RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis

Tumor suppression that is mediated by oncogene-induced senescence (OIS) is considered to function as a safeguard during development of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that regulate OIS in PDAC are poorly understood. Here, we have determined that nuclear RelA reinforces OIS to inhibit carcinogenesis in the Kras mouse model of PDAC. Inactivation of RelA accelerated pancreatic lesion formation in Kras mice by abrogating the senescence-associated secretory phenotype (SASP) gene transcription signature. Using genetic and pharmacological tools, we determined that RelA activation promotes OIS via elevation of the SASP factor CXCL1 (also known as KC), which activates CXCR2, during pancreatic carcinogenesis. In Kras mice, pancreas-specific inactivation of CXCR2 prevented OIS and was correlated with increased tumor proliferation and decreased survival. Moreover, reductions in CXCR2 levels were associated with advanced neoplastic lesions in tissue from human pancreatic specimens. Genetically disabling OIS in Kras mice caused RelA to promote tumor proliferation, suggesting a dual role for RelA signaling in pancreatic carcinogenesis. Taken together, our data suggest a pivotal role for RelA in regulating OIS in preneoplastic lesions and implicate the RelA/CXCL1/CXCR2 axis as an essential mechanism of tumor surveillance in PDAC

Risk Factors and Therapeutic Targets in Pancreatic Cancer

Pancreatic cancer (PC) is one of the most challenging tumor entities worldwide, characterized as a highly aggressive disease with dismal overall prognosis and an incidence rate equalling mortality rate. Over the last decade, substantial progress has been made to define the morphological changes and key genetic events in pancreatic carcinogenesis. And yet, it is still unclear what factors trigger PC. Some risk factors appear to be associated with sex, age, race/ethnicity, or other rare genetic conditions. Additionally, modifying factors such as smoking, obesity, diabetes, occupational risk factors, etc. increase the potential for acquiring genetic mutations that may result in PC.Another hallmark of PC is its poor response to radio- and chemotherapy. Current chemotherapeutic regimens could not provide substantial survival benefit with a clear increase in overall survival. Recently, several new approaches to significantly improve the clinical outcome of PC have been described involving downstream signalling cascades desmoplasia and stromal response as well as tumor microenvironment, immune response, vasculature, and angiogenesis. This review summarizes major risk factors for PC and tries to illuminate relevant targets considerable for new therapeutic approaches

Basophil Recruitment into Tumor-Draining Lymph Nodes Correlates with Th2 Inflammation and Reduced Survival in Pancreatic Cancer Patients

In pancreatic ductal adenocarcinomas (PDAC), lymphoid infiltrates, comprised mainly of Th2 cells, predict a poor survival outcome in patients. IL4 signaling has been suggested to stabilize the Th2 phenotype in this setting, but the cellular source of IL4 in PDAC is unclear. Here, we show that basophils expressingIL4are enriched in tumor-draining lymph nodes (TDLN) of PDAC patients. Basophils present in TDLNs correlated significantly with the Th2/Th1 cell ratio in tumors, where they served as an independent prognostic biomarker of patient survival after surgery. Investigations in mouse models of pancreatic cancer confirmed a functional role for basophils during tumor progression. The recruitment of basophils into TDLN relied partly upon the release of chemokine CCL7/MCP3 by "alternatively activated" monocytes, whereas basophil activation was induced by T-cell-derived IL3. Our results show how basophils recruited and activated in TDLNs under the influence of the tumor microenvironment regulate tumor-promoting Th2 inflammation in PDAC, helping in illuminating a key element of the immune milieu of pancreatic cancer.Cancer Res; 76(7); 1-12. ©2016 AACR

Anwendungen der Fourier-Transformation auf Bilddaten aus der zerstoerungsfreien Pruefung

TIB: RA 3123 (122),2 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLE2. ed.DEGerman

Lungenkarzinom, nicht-kleinzellig (NSCLC)

Das Lungenkarzinom ist bei Frauen der dritt-, bei Männern der zweithäufigste maligne Tumor in den deutschsprachigen Ländern. Das mediane Erkrankungsalter liegt zwischen 68 und 70 Jahren. Hauptrisikofaktor ist Rauchen. Screening asymptomatischer Risikopersonen mittels einer Niedrigdosis-Computertomographie kann Lungenkarzinome in frühen Stadien erkennen und die Mortalität bei Rauchern und in noch größerem Ausmaß bei Raucherinnen senken, ist aber in den deutschsprachigen Ländern bisher noch nicht als Früherkennungsprogramm implementiert. Das Lungenkarzinom ist ein Paradebeispiel für die Entwicklung der modernen Onkologie. Noch bis vor kurzem in zwei wesentlichen Diagnosen (kleinzelliges und nicht-kleinzelliges Lungenkarzinom) zusammengefasst, wird das Lungenkarzinom heute in zahlreiche, biologisch unterschiedliche Entitäten mit eigenen Behandlungskonzepten eingeteilt. Die Prognose der Patient*innen wird u. a. vom Stadium, dem Genotyp, der Histologie, dem Geschlecht, dem Allgemeinzustand und der Komorbidität bestimmt. Therapieoptionen sind Operation, Bestrahlung und systemische Therapie, häufig kombiniert als multimodales Konzept. Patient*innen mit nicht-kleinzelligem Lungenkarzinom (NSCLC) haben in frühen und in einem Teil der fortgeschrittenen Stadien einen kurativen Therapieanspruch. Für die große Mehrzahl von Patient*innen im Stadium IIIB/C und IV ist die Therapie nicht kurativ. In den letzten Jahren hat die Integration von Immuncheckpoint- und Kinase-Inhibitoren im Zusammenhang mit prädiktiven Biomarkern die Prognose vieler Patient*innen deutlich verbessert. Darüber hinaus stehen Zytostatika, Angiogenese-Inhibitoren, lokale endoskopische und perkutane interventionelle Therapien sowie unterstützende Maßnahmen zur Verfügung. Die Behandlung von Patient*innen mit kleinzelligem Lungenkarzinom ist Gegenstand von Onkopedia Kleinzelliges Lungenkarzinom