Einfluss der Interleukin-4-Interleukin-4-Rezeptor-Kaskade auf den malignen Phänotyp kultivierter Pankreaskarzinomzellen

Ein Einfluss von exogenem Interleukin- (IL-) 4 auf das Wachstum verschiedener humaner Malignome, inklusive des Pankreaskarzinomes konnte bereits beschrieben werden. Ziel dieser Studie war es den endogenen Einfluss der IL-4 Rezeptorkette IL-4Rα auf den malignen Phänotyp kultivierter Pankreaskarzinomzellen darzustellen. Hierfür wurden Klonen mit Herunterregulation von IL-4Rα durch Transfektion mit einem gegen IL-4Rα gerichteten Plasmid etabliert. Anhand dieser erfolgte die Charakterisierung von Wachstums- und Migrationsverhalten. Die Herunterregulation von IL-4Rα führte dabei zu reduziertem Zellwachstum in vitro und in vivo sowie zu reduzierter Zellmigration. Anhand der Stimulation von Wildtypzellen und transfizierten Zellen mit IL-4 und IL-13 sowie hierdurch der Untersuchung beteiligter Signalwege konnten mögliche Mechanismen der reduzierten Pathogenität nach Herunterregulation von IL-4Rα dargestellt werden. Im zweiten Teil der Arbeit wurde der Einfluss von IL-4 und IL-4Rα auf die Sensibilität von Karzinomzellen, insbesondere in Bezug auf Karzinomstammzellen gegenüber Standard-Chemotherapeutika dargestellt. Hierbei konnten Hinweise auf eine Förderung der Therapieresistenz durch IL-4 gezeigt werden. Die therapeutische Blockade von IL-4 und auch IL-13 könnte also in mehrfacher Hinsicht durch direkte Wachstumshemmung sowie reduziertes Metastasierungsriskio und Sensibiliserung gegenüber der Systemtherapie zur Behandlung des Pankreaskarzinomes beitragen

Role of Epithelial to Mesenchymal Transition in Colorectal Cancer

The epithelial–mesenchymal transition (EMT) is a cellular reprogramming process that occurs during embryonic development and adult tissue homeostasis. This process involves epithelial cells acquiring a mesenchymal phenotype. Through EMT, cancer cells acquire properties associated with a more aggressive phenotype. EMT and its opposite, mesenchymal–epithelial transition (MET), have been described in more tumors over the past ten years, including colorectal cancer (CRC). When EMT is activated, the expression of the epithelial marker E-cadherin is decreased and the expression of the mesenchymal marker vimentin is raised. As a result, cells temporarily take on a mesenchymal phenotype, becoming motile and promoting the spread of tumor cells. Epithelial–mesenchymal plasticity (EMP) has become a hot issue in CRC because strong inducers of EMT (such as transforming growth factor β, TGF-β) can initiate EMT and regulate metastasis, microenvironment, and immune system resistance in CRC. In this review, we take into account the significance of EMT-MET in CRC and the impact of the epithelial cells’ plasticity on the prognosis of CRC. The analysis of connection between EMT and colorectal cancer stem cells (CCSCs) will help to further clarify the current meager understandings of EMT. Recent advances affecting important EMT transcription factors and EMT and CCSCs are highlighted. We come to the conclusion that the regulatory network for EMT in CRC is complicated, with a great deal of crosstalk and alternate paths. More thorough research is required to more effectively connect the clinical management of CRC with biomarkers and targeted treatments associated with EMT

Possible Roles of Interleukin-4 and -13 and Their Receptors in Gastric and Colon Cancer

Interleukin (IL)-4 and -13 are structurally and functionally related cytokines sharing common receptor subunits. They regulate immune responses and, moreover, are involved in the pathogenesis of a variety of human neoplasms. Three different receptors have been described for IL-4, but only IL-4 receptor type II (IL-4Rα/IL-13Rα1) is expressed in solid tumors. While IL-13 can also bind to three different receptors, IL-13 receptor type I (IL-4Rα/IL-13Rα1/IL-13Rα2) and type II (IL-4Rα/IL-13Rα1) are expressed in solid tumors. After receptor binding, IL-4 and IL-13 can mediate tumor cell proliferation, survival, and metastasis in gastric or colon cancer. This review summarizes the results about the role of IL-4/IL-13 and their receptors in gastric and colon cancer

