Relationship between circulating FSH levels and body composition and bone health in patients with prostate cancer who undergo androgen deprivation therapy: The BLADE study.

Background: Among its extragonadal effects, follicle-stimulating hormone (FSH) has an impact on body composition and bone metabolism. Since androgen deprivation therapy (ADT) has a profound impact on circulating FSH concentrations, this hormone could potentially be implicated in the changes of fat body mass (FBM), lean body mass (LBM), and bone fragility induced by ADT. The objective of this study is to correlate FSH serum levels with body composition parameters, bone mineral density (BMD), and bone turnover markers at baseline conditions and after 12 months of ADT. Methods: Twenty-nine consecutive non-metastatic prostate cancer (PC) patients were enrolled from 2017 to 2019 in a phase IV study. All patients underwent administration of the luteinizing hormone-releasing hormone antagonist degarelix. FBM, LBM, and BMD were evaluated by dual-energy x-ray absorptiometry at baseline and after 12 months of ADT. FSH, alkaline phosphatase, and C-terminal telopeptide of type I collagen were assessed at baseline and after 6 and 12 months. For outcome measurements and statistical analysis, t-test or sign test and Pearson or Spearman tests for continuous variables were used when indicated. Results: At baseline conditions, a weak, non-significant, direct relationship was found between FSH serum levels and FBM at arms (r = 0.36) and legs (r = 0.33). Conversely, a stronger correlation was observed between FSH and total FBM (r = 0.52, p = 0.006), fat mass at arms (r = 0.54, p = 0.004), and fat mass at trunk (r = 0.45, p = 0.018) assessed after 12 months. On the other hand, an inverse relationship between serum FSH and appendicular lean mass index/FBM ratio was observed (r = -0.64, p = 0.001). This is an ancillary study of a prospective trial and this is the main limitation. Conclusions: FSH serum levels after ADT could have an impact on body composition, in particular on FBM. Therefore, FSH could be a promising marker to monitor the risk of sarcopenic obesity and to guide the clinicians in the tailored evaluation of body composition in PC patients undergoing ADT. Funding: This research was partially funded by Ferring Pharmaceuticals. The funder had no role in design and conduct of the study, collection, management, analysis, and interpretation of the data and in preparation, review, or approval of the manuscript. Clinical trial number: clinicalTrials.gov NCT03202381, EudraCT Number 2016-004210-10.

Treatments given to cancer patients can cause negative side effects. For example, a treatment known as androgen deprivation therapy ­ which is used to reduce male sex hormone levels in prostate cancer patients ­ can lead to increased body fat percentage and decreased bone density. These adverse effects can have further negative impacts on patient health, such as increasing the risk of cardiovascular disease and fractures from falls from standing height or less, respectively. Understanding how androgen deprivation therapy contributes to these negative side effects may help clinicians better manage care and outcomes for patients with prostate cancer. Follicle stimulating hormone (or FSH for short) has roles in male and female reproduction but has also been linked to changes in body composition. For example, elevated FSH levels are associated with higher total fat body mass in post-menopausal women. While androgen deprivation therapy is known to alter FSH blood levels, the impact of this change in prostate cancer patients was not well understood. To investigate the effect of androgen deprivation therapy on FSH levels and body composition, Bergamini et al. used X-ray technology to measure total fat body mass in prostate cancer patients before and after undergoing 12 months of androgen deprivation therapy. The findings showed that patient FSH blood levels significantly decreased after 12 months of treatment. Higher FSH blood levels strongly correlated with increased total fat body mass after 12 months of treatment. The findings of this clinical trial suggest that FSH blood levels impact the body composition of patients undergoing androgen deprivation therapy. As a result, FSH blood levels may be a suitable biomarker for identifying patients that are more likely to develop obesity and are therefore at greater risk of complications such as cardiovascular disease.

Potential Diagnostic Role of Hepcidin in Anemic Patients Affected by Inflammatory Bowel Disease: A Systematic Review.

