Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties.

Cell-type plasticity within a tumor has recently been suggested to cause a bidirectional conversion between tumor-initiating stem cells and nonstem cells triggered by an inflammatory stroma. NF-κB represents a key transcription factor within the inflammatory tumor microenvironment. However, NF-κB's function in tumor-initiating cells has not been examined yet. Using a genetic model of intestinal epithelial cell (IEC)-restricted constitutive Wnt-activation, which comprises the most common event in the initiation of colon cancer, we demonstrate that NF-κB modulates Wnt signaling and show that IEC-specific ablation of RelA/p65 retards crypt stem cell expansion. In contrast, elevated NF-κB signaling enhances Wnt activation and induces dedifferentiation of nonstem cells that acquire tumor-initiating capacity. Thus, our data support the concept of bidirectional conversion and highlight the importance of inflammatory signaling for dedifferentiation and generation of tumor-initiating cells in vivo.

Opposing functions of IKKbeta during acute and chronic intestinal inflammation.

NF-kappaB is a key transcriptional regulator of inflammatory responses, but also controls expression of prosurvival genes, whose products protect tissues from damage and may thus act indirectly in an antiinflammatory fashion. The variable importance of these two distinct NF-kappaB-controlled responses impacts the potential utility of NF-kappaB inhibition as a treatment strategy for intractable inflammatory conditions, such as inflammatory bowel disease. Here, we show in murine models that inhibition of IKKbeta-dependent NF-kappaB activation exacerbates acute inflammation, but attenuates chronic inflammatory disease in the intestinal tract. Acute ulcerating inflammation is aggravated because of diminished NF-kappaB-mediated protection against epithelial cell apoptosis and delayed mucosal regeneration secondary to reduced NF-kappaB-dependent recruitment of inflammatory cells that secrete cytoprotective factors. In contrast, in IL-10-deficient mice, which serve as a model of chronic T cell-dependent colitis, ablation of IKKbeta in the intestinal epithelium has no impact, yet IKKbeta deficiency in myeloid cells attenuates inflammation and prolongs survival. These results highlight the striking context and tissue dependence of the proinflammatory and antiapoptotic functions of NF-kappaB. Our findings caution against the therapeutic use of IKKbeta/NF-kappaB inhibitors in acute inflammatory settings dominated by cell loss and ulceration.

Preinterventional hydrocortisone sustains the endothelial glycocalyx in cardiac surgery.

BACKGROUND: Patients undergoing cardiac surgery commonly develop systemic inflammation associated with tissue edema, which impairs outcome. One main pathomechanism leading to the edema is the deterioration of the endothelial glycocalyx, a key component of the vascular barrier. In animal models hydrocortisone has proved to be protective for the glycocalyx. OBJECTIVE: This trial evaluates the effect of hydrocortisone on glycocalyx integrity in patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: In a prospective, randomized interventional pilot trial, 30 patients received either hydrocortisone (100 mg over 10 min) or placebo (saline control) before surgery. Plasma concentrations of glycocalyx constituents (syndecan-1, heparan sulfate) and various clinical parameters (respiratory and renal function, inflammatory markers, use of vasopressors, length of stay at the intensive care unit) were measured. Primary endpoint was a significant difference of glycocalyx constituents in plasma. Comparisons were made with Friedman's and Wilcoxon tests (paired data), or the Kruskal-Wallis and Mann-Whitney U tests (unpaired data). Holm-Bonferroni method was used for post-hoc corrections. RESULTS: Heparan sulfate and syndecan-1 increased significantly during and after cardiac surgery with cardiopulmonary bypass in both groups. Whereas the maximum increase of heparan sulfate was 12.3-fold in the control vs. 3.8-fold in the pretreated group (p < 0.05), syndecan-1 values showed no significant difference between the groups (maximal increase 3-fold). The inflammatory markers C-reactive protein and interleukin-6 were also higher in the control than in the hydrocortisone group, but there was no difference in patient mortality (zero), or in any clinical parameters. CONCLUSIONS: Pretreatment with hydrocortisone ameliorated shedding of heparan sulfate, a major constituent of the endothelial glycocalyx, in patients undergoing cardiac surgery with cardiopulmonary bypass, but had no relevant influence on various clinical parameters or patient mortality. The relatively small number of patients in this pilot study probably precluded detection of positive outcome differences.

Perioperative intra-aortic balloon counterpulsation in a patient with myocardium at risk undergoing urgent noncardiac surgery.

We are presenting the case of a 76-year-old female scheduled for major abdominal surgery. Her past medical history was remarkable for a three-vessel coronary artery disease, with a severely impaired left ventricular function. She had already undergone complex coronary artery bypass surgery. Currently, she presented with the rare constellation of a hemodynamic relevant and interventionally intractable stenosis of the left subclavian artery proximal to a crucial coronary bypass from left internal mammary artery to the left anterior descending. To protect this patient from perioperative myocardial infarction, an intra-aortic balloon pump was successfully used.

IKKα promotes intestinal tumorigenesis by limiting recruitment of M1-like polarized myeloid cells.

The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify IκB kinase α (IKKα) as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon γ (IFNγ)-expressing M1-like myeloid cells. In IKKα mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKKα mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKKα as a promising target for colorectal cancer (CRC) therapy.

Routine use of corticosteroids to prevent inflammation response in cardiac surgery.

Cardiac surgery, especially if it involves cardiopulmonary bypass, is associated with a severe systemic inflammatory response. It is characterized by complement activation and initiation of coagulation, fibrinolysis and kallikrein cascades. Consecutive activation of immunoregulatory cells results in an extensive release of pro- and anti-inflammatory cytokines. This inflammatory storm is related to organ dysfunction or failure and correlates with postoperative morbidity. In order to attenuate this deleterious inflammatory response in the perioperative period alternative surgical techniques, novel extracorporeal circulation devices and immunomodulatory pharmacological strategies are in focus of contemporary research. Since decades corticosteroids have been used and studied in patients undergoing cardiac surgery. Although it could be shown that glucocorticoids seem to change the pro-inflammatory cytokine profile in a favourable manner, it still remains controversial if this effect translates into a better clinical outcome. Several clinical trials have proclaimed an association between this inflammatory response and the incidence of major complications i.e, myocardial infarction and pulmonary complications, but until now they have failed to show conclusive results. This article describes the different types and recommended dose schemes of corticosteroids in the perioperative period of cardiac surgery along with the discussion of few patents. It will comment on potential side effects and review the effect on the postoperative outcome.

gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis.

Although gastrointestinal cancers are frequently associated with chronic inflammation, the underlying molecular links have not been comprehensively deciphered. Using loss- and gain-of-function mice in a colitis-associated cancer model, we establish here a link comprising the gp130/Stat3 transcription factor signaling axis. Mutagen-induced tumor growth and multiplicity are reduced following intestinal epithelial cell (IEC)-specific Stat3 ablation, while its hyperactivation promotes tumor incidence and growth. Conversely, IEC-specific Stat3 deficiency enhances susceptibility to chemically induced epithelial damage and subsequent mucosal inflammation, while excessive Stat3 activation confers resistance to colitis. Stat3 has the capacity to mediate IL-6- and IL-11-dependent IEC survival and to promote proliferation through G1 and G2/M cell-cycle progression as the common tumor cell-autonomous mechanism that bridges chronic inflammation to tumor promotion.