Results of robotic liver surgery in association with IWATE criteria - the first 100 cases.

BACKGROUND: Aim of the current study was to present the results of the implementation phase of a robotic liver surgery program and to assess the validity of the IWATE difficulty score in predicting difficulty and postoperative complications in robotic liver surgery. METHODS: Based on the prospective database of the Interdisciplinary Robotic Center of Ulm University Hospital, the first 100 robotic liver surgeries were identified and analyzed. Perioperative parameters (duration of surgery and blood loss) and postoperative parameters including morbidity, mortality, and length of hospital stay were assessed and the results were compared between different IWATE difficulty categories. RESULTS: From November 2020 until January 2023, 100 robotic liver surgeries were performed (41 female, 59 male; median age 60.6 years, median BMI 25.9 kg/m2). Median duration of surgery was 180 min (IQR: 128.7), and median blood loss was 300 ml (IQR: 550). Ninety-day mortality was 2%, and overall morbidity was 21%, with major complications occurring in 13% of patients (≥ grade 3 according to Clavien/Dindo). A clinically relevant postoperative biliary leakage was observed in 3 patients. Posthepatectomy liver failure occurred in 7% (4 Grade A, 3 Grade B). Duration of surgery (p < 0.001), blood loss (p < 0.001), CCI (p = 0.004), overall morbidity (p = 0.004), and length of hospital stay (p < 0.001) were significantly increased in the IWATE 'expert' category compared to lower categories. DISCUSSION: Robotic surgery offers a minimally invasive approach for liver surgery with favorable clinical outcomes, even in the implementation phase. In the current study the IWATE difficulty score had the ability to predict both difficulty of surgery as well as postoperative outcomes when assessing the complexity of robotic liver surgery. Therefore, the role of the IWATE score in predicting these outcomes highlights its importance as a tool in surgical planning and decision-making.

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 ß, TGF-ß) 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.

Evaluation of CDK9 Inhibition by Dinaciclib in Combination with Apoptosis Modulating izTRAIL for the Treatment of Colorectal Cancer.

Treatment options for colorectal cancer (CRC), especially in advanced stages are still insufficient. There, the discovery of Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was a bright spot. However, most cancers show resistance toward apoptotic signals. Cyclin-dependent kinase 9 (CDK9) plays a crucial role in cell cycle progression in most tissues. We recently demonstrated the role of CDK9 in mediating TRAIL resistance. In this work, we investigated the role of CDK9 in colorectal cancer. Immunohistochemical analysis of CDK9 expression in cancer and normal tissues of CRC specimens was performed. The effect of selective CDK9 inhibition in combination with TRAIL on CRC cells was analyzed via cell viability, colony formation, and induction of apoptosis by flow cytometry. The mechanism of action was conducted via western blotting. We now have confirmed overexpression of CDK9 in cancer tissues, with low expression associated with poorer survival in a subset of CRC patients. In-vitro, CDK9 inhibition could strongly promote TRAIL-induced cell death in TRAIL-resistant CRC cells. Mechanistically, CDK9 inhibition induced apoptosis by downregulation of antiapoptotic proteins, myeloid leukemia cell differentiation protein 1 (Mcl-1) and FLICE-inhibitory protein (c-FLIP). Overall, we identified CDK9 as a prognostic marker and combined CDK9 inhibition and TRAIL as a novel and promising therapeutic approaches for colorectal cancer.

[Treatment concepts for hepatic echinococcosis]. / Therapiekonzepte bei hepatischer Echinokokkose.

The incidence of both cystic (CE) and alveolar echinococcosis (AE) is increasing in Germany. The CE can often be managed with drug treatment and interventional strategies. In contrast, AE shows characteristics of a malignant disease with a high morbidity and mortality. Benzimidazoles are potent drugs for both entities but with the necessity for a lifelong follow-up and the risk of side effects as well as progression under treatment. Therefore, the indications for surgical resection have to be carefully considered; however, the combination of drug treatment and surgery is the only curative approach. Recently, the use of minimally invasive surgery with reduced morbidity and mortality has justified surgical resection for a broader set of patients; however, minimally invasive surgery requires a high level of expertise and optimal perioperative planning. Therefore, treatment strategies, especially for AE require an individual stratified risk-benefit assessment in an interdisciplinary consensus.

