utilizing-high-resolution-ultrasound-to-monitor-tumor-onset-growth

Utilizing High Resolution Ultrasound to Monitor Tumor Onset and Growth in Genetically Engineered Pancreatic Cancer Models

The LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mouse model represents an established and frequently used transgenic model to evaluate novel ...

University Medical Center Goettingen

In adaptation to oncogenic signals, pancreatic ductal adenocarcinoma (PDAC) cells undergo epithelial-mesenchymal transition (EMT), a process combining tumor cell dedifferentiation with acquisition of stemness features. However, the mechanisms linking oncogene-induced signaling pathways with EMT and stemness remain largely elusive. Here, we uncover the inflammation-induced transcription factor NFATc1 as a central regulator of pancreatic cancer cell plasticity. In particular, we show that NFATc1 drives EMT reprogramming and maintains pancreatic cancer cells in a stem cell-like state through Sox2-dependent transcription of EMT and stemness factors. Intriguingly, NFATc1-Sox2 complex-mediated PDAC dedifferentiation and progression is opposed by antithetical p53-miR200c signaling, and inactivation of the tumor suppressor pathway is essential for tumor dedifferentiation and dissemination both in genetically engineered mouse models (GEMM) and human PDAC. Based on these findings, we propose the existence of a hierarchical signaling network regulating PDAC cell plasticity and suggest that the molecular decision between epithelial cell preservation and conversion into a dedifferentiated cancer stem cell-like phenotype depends on opposing levels of p53 and NFATc1 signaling activities.

Antithetical NFATc1-Sox2 and p53-miR200 signaling networks govern pancreatic cancer cell plasticity.

Oncogenic mutations in KRAS contribute to the development of pancreatic ductal adenocarcinoma, but are not sufficient to initiate carcinogenesis. Secondary events, such as inflammation-induced signaling via the epidermal growth factor receptor (EGFR) and expression of the SOX9 gene, are required for tumor formation. Herein we sought to identify the mechanisms that link EGFR signaling with activation of SOX9 during acinar-ductal metaplasia, a transdifferentiation process that precedes pancreatic carcinogenesis.

NFATc1 Links EGFR Signaling to Induction of Sox9 Transcription and Acinar-Ductal Transdifferentiation in the Pancreas.

Hepatocellular carcinoma (HCC) is the most common liver-derived malignancy with a high fatality rate. Risk factors for the development of HCC have been identified and are clearly described. However, due to the lack of tumor-specific symptoms, HCC are diagnosed at progressed tumor stages in most patients, and thus curative therapeutic options are limited. The focus of this review is on surgical therapeutic options which can be offered to patients with HCC with special regard to recent findings, not exclusively focused on surgical therapy, but also to other treatment modalities. Further, potential promising future perspectives for the treatment of HCC are discussed.

Hepatocellular carcinoma: Surgeon's view on latest findings and future perspectives.

Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) is known to play an important role in hepatic inflammation. Therefore, we investigated the role of PECAM-1 in wild-type (WT) and knock-out (KO)-mice after single-dose liver irradiation (25 Gy). Both, at mRNA and protein level, a time-dependent decrease in hepatic PECAM-1, corresponding to an increase in intercellular cell adhesion molecule-1 (ICAM-1) (6 hrs) was detected in WT-mice after irradiation. Immunohistologically, an increased number of neutrophil granulocytes (NG) (but not of mononuclear phagocytes) was observed in the liver of WT and PECAM-1-KO mice at 6 hrs after irradiation. The number of recruited NG was higher and prolonged until 24 hrs in KO compared to WT-mice. Correspondingly, a significant induction of hepatic tumour necrosis factor (TNF)-α and CXC-chemokines (KC/CXCL1 interleukin-8/CXCL8) was detected together with an elevation of serum liver transaminases (6-24 hrs) in WT and KO-mice. Likewise, phosphorylation of signal transducer and activator of transcription-3 (STAT-3) was observed in both animal groups after irradiation. The level of all investigated proteins as well as of the liver transaminases was significantly higher in KO than WT-mice. In the cell-line U937, irradiation led to a reduction in PECAM-1 in parallel to an increased ICAM-1 expression. TNF-α-blockage by anti-TNF-α prevented this change in both proteins in cell culture. Radiation-induced stress conditions induce a transient accumulation of granulocytes within the liver by down-regulation/absence of PECAM-1. It suggests that reduction/lack in PECAM-1 may lead to greater and prolonged inflammation which can be prevented by anti-TNFα.

Role of PECAM-1 in radiation-induced liver inflammation.

Necrotising pancreatitis, and particularly infected necrosis, are still associated with high morbidity and mortality. Since 2011, a step-up approach with lower morbidity rates compared to initial open necrosectomy has been established. However, mortality and complication rates of this complex treatment are hardly studied thereafter.

