Autocrine insulin-like growth factor 1 and stem cell factor but not interleukin 6 support self-renewal of human myeloma cells

In this study, we have identified the growth factors supporting myeloma self-renewal in eight myeloma cell lines. All cell lines able to form self-colonies displayed constitutive P-AKT and P-ERK1,2 but not P-STAT3 and did not express CD45, suggesting the presence of an insulin-like growth factor 1 (IGF1) loop. We showed that a blocking anti-insulin-like growth factor 1 receptor (IGF1R) monoclonal antibody (mAb) inhibited colony formation in correlation with IGF1R expression and decreased P-AKT. Imatinib or a blocking anti-stem cell factor (SCF) mAb also inhibited colony formation of two cell lines expressing C-KIT and SCF, and decreased P-AKT. Moreover, the PI3K/AKT pathway inhibitor wortmannin inhibited colony formation. Blocking interleukin (IL)6R did not inhibit colony formation in good agreement with a lack of constitutive P-STAT3. We showed that primary cells frequently co-expressed IGF1R/IGF1 but not C-KIT/SCF or IL6R/IL6, suggesting that in vivo autonomous growth could be possible via IGF1R. Despite their similar role in clonogenic growth and shared signaling pathway, IGF1R and C-KIT had opposite prognostic values, suggesting that they were surrogate markers. Indeed, we showed that both C-KIT and IGF1R prognostic values were not independent of MMSET expression. This study highlights the autocrine role of IGF1 in myeloma cells and reinforces the interest in targeting IGF1R in IGFR1⁺ CD45^+/− patients, such as MMSET⁺ patients.     

Regional sympathetic activity, severity of liver disease and hemodynamics in patients with cirrhosis.

One hundred and eight patients with cirrhosis (23 grade A, 46 grade B and 39 grade C, according to Pugh's classification) underwent hemodynamic studies and plasma catecholamine concentration measurements. Blood samples were withdrawn from the pulmonary artery (n = 108), the hepatic vein (n = 108), the azygos vein (n = 59), the right renal vein (n = 66), the right jugular vein (n = 34) and the femoral vein (n = 33). Plasma noradrenaline concentrations in the pulmonary artery and the hepatic vein were more elevated in grade B (607 +/- 52 and 402 +/- 42 pg/ml, respectively) and C patients (630 +/- 59 and 475 +/- 53 pg/ml, respectively) than in grade A patients (411 +/- 51 and 243 +/- 40 pg/ml, respectively). Plasma noradrenaline concentrations from these two vessels were negatively correlated with indocyanine green clearance. These results indicate that both overall and splanchnic sympathetic activities are dependent on altered hepatic function. Significant correlations were found between the wedged hepatic venous pressure and plasma noradrenaline concentrations from either the pulmonary artery, the hepatic vein or the azygos vein. These correlations indicate that both overall and splanchnic sympathetic activities are dependent on the degree of portal hypertension. Moreover, significant correlations were found between hepatic venous plasma noradrenaline concentrations and systemic hemodynamic values, suggesting that splanchnic sympathetic nervous activity could either play a role in the systemic hyperkinetic syndrome or be a consequence of this hyperkinetic syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevalence and short-term mortality of acute-on-chronic liver failure: A national cohort study from the USA

1. Download high-res image (177KB)
2. Download full-size image

     

Acute renal failure in patients with cirrhosis: perspectives in the age of MELD

In patients with cirrhosis, acute renal failure is mainly due to prerenal failure (caused by renal hypoperfusion) and tubular necrosis. The main causes of prerenal failure are "true hypovolemia" (induced by hemorrhage or gastrointestinal or renal fluid losses), sepsis, or type 1 hepatorenal syndrome (HRS). The frequency of prerenal failure due to the administration of nonsteroidal anti-inflammatory drugs or intravascular radiocontrast agents is unknown. Prerenal failure is rapidly reversible after restoration of renal blood flow. Treatment is directed to the cause of hypoperfusion, and fluid replacement is used to treat most cases of "non-HRS" prerenal failure. In patients with type 1 HRS with very low short-term survival rate, liver transplantation is the ideal treatment. Systemic vasoconstrictor therapy (with terlipressin, noradrenaline, or midodrine [combined with octreotide]) may improve renal function in patients with type 1 HRS waiting for liver transplantation. MARS (for molecular adsorbent recirculating system) and the transjugular intrahepatic portosystemic shunt may also improve renal function in these patients. In patients with cirrhosis, acute tubular necrosis is mainly due to an ischemic insult to the renal tubules. The most common condition leading to ischemic acute tubular necrosis is severe and sustained prerenal failure. Little is known about the natural course and treatment (i.e., renal replacement therapy) of cirrhosis-associated acute tubular necrosis.     

