Extracellular citrate and metabolic adaptations of cancer cells

It is well established that cancer cells acquire energy via the Warburg effect and oxidative phosphorylation. Citrate is considered to play a crucial role in cancer metabolism by virtue of its production in the reverse Krebs cycle from glutamine. Here, we review the evidence that extracellular citrate is one of the key metabolites of the metabolic pathways present in cancer cells. We review the different mechanisms by which pathways involved in keeping redox balance respond to the need of intracellular citrate synthesis under different extracellular metabolic conditions. In this context, we further discuss the hypothesis that extracellular citrate plays a role in switching between oxidative phosphorylation and the Warburg effect while citrate uptake enhances metastatic activities and therapy resistance. We also present the possibility that organs rich in citrate such as the liver, brain and bones might form a perfect niche for the secondary tumour growth and improve survival of colonising cancer cells. Consistently, metabolic support provided by cancer-associated and senescent cells is also discussed. Finally, we highlight evidence on the role of citrate on immune cells and its potential to modulate the biological functions of pro- and anti-tumour immune cells in the tumour microenvironment. Collectively, we review intriguing evidence supporting the potential role of extracellular citrate in the regulation of the overall cancer metabolism and metastatic activity

Cancer-associated cells release citrate to support tumour metastatic progression

Citrate is important for lipid synthesis and epigenetic regulation in addition to ATP production. We have previously reported that cancer cells import extracellular citrate via the pmCiC transporter to support their metabolism. Here, we show for the first time that citrate is supplied to cancer by cancer-associated stroma (CAS) and also that citrate synthesis and release is one of the latter’s major metabolic tasks. Citrate release from CAS is controlled by cancer cells through cross-cellular communication. The availability of citrate from CAS regulated the cytokine profile, metabolism and features of cellular invasion. Moreover, citrate released by CAS is involved in inducing cancer progression especially enhancing invasiveness and organ colonisation. In line with the in vitro observations, we show that depriving cancer cells of citrate using gluconate, a specific inhibitor of pmCiC, significantly reduced the growth and metastatic spread of human pancreatic cancer cells in vivo and muted stromal activation and angiogenesis. We conclude that citrate is supplied to tumour cells by CAS and citrate uptake plays a significant role in cancer metastatic progression

Sciatic lateral popliteal block with clonidine alone or clonidine plus 0.2% ropivacaine: effect on the intra-and postoperative analgesia for lower extremity surgery in children: a randomized prospective controlled study

<p>Abstract</p> <p>Background</p> <p>The effect of adding clonidine to local anesthetics for nerve or plexus blocks remains unclear. Most of the studies in adults have demonstrated the positive effects of clonidine on intra- and postoperative analgesia when used as an adjunctive agent or in some cases as a single to regional techniques. In the pediatric population, there are only few trials involving clonidine as an adjunct to regional anesthesia, and the analgesic benefits are not definite in this group of patients. The evidence concerning perineural administration of clonidine is so far inconclusive in children, as different types and volume of local anesthetic agents have been used in these studies. Moreover, the efficacy of regional anesthesia is largely affected by the operator's technique, accuracy and severity of operation.</p> <p>Methods</p> <p>The use of clonidine alone or combined with 0.2% ropivacaine for effective analgesia after mild to moderate painful foot surgery was assessed in 66 children, after combined sciatic lateral popliteal block (SLPB) plus femoral block. The patients were randomly assigned into three groups to receive placebo, clonidine, and clonidine plus ropivacaine. Time to first analgesic request in the groups was analyzed by using Kaplan-Meier and the log-rank test (mean time, median time, 95% CI).</p> <p>Results</p> <p>In our study, clonidine administered alone in the SLPB seems promising, maintaining intraoperatively the hemodynamic parameters SAP, DAP, HR to the lower normal values so that no patient needed nalbuphine under 0.6 MAC sevoflurane anesthesia, and postoperatively without analgesic request for a median time of 6 hours. In addition, clonidine administered as adjuvant enhances ropivacaine's analgesic effect for the first postoperative day in the majority of children (p = 0.001). Clonidine and clonidine plus ropivacaine groups also didn’t demonstrate PONV, motor blockade, and moreover, the parents of children expressed their satisfaction with the excellent perioperative management of their children, with satisfaction score 9.74 ± 0.45 and 9.73 ± 0.70 respectively. On the contrary all the patients in the control group required rescue nalbuphine in the recovery room, and postoperatively, along with high incidence of PONV, and the parents of children reported a low satisfaction score (7.50 ± 0.70).</p> <p>Conclusions</p> <p>Clonidine appears promising more as an adjuvant in 0.2% ropivacaine and less than alone in the SLPB plus femoral block in children undergoing mild to moderate painful foot surgery, with no side effects.</p> <p>Trial registration</p> <p>ClinicalTrials.gov, <a href="http://www.controlled-trials.com/ISRCTN90832436">ISRCTN90832436</a>, (ref: CCT-NAPN-20886).</p

Elevated tumor and serum levels of the hypoxia-associated protein osteopontin are associated with prognosis for soft tissue sarcoma patients

<p>Abstract</p> <p>Background</p> <p>Osteopontin (OPN) overexpression is correlated with a poor prognosis for tumor patients. However, only a few studies investigated the prognostic impact of expression of OPN in soft tissue sarcomas (STS) yet.</p> <p>Methods</p> <p>This study is based on tumor and serum samples from 93 adult STS patients. We investigated OPN protein levels in serum (n = 86) and tumor tissue (n = 80) by ELISA and OPN mRNA levels in tumor tissue (n = 68) by quantitative real-time PCR.</p> <p>Results</p> <p>No correlation was found between OPN levels in serum and tumor tissue. Moreover, an elevated OPN protein level in the serum was significantly associated with clinical parameters such as higher stage (p = 0.004), higher grade (p = 0.003), subtype (p = 0.002) and larger tumor size (p = 0.03). OPN protein levels in the tumor tissue were associated with higher stage (p = 0.06), higher grade (p = 0.003), subtype (p = 0.07) and an increased rate of relapse (p = 0.02). In addition, using a Cox's proportional hazards regression model, we found that an elevated OPN protein level in the serum and tumor tissue extracts is a significant negative prognostic factor for patients with STS. The relative risks of tumor-related death were 2.2 (p < 0.05) and 3.7 (p = 0.01), respectively.</p> <p>Conclusion</p> <p>Our data suggest OPN protein in serum as well as in tumor tissue extracts is an important prognostic factor for soft tissue sarcoma patients.</p

The Nuclear Protein Sge1 of Fusarium oxysporum Is Required for Parasitic Growth

Dimorphism or morphogenic conversion is exploited by several pathogenic fungi and is required for tissue invasion and/or survival in the host. We have identified a homolog of a master regulator of this morphological switch in the plant pathogenic fungus Fusarium oxysporum f. sp. lycopersici. This non-dimorphic fungus causes vascular wilt disease in tomato by penetrating the plant roots and colonizing the vascular tissue. Gene knock-out and complementation studies established that the gene for this putative regulator, SGE1 (SIX Gene Expression 1), is essential for pathogenicity. In addition, microscopic analysis using fluorescent proteins revealed that Sge1 is localized in the nucleus, is not required for root colonization and penetration, but is required for parasitic growth. Furthermore, Sge1 is required for expression of genes encoding effectors that are secreted during infection. We propose that Sge1 is required in F. oxysporum and other non-dimorphic (plant) pathogenic fungi for parasitic growth