the TGF-β signaling pathway in the resistance of GI cancers to conventional chemotherapy, targeted therapy, immunotherapy, and traditional medicine. Various processes, including epithelial-mesenchymal transition, cancer stem cell development, tumor microenvironment alteration, and microRNA biogenesis, are proposed as the main mechanisms of TGF-β-mediated drug resistance in GI cancers. Several studies have already indicated the benefit of combining antitumor drugs with agents that suppress the TGF-β signaling pathway, but this approach needs to be verified in additional clinical studies. Moreover, the identification of potential biological markers that can be used to predict the response to TGF-β signaling pathway inhibitors during anticancer treatments will have important clinical implications in the future.

• Drug resistance
• Gastrointestinal cancer
• Transforming growth factor-β
• Epithelial-mesenchymal transition
• Cancer stem cells
• MicroRNAs

• Esophageal carcinoma
• Gastric carcinoma
• Systematic review
• TGF-β
• Targeted therapy

Esophageal cancer is one of the top ten most deadly cancers. Even when diagnosed in a curable stage, patients prognosis poor. One of the parameters that is very relevant for long-term survival is response to radio(chemo)therapy prior surgery. Complete response rates are between 24 and 50 percent. This puts more than a half of every esophageal cancer patient that is diagnosed in a non-metastasized stage at high risk of recurrence. To improve response rates of treatment regimens prior curative surgery is, therefore, a major challenge in treating esophageal cancer. Not only the response of the cancer cell itself to cancer therapy is determining patients’ fate. Cells around the tumor cells called the tumor microenvironment that together with the cancer cell constitute a malignant tumor are also involved in tumor progression and therapy response. This review depicts the most important parts of the esophageal cancer microenvironment, evaluates chances and challenges of current already established therapeutic concepts that target this microenvironment. It furthermore elucidates specific pathways that are potential valuable targets in the future.

Esophageal cancer is among the top ten most deadly cancers worldwide with adenocarcinomas of the esophagus showing increasing incidences over the last years. The prognosis is determined by tumor stage at diagnosis and in locally advanced stages by response to (radio-)chemotherapy followed by radical surgery. Less than a third of patients with esophageal adenocarcinomas completely respond to neoadjuvant therapies which urgently asks for further strategies to improve these rates. Aiming at the tumor microenvironment with novel targeted therapies can be one strategy to achieve this goal. This review connects experimental, translational, and clinical findings on each component of the esophageal cancer tumor microenvironment involving tumor angiogenesis, tumor-infiltrating immune cells, such as macrophages, T-cells, myeloid-derived suppressor cells, and cancer-associated fibroblasts. The review evaluates the current state of already approved concepts and depicts novel potentially targetable pathways related to esophageal cancer tumor microenvironment.

• cancer-associated fibroblasts
• esophageal adenocarcinoma
• esophageal cancer
• esophageal squamous cell cancer
• immunotherapy
• tumor angiogenesis
• tumor microenvironment
• tumor-associated macrophages

• autocrine signaling
• cancer
• feedback loop
• transforming growth factor-β

• Animals
• Autocrine Communication/drug effects
• Autocrine Communication/physiology
• Biomedical Research/methods
• Biomedical Research/standards
• Feedback, Physiological/drug effects
• Feedback, Physiological/physiology
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Receptors, Transforming Growth Factor beta/genetics
• Receptors, Transforming Growth Factor beta/metabolism
• Research Design
• Transforming Growth Factor beta/pharmacology
• Transforming Growth Factor beta/physiology

• Adenocarcinoma
• Chemotherapy
• Gastroesophageal
• Neoadjuvant
• Radiotherapy

• Adenocarcinoma/pathology
• Adenocarcinoma/therapy
• Aged
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Capecitabine/administration & dosage
• Chemoradiotherapy/methods
• Disease-Free Survival
• Docetaxel/administration & dosage
• Epirubicin/administration & dosage
• Esophageal Neoplasms/pathology
• Esophageal Neoplasms/therapy
• Esophageal Squamous Cell Carcinoma/pathology
• Esophageal Squamous Cell Carcinoma/therapy
• Esophagectomy
• Esophagogastric Junction/pathology
• Female
• Fluorouracil/administration & dosage
• Hospital Mortality
• Humans
• Length of Stay
• Leucovorin/administration & dosage
• Lymph Node Excision
• Male
• Middle Aged
• Neoadjuvant Therapy
• Neoplasm Staging
• Oxaliplatin/administration & dosage
• Postoperative Complications/epidemiology
• Propensity Score
• Survival Rate
• Treatment Outcome

• 23924 Cancer Research UK

• CBLB
• EAC
• cisplatin resistance
• miR-181a-5p

• CSF-1
• Pancreatic ductal adenocarcinoma
• collagen
• deactivation
• pancreatic stellate cells

• Carcinoma, Pancreatic Ductal/genetics
• Cell Line, Tumor
• Cell Movement
• Humans
• Macrophage Colony-Stimulating Factor/genetics
• Pancreatic Neoplasms/genetics
• Pancreatic Stellate Cells
• Stromal Cells
• Tumor Microenvironment

• UVA 2013-5932 KWF Kankerbestrijding (Dutch Cancer Society)
• UVA 2012-5607 KWF Kankerbestrijding (Dutch Cancer Society)
• KWF Kankerbestrijding (Dutch Cancer Society)

• artesunate
• carboplatin
• cell apoptosis
• cell cycle
• non-small cell lung cancer