Relationship between oxygen transport and oxygen uptake in patients with cirrhosis: effects of vasoactive drugs

To elucidate the relationship between oxygen transport and uptake in cirrhosis, we studied the effects of three vasoactive drugs that change O2 transport. Systemic hemodynamics, blood gases and lactate concentration were measured in patients with alcoholic cirrhosis before and after intravenous dobutamine, propranolol and nitroglycerin. Nine patients received successively dobutamine and then propranolol. Ten patients received nitroglycerin. Three other patients without cirrhosis (controls) received dobutamine. In patients with cirrhosis, dobutamine infusion was accompanied by a significant increase in cardiac output (+21%), systemic O2 transport (+21%) and O2 uptake (+12%), whereas O2 extraction ratio and arterial lactate concentration did not change significantly. Propranolol administration was followed by a significant decrease in cardiac output (-24%) and systemic O2 transport (-25%) and a significant increase in O2 extraction ratio (+19%), whereas O2 uptake and arterial lactate concentration did not change. Nitroglycerin infusion was accompanied by a significant decrease in cardiac output (-21%), systemic O2 transport (-26%) and O2 uptake (-10%), whereas O2 extraction ratio (+18%) and arterial lactate concentration (+31%) significantly increased. In control patients, dobutamine infusion was accompanied by an increase in cardiac output and in systemic O2 transport and by a decrease in O2 extraction ratio, whereas O2 uptake was not modified. These results suggest that O2 uptake may be abnormally dependent on O2 transport in patients with cirrhosis.     

Interleukin-10 is a growth factor for human myeloma cells by induction of an oncostatin M autocrine loop

We have a previously reported that interleukin-10 (IL-10) is a potent but IL-6-unrelated growth factor for freshly explanted myeloma cells (Lu et al, Blood 85:2521, 1995). We have also shown that exogenous IL- 10 supported the growth of XG-1 and XG-2 human myeloma cell lines (HMCL) through an IL-6-independent mechanism. (Lu et al, Blood 85:2521, 1995). Because the IL-10 receptor does not involve the gp 130 IL-6 transducer, we have attempted to elucidate the mechanisms of IL-10 action on myeloma cells. Our results indicate that the myeloma cell growth factor activity of IL-10 was abrogated by an antibody to the gp 130 IL-6 transducer, indicating that it was mediated through one of the gp 130-activating cytokines. We found that myeloma cells from XG-1 and XG-2 HMCL and from 5 of 6 patients' tumoral samples produced oncostatin M (OM) constitutively but failed to produce IL-6, IL-11 and leukemia- inhibitory factor (LIF). The autocrine OM was inactive in the absence of IL-10 due to lack of a functional OM receptor on myeloma cells. IL- 10, by inducing the receptor for LIF (LIFR), produced a functional autocrine OM loop in XG-1 and XG-2 cells and in primary myeloma cells from 2 patients. We also found that some myeloma cell lines (XG-4, XG- 6, and XG-7) an fresh myeloma cells from 3 of 6 patients produced an autocrine IL-10 and that these cells constitutively expressed LIFR. One HMCL (XG-7) produced IL-10, OM, and IL-6 an expressed LIFR. The XG-7 cells used OM and IL-6 as autocrine growth factors. We have previously shown that IL-10 could induce IL-11 receptor in myeloma cells and confer on them sensitivity to IL-11 (Lu et al, FEBS Lett 377:515, 1995). Taken together, these results show that IL-10 is a key cytokine for inducing the expression of LIFR and IL-11R and possibly another uncharacterized OM coreceptor on myeloma cells and that OM and IL-10 might be produced by myeloma cells. They also emphasize that all myeloma cell growth factors reported to data involve an activation of the gp130 IL-6 transducer.     

The protective role of glucose on ischemic-reperfused hearts: effect of dietary fats.

The dietary polyunsaturated fatty acids are well known to promote the cardiac output and to protect the myocardium against arrhythmias. The exogenous glucose is generally considered as a protective agent against arrhythmias resulting from ischemia and reperfusion. But the effects of dietary fats, which also influence arrhythmias, on this beneficial effect of glucose has not been yet considered. We have studied the effects of a 7 days diet with or without polyunsaturated fatty acids on the cardiac performance and arrhythmias of isolated rat hearts, perfused with saline containing either glucose 5.5 mM or 11 mM. Acute regional ischemia was produced by ligature of the left main coronary artery with subsequent release to achieve reperfusion for some hearts. Previously, our results showed that the dietary polyunsaturated fatty acids led to an enhancement of the cardiac performance and to a decreased susceptibility to arrhythmias. The present data showed that the protective action of the exogenous glucose appeared to be dependent of the dietary lipid profile. Dietary polyunsaturated fatty acids increase cardiac performance under ischemia and decrease ventricular arrhythmias' occurrence under ischemia and on reperfusion. It might be related to endogenous substrate utilization and exogenous glucose availability which was influenced by the coronary flow.     