Involvement of IL-4, IL-13 and Their Receptors in Pancreatic Cancer

Interleukin (IL)-4 and IL-13 are known as pleiotropic Th2 cytokines with a wide range of biological properties and functions especially in immune responses. In addition, increasing activities have also been determined in oncogenesis and tumor progression of several malignancies. It is now generally accepted that IL-4 and IL-13 can exert effects on epithelial tumor cells through corresponding receptors. Type II IL-4 receptor (IL-4Rα/IL-13Rα1), predominantly expressed in non-hematopoietic cells, is identified to be the main target for both IL-4 and IL-13 in tumors. Moreover, IL-13 can also signal by binding to the IL-13Rα2 receptor. Structural similarity due to the use of the same receptor complex generated in response to IL-4/IL-13 results in overlapping but also distinct signaling pathways and functions. The aim of this review was to summarize knowledge about IL-4 and IL-13 and their receptors in pancreatic cancer in order understand the implication of IL-4 and IL-13 and their receptors for pancreatic tumorigenesis and progression and for developing possible new diagnostic and therapeutic targets

Loss of Interleukin-13-Receptor-Alpha-1 Induces Apoptosis and Promotes EMT in Pancreatic Cancer

In search of new therapies for pancreatic cancer, cytokine pathways have attracted increasing interest in recent years. Cytokines play a vital role in the crosstalk between tumour cells and the tumour microenvironment. The related inflammatory cytokines IL-4 and IL-13 can regularly be detected at increased levels in the microenvironment of pancreatic cancer. They share a receptor heterodimer consisting of IL-4Rα and IL-13Rα1. While IL-4Rα induces a more oncogenic phenotype, the role of IL-13Rα1 was yet to be determined. ShRNA-based knockdown of IL-13Rα1 was performed in Capan-1 and MIA PaCa-2. We assessed cell growth and migratory capacities under the influence of IL-13Rα1. Pathway alterations were detected by immunoblot analysis. We now have demonstrated that the loss of IL-13Rα1 induces apoptosis in pancreatic cancer cells. This was associated with an epithelial-to-mesenchymal transition. Loss of IL-13Rα1 also abolished the effects of exogenous IL-4 and IL-13 stimulation. Interestingly, in wild type cells, cytokine stimulation caused a similar increase in migratory capacities as after IL-13Rα1 knockdown. Overall, our results indicate the vital role of IL-13Rα1 in the progression of pancreatic cancer. The differential expression of IL-4Rα and IL-13Rα1 has to be taken into account when considering a cytokine-targeted therapy in pancreatic cancer

Loss of Interleukin-13-Receptor-Alpha-1 Induces Apoptosis and Promotes EMT in Pancreatic Cancer

In search of new therapies for pancreatic cancer, cytokine pathways have attracted increasing interest in recent years. Cytokines play a vital role in the crosstalk between tumour cells and the tumour microenvironment. The related inflammatory cytokines IL-4 and IL-13 can regularly be detected at increased levels in the microenvironment of pancreatic cancer. They share a receptor heterodimer consisting of IL-4Rα and IL-13Rα1. While IL-4Rα induces a more oncogenic phenotype, the role of IL-13Rα1 was yet to be determined. ShRNA-based knockdown of IL-13Rα1 was performed in Capan-1 and MIA PaCa-2. We assessed cell growth and migratory capacities under the influence of IL-13Rα1. Pathway alterations were detected by immunoblot analysis. We now have demonstrated that the loss of IL-13Rα1 induces apoptosis in pancreatic cancer cells. This was associated with an epithelial-to-mesenchymal transition. Loss of IL-13Rα1 also abolished the effects of exogenous IL-4 and IL-13 stimulation. Interestingly, in wild type cells, cytokine stimulation caused a similar increase in migratory capacities as after IL-13Rα1 knockdown. Overall, our results indicate the vital role of IL-13Rα1 in the progression of pancreatic cancer. The differential expression of IL-4Rα and IL-13Rα1 has to be taken into account when considering a cytokine-targeted therapy in pancreatic cancer