BACKGROUND: Anemia is the main extraintestinal comorbidity of Inflammatory Bowel Disease (IBD). Differentiating the type of anemia in these disorders is still a challenge. Hepcidin could be a promising biomarker to identify iron deficiency anemia (IDA), anemia of chronic disease (ACD) and the concomitant presence of both IDA and ACD. METHODS: To evaluate the potential role of hepcidin dosage in the management of anemia in IBD patients, we performed a systematic review by a comprehensive literature analysis of original papers reporting the dosage of hepcidin in IBD patients. In all the articles reviewed, the dosage of ferritin was reported, and the correlation between hepcidin and ferritin has been used to compare these two biomarkers. RESULTS: A total of 12 articles concerning the dosage of hepcidin in IBD were included, comprising in total of 976 patients. The results of the hepcidin values in IBD patients when compared with controls were conflicting. In fact, four articles described an increase in this biomarker, three showed a decrease and five did not find significant differences. The correlation with ferritin was positive and significant. In three studies, some differences between hepcidin dosages and ferritin levels indicate a possible role when IDA and ACD could be present at the same time. CONCLUSIONS: Considering the contradictory data of the studies, the diagnostic role of hepcidin as a biomarker remains elusive in IBD patients. These differences could be due to the clinical characteristics of the patients enrolled that should be better defined in the future. A suitable clinical trial should be designed to outline the possible role of hepcidin in differentiating IDA, ACD and concomitant IDA and ACD in IBD patients. At the moment, ferritin still remains the best marker to diagnose these conditions, in addition to hemoglobin, transferrin saturation and CRP as recommended by the ECCO guidelines.

Frequency Evaluation of the Interleukin-6 -174G>C Polymorphism and Homeostatic Iron Regulator (HFE) Mutations as Disease Modifiers in Patients Affected by Systemic Lupus Erythematosus and Rheumatoid Arthritis.

Autoimmune diseases are generally characterized by a multifactorial etiology and are often associated with a genetic predisposition. Both iron metabolism and the inflammatory cytokine system have been shown to play a pivotal role in the dysregulation of the immune response in many different autoimmune conditions, rheumatologic diseases included. The purpose of this work was to analyze the frequency of mutations altering the expression of IL-6 or influencing iron metabolism in patients affected by autoimmune diseases such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). In this study, 144 patients were enrolled: 77 and 67 patients were affected by RA and SLE, respectively. In these cohorts, the frequency of the IL-6 polymorphism -174G>C located in the IL-6 gene promoter was tested. Moreover, the frequencies of the three HFE gene variations associated with iron overload were analyzed: p.His63Asp, p.Ser65Cys and p.Cys282Tyr. The two mutations p.His63Asp and p.Ser65Cys in the HFE gene did not reach statistical significance in any of the comparisons, regardless of the statistical model, cohorts of patients and control populations analyzed. The frequencies of the p.Cys282Tyr mutation and the IL-6 polymorphism -174G>C were found to be overall significantly decreased in RA and SLE patients when the Dominant model and Allele contrast were adopted with both the Odds Ratio and Chi-square. Although further investigation is needed, the examination of the frequencies of the -174G>C IL-6 promoter polymorphism and HFE mutations may add some valuable information on the interplay linking iron metabolism, inflammation and immunity in autoimmune diseases such as SLE and RA.

The D647N mutation of FGFR1 induces ligand-independent receptor activation.

The activation loop (A-loop) of kinases, a key regulatory region, is recurrently mutated in several kinase proteins in cancer resulting in dysregulated kinase activity and response to kinase inhibitors. FGFR1 receptor tyrosine kinase represents an important oncogene and therapeutic target for solid and hematological tumors. Here we investigate the biochemical and molecular effects of D647N mutation lying in the A-loop of FGFR1. When expressed in normal and tumoral in vitro cell models, FGFR1D647N is phosphorylated also in the absence of ligands, and this is accompanied by the activation of intracellular signaling. The expression of FGFR1D647N significantly increases single and collective migration of cancer cells in vitro and in vivo, when compared to FGFR1WT. FGFR1D647N expression exacerbates the aggressiveness of cancer cells, increasing their invasiveness in vitro and augmenting their pro-angiogenic capacity in vivo. Remarkably, the D647N mutation significantly increases the sensitivity of FGFR1 to the ATP-competitive inhibitor Erdafitinib suggesting the possibility that this mutation could become a specific target for the development of new inhibitors. Although further efforts are warranted for an exhaustive description of the activation mechanisms, for the identification of more specific inhibitors and for confirming the clinical significance of mutated FGFR1D647N, overall our data demonstrate that the D647N substitution of FGFR1 is a novel pro-oncogenic activating mutation of the receptor that, when found in cancer patients, may anticipate good response to erdafitinib treatment.

Effect of Degarelix Administration on Bone Health in Prostate Cancer Patients Without Bone Metastases. The Blade Study.

