Cancer stem cells (CSCs) account for tumor initiation, invasiveness, metastasis, and recurrence in a broad range of human cancers. Although being a key player in cancer development and progression by stimulating proliferation and metastasis and preventing apoptosis, the role of the transcription factor NF-κB in cancer stem cells is still underestimated. In the present review, we will evaluate the role of NF-κB in CSCs of glioblastoma multiforme, ovarian cancer, multiple myeloma, lung cancer, colon cancer, prostate cancer, as well as cancer of the bone. Next to summarizing current knowledge regarding the presence and contribution of CSCs to the respective types of cancer, we will emphasize NF-κB-mediated signaling pathways directly involved in maintaining characteristics of cancer stem cells associated to tumor progression. Here, we will also focus on the status of NF-κB-activity predominantly in CSC populations and the tumor mass. Genetic alterations leading to NF-κB activity in glioblastoma, ependymoma, and multiple myeloma will be discussed.

Introduction: Several recent studies have shown that a positive fluid balance in critical illness is associated with worse outcome. We tested the effects of moderate vs. high-volume resuscitation strategies on mortality, systemic and regional blood flows, mitochondrial respiration, and organ function in two experimental sepsis models. Methods: 48 pigs were randomized to continuous endotoxin infusion, fecal peritonitis, and a control group (n = 16 each), and each group further to two different basal rates of volume supply for 24 hours [moderate-volume (10 ml/kg/h, Ringer's lactate, n = 8); high-volume (15 + 5 ml/kg/h, Ringer's lactate and hydroxyethyl starch (HES), n = 8)], both supplemented by additional volume boli, as guided by urinary output, filling pressures, and responses in stroke volume. Systemic and regional hemodynamics were measured and tissue specimens taken for mitochondrial function assessment and histological analysis. Results: Mortality in high-volume groups was 87% (peritonitis), 75% (endotoxemia), and 13% (controls). In moderate-volume groups mortality was 50% (peritonitis), 13% (endotoxemia) and 0% (controls). Both septic groups became hyperdynamic. While neither sepsis nor volume resuscitation strategy was associated with altered hepatic or muscle mitochondrial complex I- and II-dependent respiration, non-survivors had lower hepatic complex II-dependent respiratory control ratios (2.6 +/- 0.7, vs. 3.3 +/- 0.9 in survivors; P = 0.01). Histology revealed moderate damage in all organs, colloid plaques in lung tissue of high-volume groups, and severe kidney damage in endotoxin high-volume animals. Conclusions: High-volume resuscitation including HES in experimental peritonitis and endotoxemia increased mortality despite better initial hemodynamic stability. This suggests that the strategy of early fluid management influences outcome in sepsis. The high mortality was not associated with reduced mitochondrial complex I- or II-dependent muscle and hepatic respiration.

Several studies have demonstrated a direct correlation between lymph node yield and survival after colectomy for cancer. Complete mesocolic excision (CME) in right colectomy (RC) reduces local recurrence but is technically demanding. Here we report our early single center experience with robotic right colectomy comparing our standardized bottom-to-up (BTU) approach of robotic RC with CME and central vessel ligation (CVL) facilitated by a suprapubic access with the “classical” medial-to-lateral (MTL) strategy. A 4-step BTU approach of robotic RC guided by embryonal planes in the process of retrocolic mobilization with suprapubic port placement was performed in the BTU-group (n = 24; all with intention to treat cancer). In step 1 CME was initiated with caudolateral mobilization of the right colon guided by the fascia of Toldt across the duodenum and up to the Trunk of Henle. Subsequently, dissection was performed BTU right of the middle supramesenteric vessels with central ileocolic vessel ligation in step 2. Subsequent to separation of the transverse retromesenteric space and completion of mobilization the hepatic flexure in step 3, the transverse mesocolon was then transected right of the middle colic vessels in step 4. An extracorporeal side to side anastomosis was performed. We compared the outcome of the BTU-group with a MTL-group (n = 7). Patient characteristics like age, gender, BMI, comorbidity (ASA) and M-status were comparable among groups. There was no conversion. Overall complication rate was 35.5%. We experienced no anastomoses insufficiency, grade Dindo/Clavien III/IV complication or mortality in this study. Type I and II complications and surgical characteristics incl. OR-time, ICU- and hospital-stay were comparable between the two groups. However, the lymph node yield was superior in the BTU-group (mean 40.2 ± 17.1) when compared with the MTL-group (16,3 nodes ±8.5; p < 0,001). Compared to the classical MTL approach, robotic suprapubic BTU RC changes from a search of the layers bordering the oncological dissection to a consequent utilization of the planes as a retro-mesocolic guide during CME. The BTU strategy could bear the potential to increase the lymph node yield. Robotic systems may provide the technical requirements to combine advantages of both open and minimally invasive RC.

This study aimed to investigate the role of Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase 2 (PLOD2) in glioblastoma (GBM) pathophysiology. To this end, PLOD2 protein expression was assessed by immunohistochemistry in two independent cohorts of patients with primary GBM (n₁ = 204 and n₂ = 203, respectively). Association with the outcome was tested by Kaplan–Meier, log-rank and multivariate Cox regression analysis in patients with confirmed IDH wild-type status. The biological effects and downstream mechanisms of PLOD2 were assessed in stable PLOD2 knock-down GBM cell lines. High levels of PLOD2 significantly associated with (p₁ = 0.020; p₂< 0.001; log-rank) and predicted (cohort 1: HR = 1.401, CI [95%] = 1.009–1.946, p₁ = 0.044; cohort 2: HR = 1.493; CI [95%] = 1.042–2.140, p₂ = 0.029; Cox regression) the poor overall survival of GBM patients. PLOD2 knock-down inhibited tumor proliferation, invasion and anchorage-independent growth. MT1-MMP, CD44, CD99, Catenin D1 and MMP2 were downstream of PLOD2 in GBM cells. GBM cells produced soluble factors via PLOD2, which subsequently induced neutrophils to acquire a pro-tumor phenotype characterized by prolonged survival and the release of MMP9. Importantly, GBM patients with synchronous high levels of PLOD2 and neutrophil infiltration had significantly worse overall survival (p < 0.001; log-rank) compared to the other groups of GBM patients. These findings indicate that PLOD2 promotes GBM progression and might be a useful therapeutic target in this type of cancer.

There is growing evidence that cancer stem cells (CSCs), a small subpopulation of self-renewal cancer cells, are responsible for tumor growth, treatment resistance, and cancer relapse and are thus of enormous clinical interest. Here, we aimed to isolate new CSC-like cells derived from human primary non-small cell lung cancer (NSCLC) specimens and to analyze the influence of different inhibitors of NF-κB and MYC signaling on cell survival. CSC-like cells were established from three squamous cell carcinomas (SCC) and three adenocarcinomas (AC) of the lung and were shown to express common CSC markers such as Prominin-1, CD44-antigen, and Nestin. Further, cells gave rise to spherical cancer organoids. Inhibition of MYC and NF-κB signaling using KJ-Pyr-9, dexamethasone, and pyrrolidinedithiocarbamate resulted in significant reductions in cell survival for SCC- and AC-derived cells. However, inhibition of the protein–protein interaction of MYC/NMYC proto-oncogenes with Myc-associated factor X (MAX) using KJ-Pyr-9 revealed the most promising survival-decreasing effects. Next to the establishment of six novel in vitro models for studying NSCLC-derived CSC-like populations, the presented investigations might provide new insights into potential novel therapies targeting NF-κB/MYC to improve clinical outcomes in NSCLC patients. Nevertheless, the full picture of downstream signaling still remains elusive.