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Colorectal cancer (CRC) is one of the leading causes of cancer‐related deaths worldwide and the need for novel biomarkers and therapeutic strategies to improve diagnosis and surveillance is obvious. This study aims to identify β6‐integrin (ITGB6) as a novel serum tumor marker for diagnosis, prognosis, and surveillance of CRC. ITGB6 serum levels were validated in retro‐ and prospective CRC patient cohorts. ITGB6 serum levels were analyzed by ELISA. Using an initial cohort of 60 CRC patients, we found that ITGB6 is present in the serum of CRC, but not in non‐CRC control patients. A cut‐off of ≥2 ng/mL ITGB6 reveals 100% specificity for the presence of metastatic CRC. In an enlarged study cohort of 269 CRC patients, ITGB6 predicted the onset of metastatic disease and was associated with poor prognosis. Those data were confirmed in an independent, prospective cohort consisting of 40 CRC patients. To investigate whether ITGB6 can also be used for tumor surveillance, serum ITGB6‐levels were assessed in 26 CRC patients, pre‐ and post‐surgery, as well as during follow‐up visits. After complete tumor resection, ITGB6 serum levels declined completely. During follow‐up, a new rise in ITGB6 serum levels indicated tumor recurrence or the onset of new metastasis as confirmed by CT scan. ITGB6 was more accurate for prognosis of advanced CRC and for tumor surveillance as the established marker carcinoembryonic antigen (CEA). Our findings identify ITGB6 as a novel serum marker for diagnosis, prognosis, and surveillance of advanced CRC. This might essentially contribute to an optimized patient care.

Einleitung: Die Einbindung von Nachwuchswissenschaftlern in die chirurgische Forschung ist eine unabdingbare Voraussetzung für die Weiterentwicklung des Faches Chirurgie. Nachwuchswissenschaftler müssen für eine Karriere in der chirurgischen Forschung motiviert und begeistert werden. [for full text, please go to the a.m. URL], 132. Kongress der Deutschen Gesellschaft für Chirurgie

The human pathogen Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease, establishes lifelong latency upon infection. Murine gammaherpesvirus 68 (MHV68) is a well-established model for KSHV. Toll-like receptors (TLRs) play a crucial role for the innate immune response to pathogens. Although KSHV and MHV68 are detected by TLRs, studies suggest they modulate TLR4 and TLR9 signaling, respectively. In this study we show that in bone marrow-derived macrophages (BMDMs), MHV68 did not induce a detectable proinflammatory cytokine response. Furthermore, MHV68 abrogated the response to TLR2, 4, 7, and 9 agonists in BMDMs. Similarly to observations with MHV68, infection with KSHV efficiently inhibited TLR2 signaling in THP-1 monocytes. Using a KSHV ORF library, we found that K4.2, ORF21, ORF31, and RTA/ORF50 inhibited TLR2-dependent nuclear factor kappa B (NF-κB) activation in HEK293 TLR2-YFP and Flag-TLR2 transfected HEK 293T cells. Of the identified ORFs, the replication and transcription activator protein, RTA/ORF50, strongly downregulated TLR2 and TLR4 signaling by reducing TLR2 and TLR4 protein expression. Confocal microscopy revealed that TLR2 and TLR4 were no longer localized to the plasma membrane in cells expressing RTA/ORF50. In this study, we have shown that the gammaherpesviruses MHV68 and KSHV efficiently downmodulate TLR signaling in macrophages and have identified a novel function of RTA/ORF50 in modulation of the innate immune response. Importance Statement The Toll-like receptors (TLR) are an important class of pattern recognition receptors of the innate immune system. They induce a potent proinflammatory cytokine response upon detection of a variety of pathogens. In this study, we found that the gammaherpesviruses murine gammaherpesvirus 68 (MHV68) and Kaposi's sarcoma-associated herpesvirus (KSHV) efficiently inhibit the TLR-mediated innate immune response. We further identified the KSHV-encoded replication and transcription activator protein (RTA) as a novel modulator of TLR signaling. Our data suggest that the gammaherpesviruses MHV68 and KSHV prevent activation of the innate immune response by targeting TLR signaling.

The present study was designed to investigate whether cells cultured from Kaposi's sarcoma (KS), a vascular tumor with a prominent leukocyte infiltration, express molecules important for the recruitment and activation of leukocytes. KS cells expressed intercellular adhesion molecule-1, which was augmented by exposure to IL-1 beta or TNF-alpha. Unlike endothelial cells, resting or cytokine-activated KS cells did not express appreciable levels of intercellular adhesion molecule-2, vascular cell adhesion molecule-1, and E-selectin on their surface. Weak expression of vascular cell adhesion molecule-1 mRNA was detectable by Northern blot analysis and, most clearly, by PCR analysis. Upon exposure to inflammatory cytokines, KS cells produced the attractant/activating lipid platelet-activating factor. KS cells expressed appreciable levels of the chemotactic cytokines, monocyte chemotactic protein-1 (MCP-1) and IL-8, as determined by Northern blot analysis, immunoassay, or bioassay. Chemokine production was augmented by IL-1 beta or TNF-alpha. MCP-1 expression was also detected in KS lesions by in situ hybridization. The set of molecules identified in the present study is probably important in determining the prominent leukocyte infiltration observed in KS. Tumor-associated leukocytes may amplify autocrine/paracrine circuits that sustain KS proliferation and contribute to recruitment of host vascular cells.

Introduction: The presence of a Th1 adaptive immune response has been associated with improved clinical outcome and survival of patients with colorectal carcinoma (CRC). The Th1 adaptive immune response is mediated by IFN-γ. Using guanylate-binding protein 1 (GBP-1) as a well established marker[for full text, please go to the a.m. URL], 128. Kongress der Deutschen Gesellschaft für Chirurgie

Einleitung: Die Entscheidung für eine adjuvante Therapie erfolgt beim kolorektalen Karzinom anhand der TNM-Kriterien nach der Aufarbeitung des chirurgischen Resektats. Molekulare Faktoren im Primärtumor determinieren dessen Therapieresponse und Prognose. Nur wenige molekulare Marker werden[for full text, please go to the a.m. URL], 127. Kongress der Deutschen Gesellschaft für Chirurgie

Einleitung: Das kolorektale Karzinom stellt in Deutschland die zweithäufigste Krebserkrankung dar. Molekulare Marker, die eine Metastasierung der Tumoren anzeigen können, werden dringend benötigt. Material und Methoden: Eingeschlossen wurden fünf Patienten mit nicht-metastasiertem[for full text, please go to the a.m. URL], 126. Kongress der Deutschen Gesellschaft für Chirurgie

Einleitung: Angiogenese sowie weitere desmoplastische Stromareaktionen, wie z.B. Inflammation, besitzen Schlüsselfunktionen bei der Progression und Metastasierung kolorektaler Karzinome (KRK). Um den Einfluß des Tumors auf seine Umgebung molekularbiologisch analysieren zu können, wurden[for full text, please go to the a.m. URL], 126. Kongress der Deutschen Gesellschaft für Chirurgie

Einleitung: In zurückliegenden Arbeiten zeigten wir, dass inflammatorische Zytokine (IL-1β, TNF-α, IFN-γ) die Proliferation und Invasionsfähigkeit von Endothelzellen hemmen. Wir identifizierten die große GTPase Guanylat-Bindungsprotein-1 (GBP-1) als den intrazellulären[for full text, please go to the a.m. URL], 126. Kongress der Deutschen Gesellschaft für Chirurgie