JNK inhibitor IX restrains pancreatic cancer through p53 and p21.

Novel treatment options for pancreatic cancer are desperately needed. De-regulated kinases can be regularly detected in pancreatic cancer. Multiple pathway inhibitors were developed to exploit these features, among them selective inhibitors of the c-Jun N-terminal kinase isoforms 1 and 2 (JNK1 and 2). We evaluated the effectiveness of four different JNK inhibitors on pancreatic cancer cell lines. Cell mobility and migration were evaluated in scratch assay and Boyden chamber assay. Mechanism of cell death was analyzed via apoptosis assays in FACS and immunoblotting as well as cell cycle analysis via FACS, and qPCR. JNK2 knockout cells were generated using siRNA transfection. Among the inhibitors, JNK inhibitor IX (JNK-in-IX), designed as specific inhibitor against JNK2 was proven highly effective in inhibiting cell growth, mobility and migration. We were able to show that JNK-in-IX caused DNA damage resulting in G2 arrest mediated through p53 and p21. Interestingly, JNK-in-IX acted independently of its primary target JNK2. In summary, JNK-in-IX was shown highly effective in pancreatic cancer. This study underlines the need for modeling systems in testing therapeutic options as JNK2 was previously not indicated as a potential target.

Impact of perioperative steroid administration in patients undergoing elective liver resection: meta-analysis.

BACKGROUND: Perioperative steroid administration may improve postoperative outcomes in major abdominal surgery by reducing the systemic inflammatory response. The aim of this systematic review was to evaluate the impact of perioperative steroid administration on outcomes after elective liver resection. METHODS: PubMed, Cochrane Library, and Web of Science were systematically searched for randomized clinical trials (RCTs) comparing perioperative steroid administration with placebo, standard of care, or no steroids with respect to postoperative outcomes, particularly postoperative complications. Two independent reviewers critically appraised the studies and extracted data. Meta-analyses were performed using a random-effects model with ORs calculated for dichotomous outcomes and mean differences (MDs) for continuous outcomes. RESULTS: Ten RCTs comprising 930 patients were included. Perioperative steroid administration significantly reduced the overall postoperative complication rate (OR 0.61, 95 per cent c.i. 0.43 to 0.87; P = 0.006; I2 = 26 per cent). No significant differences were shown for individual complications. Several postoperative laboratory parameters were positively affected, like total serum bilirubin (MD -0.46; 95 per cent c.i. -0.74 to -0.18; P = 0.001; I2 = 80 per cent), interleukin 6 (MD -48.99; 95 per cent c.i. -60.72 to -37.27; P < 0.001; I2 = 0 per cent) and C-reactive protein (MD -5.20; 95 per cent c.i. -7.62 to -2.77; P < 0.001; I2 = 71 per cent). There were no signs of an increase in potential steroid-induced adverse events, namely infectious complications, thromboembolic events, or bleeding. CONCLUSIONS: Perioperative steroid administration significantly reduces the overall complication rate after elective liver resection without an increased risk of adverse effects.

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.

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.

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.

Unclear retroperitoneal tumors, an interdisciplinary challenge - A case report and review of the literature.