Human cytomegalovirus increases constitutive production of interleukin- 6 and leukemia inhibitory factor by bone marrow stromal cells

Human cytomegalovirus (CMV) infection is often associated with myelosuppression and acute inflammatory reaction in immunocompromised patients. We have previously documented that CMV exposure of bone marrow (BM) stromal cells reduces the capacity of these cells to support hematopoiesis because of a decreased production of colony- stimulating factors. This study examines the potential role of CMV on constitutive and lipopolysaccharide (LPS)-stimulated production of cytokines involved in inflammatory reaction, interleukin-6 (IL-6) and leukemia inhibitory factor (LIF) by BM stromal cells. The release of IL- 6 was already detectable 2 hours post CMV-infection (2.5-fold increase in production) and the cumulative production of IL-6 after 5 days of infection was 23 +/- 1.2 ng/mL (ninefold increase in production). CMV was also able to induce a time-dependent production of LIF that was maximal 8 hours after CMV infection (2.5-fold increase in production). Concomitantly, there was no detectable release of granulocyte colony- stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) by CMV-infected stromal cells. The similar IL-6 and LIF production in the presence of polymyxin B ruled out the possibility that this increase could be caused by contamination of the viral stock by endotoxin. In addition, ultraviolet-inactivated virus behaved similarly to live virus and caused the release of IL-6 and LIF. However, heat-inactivated CMV was unable to induce IL-6 and LIF secretion by BM stromal cells. The production of IL-6 and LIF was also evaluated after stimulation by LPS. After 5 days of CMV exposure, the LPS-stimulated production of IL-6 and LIF was significantly lower than uninfected controls. This LPS-induced release of cytokine production was found to be dependent of viral replication. The experiments have shown that CMV is a potent inducer of IL-6 and LIF with differential effect on constitutive and LPS- stimulated cytokine production by stromal cells; we suggest that CMV induction of IL-6 and LIF during the first hours of infection could play a role in CMV-induced inflammatory reaction. Moreover, our results show that human CMV can disturb the balanced cytokine network involved in the regulation of hematopoiesis.     

A humanised tissue‐engineered bone model allows species‐specific breast cancer‐related bone metastasis in vivo

Bone metastases frequently occur in the advanced stages of breast cancer. At this stage, the disease is deemed incurable. To date, the mechanisms of breast cancer‐related metastasis to bone are poorly understood. This may be attributed to the lack of appropriate animal models to investigate the complex cancer cell–bone interactions. In this study, two established tissue‐engineered bone constructs (TEBCs) were applied to a breast cancer‐related metastasis model. A cylindrical medical‐grade polycaprolactone‐tricalcium phosphate scaffold produced by fused deposition modelling (scaffold 1) was compared with a tubular calcium phosphate‐coated polycaprolactone scaffold fabricated by solution electrospinning (scaffold 2) for their potential to generate ectopic humanised bone in NOD/SCID mice. While scaffold 1 was found not suitable to generate a sufficient amount of ectopic bone tissue due to poor ectopic integration, scaffold 2 showed excellent integration into the host tissue, leading to bone formation. To mimic breast cancer cell colonisation to the bone, MDA‐MB‐231, SUM1315, and MDA‐MB‐231BO breast cancer cells were cultured in polyethylene glycol‐based hydrogels and implanted adjacent to the TEBCs. Histological analysis indicated that the breast cancer cells induced an osteoclastic reaction in the TEBCs, demonstrating analogies to breast cancer‐related bone metastasis seen in patients.     

Liver phospholipidosis induced by parenteral nutrition: histologic, histochemical, and ultrastructural investigations

Histochemical and electron microscopic examinations of the liver were performed in 5 adults receiving parenteral nutrition for greater than 18 mo and in 4 adults receiving parenteral nutrition for less than 5 mo. Phospholipidosis, reflected by the presence of cytoplasmic phospholipid deposits at histochemical examination and the presence of multilamellar lysosomes at electron microscopy, was marked and present in hepatocytes, Kupffer cells, and portal macrophages in all 5 patients receiving parenteral nutrition for greater than 18 mo. Mild phospholipidosis, affecting only hepatocytes, was demonstrated in 3 of the 4 patients receiving parenteral nutrition for less than 5 mo. These findings indicate that liver phospholipidosis is relatively common in patients receiving parenteral nutrition and that the degree of liver phospholipidosis depends on the duration of parenteral nutrition. Liver phospholipidosis might be due to intrahepatic accumulation of intravenous phospholipids provided by fat-emulsion sources.