Robotic Liver Surgery for Alveolar Echinococcosis: A Single-Centre Experience

Alveolar echinococcosis (AE) is a rare disease caused by Echinococcosis multilocularis, which usually requires multidisciplinary management including surgery as the only curative approach. In recent years, minimally invasive strategies have been increasingly adopted for liver surgery. In particular, robotic surgery enables surgeons to perform even complex liver resections using a minimally invasive approach. However, there are only a few reports on robotic liver surgery for AE. Consecutive patients undergoing robotic liver surgery for AE were analysed based on the prospective database of the Interdisciplinary Robotic Centre of Ulm University Hospital. Between January 2021 and August 2022, a total of 16 patients with AE underwent robotic hepatectomy at our institution. Median age was 55.5 years (23–73), median body mass index (BMI) was 25.8 kg/m2 (20.2–36.8) and 12 patients (75%) were female. Anatomic resections were performed in 14 patients (87.5%), of which 4 patients (25%) underwent major hepatectomies (i.e., resection of >3 segments) including two right hemihepatectomies, one left hemihepatectomy and one extended right hemihepatectomy performed as associating liver partition with portal vein ligation staged (ALPPS) hepatectomy. There was no 90-day mortality, no postoperative bile leakage and no posthepatectomy haemorrhage. One patient developed posthepatectomy liver failure grade B after extended right hemihepatectomy using an ALPPS approach. One patient had to be converted to open surgery and developed an organ-space surgical site infection, for which he was re-admitted and underwent intravenous antibiotic therapy. Median length of postoperative hospital stay was 7 days (4–30). To our knowledge, this is the largest series of robotic liver surgeries for AE. The robotic approach seems safe with promising short-term outcomes in this selected cohort for both minor as well as major resections

Endogenously Expressed IL-4Rα Promotes the Malignant Phenotype of Human Pancreatic Cancer In Vitro and In Vivo

Exogenous interleukin-4 (IL-4) has been demonstrated to affect the growth of different human malignancies including pancreatic cancer cells. The aim of our study was to determine the role of endogenously expressed IL-4-receptor-α-chain (IL-4Rα) in pancreatic cancer cells. IL-4Rα-suppression was achieved by generating Capan-1 cells stably expressing shRNA targeting IL-4Rα. The malignant phenotype was characterized by assessing growth properties, directional and non-directional cell movement in vitro and tumor growth in vivo. Signaling pathways were analyzed upon IL-4 and IL-13 stimulation of wildtype (WT) and control-transfected cells compared to IL-4Rα-knockdown cells. Silencing of IL-4Rα resulted in reduced anchorage-dependent cell growth (p < 0.05) and reduced anchorage-independent colony size (p < 0.001) in vitro. Moreover, cell movement and migration was inhibited. IL-4 and IL-13 stimulation of Capan-1-WT cells induced activation of similar pathways like stimulation with Insulin-like growth factor (IGF)-I. This activation was reduced after IL-4Rα downregulation while IGF-I signaling seemed to be enhanced in knockdown-clones. Importantly, IL-4Rα silencing also significantly suppressed tumor growth in vivo. The present study indicates that endogenously expressed IL-4 and IL-4Rα contribute to the malignant phenotype of pancreatic cancer cells by activating diverse pro-oncogenic signaling pathways. Addressing these pathways may contribute to the treatment of the disease

c-Jun N-terminal kinase 2 suppresses pancreatic cancer growth and invasion and is opposed by c-Jun N-terminal kinase 1

The c-Jun N-terminal protein kinases (JNKs) JNK1 and JNK2 can act as either tumor suppressors or pro-oncogenic kinases in human cancers. The isoform-specific roles for JNK1 and JNK2 in human pancreatic cancer are still unclear, the question which should be addressed in this project. Human pancreatic cancer cell lines MIA PaCa-2 and PANC-1 clones were established either expressing either JNK1 or -2 shRNA in a stable manner. Basal anchorage-dependent and -independent cell growth, single-cell movement, and invasion using the Boyden chamber assay were analyzed. Xenograft growth was assessed using an orthotopic mouse model. All seven tested pancreatic cancer cell lines expressed JNKs as did human pancreatic cancer samples determined by immunohistochemistry. Pharmacological, unspecific JNK inhibition (SP600125) reduced cell growth of all cell lines but PANC-1. Especially inhibition of JNK2 resulted in overall increased oncogenic potential with increased proliferation and invasion, associated with alterations in cytoskeleton structure. Specific inhibition of JNK1 revealed opposing functions. Overall, JNK1 and JNK2 can exert different functions in human pancreatic cancer and act as counter players for tumor invasion. Specifically modulating the activity of JNKs may be of potential therapeutic interest in the future