INTRODUCTION AND IMPORTANCE: Unclear retroperitoneal tumors impose major challenges for clinicians. Tumors can originate primarily from retroperitoneal tissue or secondarily invade into the retroperitoneum. While benign lesions also occur, malignant tumors are far more common. Clinical presentation depends on replacement or invasion of other organs and is therefore highly variable. The heterogeneous tumor composition makes a definitive preoperative diagnosis difficult. Surgical resection is the gold standard for treatment but often proves challenging due to frequent involvement of large retroperitoneal vessels. CASE PRESENTATION: We present the case of a 70-year old woman diagnosed with a large, unclear retroperitoneal tumor. Initial clinical symptoms were increasing dyspnea and dysphagia in our clinic. Gastroenterologic and cardiologic workup was unremarkable. Computed Tomography (CT) revealed a large retroperitoneal mass in the right upper abdomen with severe displacement of the inferior vena cava and renal veins. The patient was scheduled for primary tumor resection. The procedure was challenging due to the vessel involvement and large blood pressure alterations during tumor mobilization. The post-op pathologic workup then revealed the rare finding of a completely resected paraganglioma. The post-surgical course was uneventful. One year after diagnosis, the patient is relapse-free. CLINICAL DISCUSSION: Among retroperitoneal tumors, paragangliomas and pheochromocytomas are rare tumor entities. Asymptomatic, sporadic disease is hard to identify preoperatively and can cause unexpected complications in the OR. An experienced team is crucial in achieving best short- and long-term outcomes. CONCLUSION: This case impressively shows the challenges of retroperitoneal tumors and the importance of interdisciplinary work in these cases.

The Novel, Orally Bioavailable CDK9 Inhibitor Atuveciclib Sensitises Pancreatic Cancer Cells to TRAIL-induced Cell Death.

BACKGROUND/AIM: This study was designed to analyse the effects of the novel, orally bioavailable CDK9-inhibitor Atuveciclib (BAY 1143572) in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) on pancreatic ductal adenocarcinoma (PDAC) cancer cells. MATERIALS AND METHODS: To assess the effect of combinatorial use of atuveciclib and TRAIL on pancreatic cancer cells, we used an MTT assay, colony formation assay, flow cytometry, and western blot analysis. RESULTS: Atuveciclib combined with TRAIL significantly reduced the viability of pancreatic cancer cells and their colony formation potential by inducing apoptosis and cell-cycle arrest. Atuveciclib sensitised PDAC cells to TRAIL-induced cell death through the concomitant suppression of cFlip and Mcl-1. A gemcitabine-resistant PDAC cell-line and patient-derived xenograft (PDX) cell lines were also suppressed by this combinatorial approach. CONCLUSION: This study provides the basis for further preclinical and clinical evaluation of combined treatment with atuveciclib and TRAIL.

Stress-activated kinases as therapeutic targets in pancreatic cancer.

Pancreatic cancer is a dismal disease with high incidence and poor survival rates. With the aim to improve overall survival of pancreatic cancer patients, new therapeutic approaches are urgently needed. Protein kinases are key regulatory players in basically all stages of development, maintaining physiologic functions but also being involved in pathogenic processes. c-Jun N-terminal kinases (JNK) and p38 kinases, representatives of the mitogen-activated protein kinases, as well as the casein kinase 1 (CK1) family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors, DNA damage, and others. In their physiologic roles, they are responsible for the regulation of cell cycle progression, cell proliferation and differentiation, and apoptosis. Dysregulation of the underlying pathways consequently has been identified in various cancer types, including pancreatic cancer. Pharmacological targeting of those pathways has been the field of interest for several years. While success in earlier studies was limited due to lacking specificity and off-target effects, more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising in vitro results. Consequently, targeting of JNK, p38, and CK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these kinases. However, further studies are warranted, especially involving in vivo investigation and clinical trials, in order to advance inhibition of stress-activated kinases to the field of translational medicine.

Curing pancreatic cancer.

