Targeting the Lactate Transporter MCT1 in Endothelial Cells Inhibits Lactate-Induced HIF-1 Activation and Tumor Angiogenesis

Switching to a glycolytic metabolism is a rapid adaptation of tumor cells to hypoxia. Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating tumor cells, it also creates a gradient of lactate that mirrors the gradient of oxygen in tumors. More than a metabolic waste, the lactate anion is known to participate to cancer aggressiveness, in part through activation of the hypoxia-inducible factor-1 (HIF-1) pathway in tumor cells. Whether lactate may also directly favor HIF-1 activation in endothelial cells (ECs) thereby offering a new druggable option to block angiogenesis is however an unanswered question. In this study, we therefore focused on the role in ECs of monocarboxylate transporter 1 (MCT1) that we previously identified to be the main facilitator of lactate uptake in cancer cells. We found that blockade of lactate influx into ECs led to inhibition of HIF-1-dependent angiogenesis. Our demonstration is based on the unprecedented characterization of lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in vascular endothelial growth factor receptor 2 (VEGFR2) and basic fibroblast growth factor (bFGF) expression. Furthermore, using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of tumor angiogenesis through intravital microscopy and immunohistochemistry, we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects. Together with the previous demonstration of MCT1 being a key regulator of lactate exchange between tumor cells, the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities

The association of N-palmitoylethanolamine with the FAAH inhibitor URB597 impairs melanoma growth through a supra-additive action

<p>Abstract</p> <p>Background</p> <p>The incidence of melanoma is considerably increasing worldwide. Frequent failing of classical treatments led to development of novel therapeutic strategies aiming at managing advanced forms of this skin cancer. Additionally, the implication of the endocannabinoid system in malignancy is actively investigated.</p> <p>Methods</p> <p>We investigated the cytotoxicity of endocannabinoids and their hydrolysis inhibitors on the murine B16 melanoma cell line using a MTT test. Enzyme and receptor expression was measured by RT-PCR and enzymatic degradation of endocannabinoids using radiolabeled substrates. Cell death was assessed by Annexin-V/Propidium iodine staining. Tumors were induced in C57BL/6 mice by s.c. flank injection of B16 melanoma cells. Mice were injected i.p. for six days with vehicle or treatment, and tumor size was measured each day and weighted at the end of the treatment. Haematoxylin-Eosin staining and TUNEL assay were performed to quantify necrosis and apoptosis in the tumor and endocannabinoid levels were quantified by HPLC-MS. Tube formation assay and CD31 immunostaining were used to evaluate the antiangiogenic effects of the treatments.</p> <p>Results</p> <p>The <it>N</it>-arachidonoylethanolamine (anandamide, AEA), 2-arachidonoylglycerol and <it>N</it>- palmitoylethanolamine (PEA) reduced viability of B16 cells. The association of PEA with the fatty acid amide hydrolase (FAAH) inhibitor URB597 considerably reduced cell viability consequently to an inhibition of PEA hydrolysis and an increase of PEA levels. The increase of cell death observed with this combination of molecules was confirmed in vivo where only co-treatment with both PEA and URB597 led to decreased melanoma progression. The antiproliferative action of the treatment was associated with an elevation of PEA levels and larger necrotic regions in the tumor.</p> <p>Conclusions</p> <p>This study suggests the interest of targeting the endocannabinoid system in the management of skin cancer and underlines the advantage of associating endocannabinoids with enzymatic hydrolysis inhibitors. This may contribute to the improvement of long-term palliation or cure of melanoma.</p

Carcinome epidermoide colorectal et hypercalcemie paraneoplasique

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Sclérose tubéreuse de Bourneville et polypose colique

Tuberous sclerosis is an autosomal dominant genetic disorder that is characterized by epilepsy, mental retardation and facial angiofibromas. Usually, the disease is diagnosed in childhood but there are frustrates form of tuberous sclerosis with or without genetic mutation. This clinical case about a man who is diagnosed a colonic polyposis, a rectal adenocarcinoma and a tuberous sclerosis. .SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Pseudo-colonic obstruction after lumbar spine surgery: a case report.

Acute colonic pseudo-obstruction (Ogilvie's syndrome) is characterised by abdominal distension and massive colonic dilatation without any mechanical cause of obstruction. The pathogenesis remains unknown but likely involves imbalance between sympathetic and parasympathetic colon innervation. This syndrome is well known in orthopaedic surgery, as trauma and orthopaedic surgery have been reported as aetiological factors. Some cases have been reported after cervical discectomy. We report a case of Ogilvie's syndrome after lumbar spine surgery. Medical treatment including parasympathetic agent was unsuccessful and the patient underwent a right colectomy. The pathophysiology and treatment are discussed based on a review of the literature.Case ReportsJournal Articleinfo:eu-repo/semantics/publishe

Enhancement of quinone redox cycling by ascorbate induces a caspase-3 independent cell death in human leukaemia cells. An in vitro comparative study.