Open Surgical versus Minimal Invasive Necrosectomy of the Pancreas-A Retrospective Multicenter Analysis of the German Pancreatitis Study Group.

Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most aggressive malignancies with a 5-year survival rate of <7%. Due to growing incidence, late diagnosis and insufficient treatment options, PDAC is predicted to soon become one of the leading causes of cancer-related death. Although intensified cytostatic combinations, particularly gemcitabine plus nab-paclitaxel and the folinic acid, fluorouracil, irinotecan, oxaliplatin (FOLFIRINOX) protocol, provide some improvement in efficacy and survival compared with gemcitabine alone, a breakthrough in the treatment of metastatic pancreatic cancer remains out of sight. Nevertheless, recent translational research activities propose that either modulation of the immune response or pharmacological targeting of epigenetic modifications alone, or in combination with chemotherapy, might open highly powerful therapeutic avenues in GI cancer entities, including pancreatic cancer. Deregulation of key epigenetic factors and chromatin-modifying proteins, particularly those responsible for the addition, removal or recognition of post-translational histone modifications, are frequently found in human pancreatic cancer and hence constitute particularly exciting treatment opportunities. This review summarises both current clinical trial activities and discovery programmes initiated throughout the biopharma landscape, and critically discusses the chances, hurdles and limitations of epigenetic-based therapy in future PDAC treatment.

Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon?

We report the case of a 70-year-old man who presented with hematochezia, anaemia, and severe abdominal pain 6 days after polypectomy. Contrast-enhanced ultrasound and computed tomography revealed no signs of free intra-abdominal air but showed intra-abdominal and intra-luminal bleeding. The patient was referred to colonoscopy in the operation room, which showed a coagula and venous bleeding at the polypectomy site. Emergency laparotomy was performed and revealed a large intra-abdominal mesocolic hematoma, which was surgically removed. The patient's post-operative recovery was uneventful. While few reports of splenic vessel rupture after colonoscopy due to traction on the splenocolic ligament have been published, delayed mesocolic hematoma without evidence of organ damage has not been reported so far. Clinicians need to be aware of these rare but life-threatening complications following colonoscopy.

A case report of delayed intra-abdominal and intra-luminal haemorrhage after polypectomy.

Chromogranin A (CgA) is a well-established marker for diagnosis and follow up of patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). Recently, it has been shown that plasma levels of CgA correlate with tumor load and predict survival of patients with NEN of the small bowel. It is assumed that this is as well valid for NEN of the colon and rectum, however, this is not supported by data. To evaluate this assumption, we analyzed 62 patients with NEN of the colon and rectum listed in the Marburg GEP-NEN registry for clinicopathological characteristics, expression and plasma levels of CgA. The present study demonstrates that immunohistochemical CgA and synaptophysin are good markers for histological diagnosis in patients with NEN of the colon and rectum. However, plasma CgA is a poor marker to follow-up these patients because only a minority exhibited increased levels which did not increase significantly during tumor progression. In contrast to NEN of the small bowel, there is no correlation of CgA plasma levels with tumor burden or survival. Patients with NEN of the colon and rectum displayed a relatively good prognosis resulting in a median survival of 8.5 years. However, a subset of patients affected by G3 neoplasms, exhibited a poorer prognosis with a median survival of 2.5 years. Taken together, CgA is a valuable marker for immunohistochemical diagnosis, but CgA plasma concentration is not suitable to mirror tumor burden or prognosis in patients with NEN of the colon and rectum.

Article	Year
Antithetical NFATc1-Sox2 and p53-miR200 signaling networks govern pancreatic cancer cell plasticity. The EMBO journal\| PubMed ID: 25586376	2015
NFATc1 Links EGFR Signaling to Induction of Sox9 Transcription and Acinar-Ductal Transdifferentiation in the Pancreas. Gastroenterology\| PubMed ID: 25623042	2015
Hepatocellular carcinoma: Surgeon's view on latest findings and future perspectives. World journal of hepatology\| PubMed ID: 26019733	2015
Role of PECAM-1 in radiation-induced liver inflammation. Journal of cellular and molecular medicine\| PubMed ID: 26177067	2015
Open Surgical versus Minimal Invasive Necrosectomy of the Pancreas-A Retrospective Multicenter Analysis of the German Pancreatitis Study Group. PloS one\| PubMed ID: 27668746	2016
Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon? Gut\| PubMed ID: 27811314	2017
A case report of delayed intra-abdominal and intra-luminal haemorrhage after polypectomy. Zeitschrift fur Gastroenterologie\| PubMed ID: 29020700	2017
Clinicopathological hallmarks and biomarkers of colorectal neuroendocrine neoplasms. PloS one\| PubMed ID: 29232390	2017

Volker Ellenrieder

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