The distinct biology of pancreatic cancer with aggressive and early invasive tumor cells, a tumor promoting microenvironment, late diagnosis, and high therapy resistance poses major challenges on clinicians, researchers, and patients. In current clinical practice, a curative approach for pancreatic cancer can only be offered to a minority of patients and even for those patients, the long-term outcome is grim. This bitter combination will eventually let pancreatic cancer rise to the second leading cause of cancer-related mortalities. With surgery being the only curative option, complete tumor resection still remains the center of pancreatic cancer treatment. In recent years, new developments in neoadjuvant and adjuvant treatment have emerged. Together with improved perioperative care including complication management, an increasing number of patients have become eligible for tumor resection. Basic research aims to further increase these numbers by new methods of early detection, better tumor modelling and personalized treatment options. This review aims to summarize the current knowledge on clinical and biologic features, surgical and non-surgical treatment options, and the improved collaboration of clinicians and basic researchers in pancreatic cancer that will hopefully result in more successful ways of curing pancreatic 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.

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.

Patient-centered developments in colon- and rectal cancer with a multidisciplinary international team: From translational research to national guidelines.

Rarely, scientific developments centered around the patient as a whole are published. Our multidisciplinary group, headed by gastrointestinal surgeons, applied this research philosophy considering the most important aspects of the diseases "colon- and rectal cancer" in the long-term developments. Good expert cooperation/knowledge at the Comprehensive Cancer Center Ulm (CCCU) were applied in several phase III trials for multimodal treatments of primary tumors (MMT) and metastatic diseases (involving nearly 2000 patients and 64 centers), for treatment individualization of MMT and of metastatic disease, for psycho-oncology/quality of life involving the patients' wishes, and for disease prevention. Most of the targets initially were heavily rejected/discussed in the scientific communities, but now have become standards in treatments and national guidelines or are topics in modern translational research protocols involving molecular biology for e.g., "patient centered individualized treatment". In this context we also describe the paths we had to tread in order to realize our new goals, which at the end were highly beneficial for the patients from many points of view. This description is also important for students and young researchers who, with an actual view on our recent developments, might want to know how medical progress was achieved.

Opposing Oncogenic Functions of p38 Mitogen-activated Protein Kinase Alpha and Beta in Human Pancreatic Cancer Cells.

BACKGROUND/AIM: The p38 family of mitogen-activated protein kinases (MAPK) includes four isoforms: p38α, -ß, -γ and -δ. The aim of this study was to elucidate possible functions of p38α and p38ß in human pancreatic cancer. MATERIALS AND METHODS: Isoform expression was determined in seven human pancreatic cancer cell lines. After shRNA based selective knockdown of p38α and p38ß, in vitro growth and migration as well as in vivo tumorigenicity were assessed. RESULTS: All pancreatic cancer cells expressed p38 isoforms. Knockdown of p38α and p38ß inhibited in vitro growth. Migration was markedly reduced in p38α shRNA expressing clones, but not altered by p38ß knockdown. While in vivo inhibition of p38ß decreased tumor formation and growth, the knockdown of p38α significantly enhanced tumorigenicity. CONCLUSION: p38 MAPKs may exert isoform specific functions in pancreatic cancer. Selective targeting may contribute to individualized treatment of pancreatic cancer in the future.

Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated; however, the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present a xenotransplantation model of PDAC in which neoplasms originate from patient-derived organoids injected directly into murine pancreatic ducts. Our model enables distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner representing the classical or basal-like subtypes of PDAC, respectively. Parameters that influence PDAC subtype specification in this intraductal model include cell plasticity and hyperactivation of the RAS pathway. Finally, through intratumoral dissection and the direct manipulation of RAS gene dosage, we identify a suite of RAS-regulated secreted and membrane-bound proteins that may represent potential candidates for therapeutic intervention in patients with PDAC. SIGNIFICANCE: Accurate modeling of the molecular subtypes of pancreatic cancer is crucial to facilitate the generation of effective therapies. We report the development of an intraductal organoid transplantation model of pancreatic cancer that models the progressive switching of subtypes, and identify stochastic and RAS-driven mechanisms that determine subtype specification.See related commentary by Pickering and Morton, p. 1448.This article is highlighted in the In This Issue feature, p. 1426.

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.