Roger R. Gomis

TGFβ Primes Breast Tumors for Lung Metastasis Seeding through Angiopoietin-like 4

Cells released from primary tumors seed metastases to specific organs by a nonrandom process, implying the involvement of biologically selective mechanisms. Based on clinical, functional, and molecular evidence, we show that the cytokine TGFbeta in the breast tumor microenvironment primes cancer cells for metastasis to the lungs. Central to this process is the induction of angiopoietin-like 4 (ANGPTL4) by TGFbeta via the Smad signaling pathway. TGFbeta induction of Angptl4 in cancer cells that are about to enter the circulation enhances their subsequent retention in the lungs, but not in the bone. Tumor cell-derived Angptl4 disrupts vascular endothelial cell-cell junctions, increases the permeability of lung capillaries, and facilitates the trans-endothelial passage of tumor cells. These results suggest a mechanism for metastasis whereby a cytokine in the primary tumor microenvironment induces the expression of another cytokine in departing tumor cells, empowering these cells to disrupt lung capillary walls and seed pulmonary metastases.

Control of glycogen deposition.

Traditionally, glycogen synthase (GS) has been considered to catalyze the key step of glycogen synthesis and to exercise most of the control over this metabolic pathway. However, recent advances have shown that other factors must be considered. Moreover, the control of glycogen deposition does not follow identical mechanisms in muscle and liver. Glucose must be phosphorylated to promote activation of GS. Glucose‐6‐phosphate (Glc‐6‐P) binds to GS, causing the allosteric activation of the enzyme probably through a conformational rearrangement that simultaneously converts it into a better substrate for protein phosphatases, which can then lead to the covalent activation of GS. The potency of Glc‐6‐P for activation of liver GS is determined by its source, since Glc‐6‐P arising from the catalytic action of glucokinase (GK) is much more effective in mediating the activation of the enzyme than the same metabolite produced by hexokinase I (HK I). As a result, hepatic glycogen deposition from glucose is subject to a system of control in which the ‘controller’, GS, is in turn controlled by GK. In contrast, in skeletal muscle, the control of glycogen synthesis is shared between glucose transport and GS. The characteristics of the two pairs of isoenzymes, liver GS/GK and muscle GS/HK I, and the relationships that they establish are tailored to suit specific metabolic roles of the tissues in which they are expressed. The key enzymes in glycogen metabolism change their intracellular localization in response to glucose. The changes in the intracellular distribution of liver GS and GK triggered by glucose correlate with stimulation of glycogen synthesis. The translocation of GS, which constitutes an additional mechanism of control, causes the orderly deposition of hepatic glycogen and probably represents a functional advantage in the metabolism of the polysaccharide.

MiniAp-4: A Venom-Inspired Peptidomimetic for Brain Delivery

Abstract Drug delivery across the blood–brain barrier (BBB) is a formidable challenge for therapies targeting the central nervous system. Although BBB shuttle peptides enhance transport into the brain non‐invasively, their application is partly limited by lability to proteases. The present study proposes the use of cyclic peptides derived from venoms as an affordable way to circumvent this drawback. Apamin, a neurotoxin from bee venom, was minimized by reducing its complexity, toxicity, and immunogenicity, while preserving brain targeting, active transport, and protease resistance. Among the analogues designed, the monocyclic lactam‐bridged peptidomimetic MiniAp‐4 was the most permeable. This molecule is capable of translocating proteins and nanoparticles in a human‐cell‐based BBB model. Furthermore, MiniAp‐4 can efficiently deliver a cargo across the BBB into the brain parenchyma of mice.

Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate.

Aims/hypothesisSodium tungstate has recently emerged as an effective oral treatment for diabetes. We examined the effects of tungstate administration in the beta-cell mass of the pancreas as well as its therapeutic potential.MethodsSodium tungstate was administered via drinking water to healthy and neonatal streptozotocin (nSTZ)-diabetic rats for one month. The pancreas from each rat was removed and morphometric and immunocytochemical studies were carried out. The molecular mechanism of tungstate’s action was also studied.ResultsIn nSTZ rats administration of this compound normalised glycaemia, and increased insulinaemia and islet insulin content. Blood glucose concentrations were normalised as early as on day 4 of treatment, and tungstate treatment produced a partial recovery of beta-cell mass. The rats remained normoglycaemic after tungstate withdrawal. Morphometric studies showed that the increase in beta-cell mass was not due to beta-cell hypertrophy but to hyperplasia, with an increase in islet density in treated diabetic rats. Tungstate treatment increased extra-islet beta-cell replication without modifying intra-islet beta-cell replication rates. Moreover, the treatment induced increases in insulin-positive cells located close to ducts; and in PDX-1 positive cells scattered in the exocrine tissue, suggesting active neogenesis. In islets from treated diabetic rats, tungstate is able to increase the phosphorylation state of PDX-1 through the activation of p38.Conclusion/interpretationThese observations indicate that tungstate treatment is able to regenerate a stable, functional pancreatic beta-cell population which leads to and maintains normoglycaemia.