Since the higher redox potential of quinone molecules has been correlated with enhanced cellular deleterious effects, we studied the ability of the association of ascorbate with several quinones derivatives (having different redox potentials) to cause cell death in K562 human leukaemia cell line. The rationale is that the reduction of quinone by ascorbate should be dependent of the quinone half-redox potential thus determining if reactive oxygen species (ROS) are formed or not, leading ultimately to cell death or cell survival. Among different ROS that may be formed during redox cycling between ascorbate and the quinone, the use of different antioxidant compounds (mannitol, desferal, N-acetylcysteine, catalase and superoxide dismutase) led to support H2O2 as the main oxidizing agent. We observed that standard redox potentials, oxygen uptake, free ascorbyl radical formation and cell survival were linked. The oxidative stress induced by the mixture of ascorbate and the different quinones decreases cellular contents of ATP and GSH while caspase-3-like activity remains unchanged. Again, we observed that quinones having higher values of half-redox potential provoke a severe depletion of ATP and GSH when they were associated with ascorbate. Such a drop in ATP content may explain the lack of activation of caspase-3. In conclusion, our results indicate that the cytotoxicity of the association quinone/ascorbate on K562 cancer cells may be predicted on the basis of half-redox potentials of quinones

Comparison of methods to measure oxygen consumption in tumor cells in vitro

The oxygen consumption rate of tumor cells affects tumor oxygenation and response to therapies. Highly sensitive methods of determining cellular oxygen consumption are therefore needed to identify treatments that can modulate this parameter. We compared the performance of three different methods of measuring cellular oxygen consumption: Electron paramagnetic resonance (EPR) oximetry, the Clark electrode, and the Mito Xpress-Xtra fluorescent assay. To compare the assays, we used K562 cells in the presence of rotenone and hydrocortisone, compounds that are known to inhibit the mitochondrial electron transport chain to different extents. The EPR method was the only method that could identify both rotenone and hydrocortisone as inhibitors of tumor cell oxygen consumption. The Clark electrode and the fluorescence assay demonstrated a significant decrease in cellular oxygen consumption after administration of the most potent inhibitor (rotenone), but failed to show any significant effect of hydrocortisone. EPR oximetry is, therefore, the most sensitive method of identifying inhibitors of oxygen consumption on cell assays, while the Clark electrode offers the unique opportunity to add external compounds during experiments, and still shows great sensitivity in studying enzyme and chemical reactions that consume oxygen (non-cell assays). Finally, the Mito Xpress-Xtra fluorescent assay has the advantage of a high-sample throughput and low bulk requirements, but at the cost of a lower sensitivity

Impact of Inhibition of the Mitochondrial Pyruvate Carrier on the Tumor Extracellular pH as Measured by CEST-MRI

(1) Background: The acidosis of the tumor micro-environment may have profound impact on cancer progression and on the efficacy of treatments. In the present study, we evaluated the impact of a treatment with UK-5099, a mitochondrial pyruvate carrier (MPC) inhibitor on tumor extracellular pH (pHe); (2) Methods: glucose consumption, lactate secretion and extracellular acidification rate (ECAR) were measured in vitro after exposure of cervix cancer SiHa cells and breast cancer 4T1 cells to UK-5099 (10 µM). Mice bearing the 4T1 tumor model were treated daily during four days with UK-5099 (3 mg/kg). The pHe was evaluated in vivo using either chemical exchange saturation transfer (CEST)-MRI with iopamidol as pHe reporter probe or 31P-NMR spectroscopy with 3-aminopropylphosphonate (3-APP). MR protocols were applied before and after 4 days of treatment; (3) Results: glucose consumption, lactate release and ECAR were increased in both cell lines after UK-5099 exposure. CEST-MRI showed a significant decrease in tumor pHe of 0.22 units in UK-5099-treated mice while there was no change over time for mice treated with the vehicle. Parametric images showed a large heterogeneity in response with 16% of voxels shifting to pHe values under 7.0. In contrast, 31P-NMR spectroscopy was unable to detect any significant variation in pHe; (4) Conclusions: MPC inhibition led to a moderate acidification of the extracellular medium in vivo. CEST-MRI provided high resolution parametric images (0.44 µL/voxel) of pHe highlighting the heterogeneity of response within the tumor when exposed to UK-5099

Concomitant chemo-radiotherapy as standard therapy in limited-stage small-cell oesophageal cancer: a summary of 3 clinical cases and review of the literature.

Small-cell carcinoma of the oesophagus (SCCO) is a rare and aggressive malignant tumour associated with a poor prognosis. Between 1994 and 2002, three patients with SCCO were treated in our institution, representing 1.96% (3 out of 153) of all oesophageal malignancies seen during this period. All of these patients had limited-stage SCCO at initial diagnosis and were treated by chemotherapy (cisplatin and etoposide) with concomitant radiotherapy. An initial complete response of the primary lesion was observed in all cases and a persistent complete remission in two of the cases. Chemo-radiotherapy should be considered as a valuable treatment alternative to surgery for limited-stage small-cell carcinoma of the oesophagus.Case ReportsJournal ArticleReviewinfo:eu-repo/semantics/publishe

Cancer : lorsque recycler devient une faiblesse

À l’origine du processus cancéreux, les descendants d’une cellule capable de proliférer de manière débridée envahissent le tissu d’origine pour former une masse tumorale de volume croissant (Figure 1). Or, à distance du vaisseau sanguin le plus proche, l’oxygène nécessaire à la chaîne respiratoire cellulaire (phosphorylations oxydatives) s’amenuise. Un équilibre dynamique s’installe donc entre la prolifération des cellules recevant suffisamment d’oxygène et la mort des cellules hypoxiques, ce qui favorise l’élimination naturelle des microlésions tumorales. Toutefois, l’hypoxie favorise aussi l’émergence de cellules cancéreuses capables de produire la majorité de leur énergie par la glycolyse plutôt que par la chaîne respiratoire. Cette adaptation et sa pérennisation permettent à la tumeur d’entrer en phase de croissance exponentielle