Serum levels of the interferon-γ-inducing cytokine interleukin-18 are increased in individuals at high risk of developing Type I diabetes

Aims/hypothesis. Interleukin (IL)-18 is a cytokine primarily produced by macrophages and capable of inducing T lymphocyte synthesis of interferon (IFN)-γ. An up-regulated synthesis of IFN-γ with consequential Type I cytokine dominance has been repeatedly shown in Type I (insulin-dependent) diabetes mellitus and thought to be involved in its pathogenesis. Because increased production of IFN-γ could be secondary to a dysregulated synthesis of IL-18, we compared the circulating levels of IL-18 in patients with newly diagnosed Type I diabetes with those of non-diabetic first-degree relatives and healthy control subjects. Methods. Serum samples were obtained from healthy control subjects, patients with newly diagnosed Type I diabetes, and their healthy first-degree relatives. The latter were subdivided into “low” and “high” risk prediabetics depending on whether they were negative or positive for two or more of the anti-pancreatic autoantibodies ICA, GAD, IA-2 and IAA. Serum levels of IL-18 were measured by solid-phase ELISA. Results. Interleukin (IL)-18 was above the detection limit of 25 pg/ml in 7 of 40 (17 %) healthy control subjects, in 5 of 35 (14 %) patients and in 3 of 30 (10 %) first-degree relatives at low risk of developing Type I diabetes. In contrast, IL-18 could be detected in 19 of 28 (68 %; p < 0.0001) relatives at high risk. The mean serum level of IL-18 was higher in these individuals when compared with the low-risk relatives, patients and control subjects. Conclusion/interpretation. IL-18 serum levels are increased selectively during the early, subclinical stage of Type I diabetes. [Diabetologia (2001) 44: 309–311]

Tungstate is an effective antidiabetic agent in streptozotocin-induced diabetic rats: a long-term study

Aims/hypothesis. Recent studies have shown the anti diabetic effects of oral sodium tungstate treatment in several animal models of diabetes based on short-term experiments. In this study, we examined the effectiveness of long-term tungstate treatment of streptozotocin-induced-diabetic rats. Methods. Tungstate was administered to the drinking water of rats for eight months. Results. The treatment resulted in a reduction in serum glucose concentrations in diabetic rats, but no change in glycaemia was detected in healthy rats. Alterations in the hepatic glucose metabolism due to diabetes were almost completely counteracted by tungstate treatment. The partial recovery of glucokinase activity, not found in diabetic animals, normalised glycogen and glucose 6-phosphate concentrations. Tungstate treatment also restored pyruvate kinase activity and fructose 2,6-bisphosphate concentrations. In healthy rats, tungstate treatment did not modify the majority of the hepatic parameters studied. Moreover, tungstate treatment prevented diabetes-induced morphological changes in the kidney and ocular lens and also reduced mortality. Furthermore, no hypoglycaemic episodes or undesirable side effects were observed in treated diabetic or healthy rats. In addition, there is no evidence of intolerance developing after prolonged use. Conclusion/interpretation. Tungstate could play a helpful part in the long-term treatment of diabetes. [Diabetologia (2001) 44: 507–513]

The metabolic co-regulator PGC1α suppresses prostate cancer metastasis

Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α–ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment.

Effect of nicotinamide therapy upon B-cell function in newly diagnosed type 1 (insulin-dependent) diabetic patients.

SummaryThis study describes the effects of nicotinamide therapy on B-cell function in Type 1 (insulin-dependent) diabetes. C-peptide secretion was studied in 20 patients newly diagnosed with Type 1 diabetes at basal state and also after an i.v. glucagon stimulus. Patients were randomly allocated according to a single-blind schedule, to one of the following treatments over a 45-day period: Group 1: 10 patients, nicotinamide 1 g/day; Group 2: 10 patients, placebo. The C-peptide secretion tests were performed before treatment and on days 15, 45, 180, 365 of the follow-up. The clinical and metabolic data were similar in the two groups of patients. Basal and stimulated C-peptide levels increased by 45 days in both groups, but the increase in stimulated C-peptide response was greater in the nicotinamide group (p<0.01). However, the B-cell function decreased after the period of nicotinamide administration. No difference in the number of clinical remissions or insulin requirement and HbA1 between the groups was observed. These data suggest that treatment of Type 1 diabetes with nicotinamide at diagnosis is associated with a moderate increase of C-peptide secretion recovery.

Colon cancer cells colonize the lung from established liver metastases through p38 MAPK signalling and PTHLH

The mechanisms that allow colon cancer cells to form liver and lung metastases, and whether KRAS mutation influences where and when metastasis occurs, are unknown. We provide clinical and molecular evidence showing that different MAPK signalling pathways are implicated in this process. Whereas ERK2 activation provides colon cancer cells with the ability to seed and colonize the liver, reduced p38 MAPK signalling endows cancer cells with the ability to form lung metastasis from previously established liver lesions. Downregulation of p38 MAPK signalling results in increased expression of the cytokine PTHLH, which contributes to colon cancer cell extravasation to the lung by inducing caspase-independent death in endothelial cells of the lung microvasculature. The concerted acquisition of metastatic traits in the colon cancer cells together with the sequential colonization of liver and lung highlights the importance of metastatic lesions as a platform for further dissemination.

Constitutive HER2 signaling promotes breast cancer metastasis through cellular senescence.

Senescence, a terminal cell proliferation arrest, can be triggered by oncogenes. Oncogene-induced senescence is classically considered a tumor defense barrier. However, several findings show that, under certain circumstances, senescent cells may favor tumor progression because of their secretory phenotype. Here, we show that the expression in different breast epithelial cell lines of p95HER2, a constitutively active fragment of the tyrosine kinase receptor HER2, results in either increased proliferation or senescence. In senescent cells, p95HER2 elicits a secretome enriched in proteases, cytokines, and growth factors. This secretory phenotype is not a mere consequence of the senescence status and requires continuous HER2 signaling to be maintained. Underscoring the functional relevance of the p95HER2-induced senescence secretome, we show that p95HER2-induced senescent cells promote metastasis in vivo in a non-cell-autonomous manner.