CONTEXT: As patients are now living with prostate cancer for longer, the long-term impact of hormonal treatment on bone health is an increasingly debated subject. OBJECTIVE: To characterize the changes in bone mineral density (BMD) and bone turnover markers after degarelix administration in prostate cancer patients without bone metastases. To explore the predictive role of body composition on treatment induced bone loss. METHODS: BMD and body composition (lean body mass, fat body mass, and appendicular mass index [ALMI]) were assessed by dual X-ray absorptiometry on study entry and after 12 months of degarelix therapy. Alkaline phosphate (ALP) and C-terminal telopeptide of type I collagen (CTX) were assessed at baseline, and 6 and 12 months. RESULTS: Twenty-nine patients entered the study. Degarelix administration was associated with a significant decrease in BMD after 12 months (2.4% reduction from baseline at lumbar spine). Serum CTX and ALP increased significantly (median increase from baseline 99% and 19.3%, respectively). An inverse correlation was observed between ALMI and CTX, but not ALP, at both baseline (Pearson r = -0.62, P < .0001) and month 12 (Pearson r = -0.41, P = .032). Moreover, a significant inverse correlation between changes in ALMI and CTX at 12 months (Pearson r = -0.43, P = .019) and a direct relationship between changes of ALMI and ALP (Pearson r = 0.44, P = .016) during degarelix therapy were observed. CONCLUSION: Degarelix administration is associated with a significant decrease in BMD and increase in bone turnover markers. ALMI is a promising predictor of bone loss in prostate cancer patients receiving androgen deprivation therapy, and ALMI changes during therapy are associated with bone turnover derangement favoring bone quality alterations.

Stratification of Oligometastatic Prostate Cancer Patients by Liquid Biopsy: Clinical Insights from a Pilot Study.

We propose a pilot, prospective, translational study with the aim of identifying possible molecular markers underlying metastatic prostate cancer (PC) evolution with the use of liquid biopsy. Twenty-eight castrate sensitive, oligometastatic PC patients undergoing bone and/or nodal stereotactic body radiotherapy (SBRT) were recruited. Peripheral blood samples were collected before the commencement of SBRT, then they were processed for circulating cell free DNA (cfDNA) extraction. Deep targeted sequencing was performed using a custom gene panel. The primary endpoint was to identify differences in the molecular contribution between the oligometastatic and polymetastatic evolution of PC to same-first oligo-recurrent disease presentation. Seventy-seven mutations were detected in 25/28 cfDNA samples: ATM in 14 (50%) cases, BRCA2 11 (39%), BRCA1 6 (21%), AR 13 (46%), ETV4, and ETV6 2 (7%). SBRT failure was associated with an increased risk of harboring the BRCA1 mutation (OR 10.5) (p = 0.043). The median cfDNA concentration was 24.02 ng/mL for ATM mutation carriers vs. 40.04 ng/mL for non-carriers (p = 0.039). Real-time molecular characterization of oligometastatic PC may allow for the identification of a true oligometastatic phenotype, with a stable disease over a long time being more likely to benefit from local, curative treatments or the achievement of long-term disease control. A prospective validation of our promising findings is desirable for a better understanding of the real impact of liquid biopsy in detecting tumor aggressiveness and clonal evolution.

Low-dose Lung Radiotherapy for COVID-19-related Pneumonia: Preliminary Results of the Italian Mono-institutional COLOR-19 Trial.

AIM: To evaluate the feasibility and tolerability of low-dose radiotherapy (LDRT) delivered to both lungs in the treatment of SARS-CoV-2-immune-mediated pneumonia in the COLOR-19 study (NCT0437747). PATIENTS AND METHODS: From May 2020 to April 2021 at Brescia University Radiation Oncology Department, three patients with COVID-19-related pneumonia were treated with LDRT according to the COLOR-19 protocol. All patients were treated with a single fraction at the average prescription dose of 0.7 Gy to both lungs. RESULTS: Three patients were enrolled (two males and one female, aged 61-81 years) and underwent LDRT. Despite LDRT being safely performed without significant side-effects, two patients died (one 81-year-old male due to septic shock secondary to Escherichia coli infection and one 79-year-old male, already in poor condition, due to worsening of COVID-19). The remaining female patient (61 years old) underwent LDRT for less severe COVID-19: her clinical condition and chest X-ray improved, and she was discharged home completely asymptomatic 27 days after hospital admission. Blood levels of C-reactive protein and ferritin generally decreased after LDRT. CONCLUSION: Early results of the COLOR-19 study demonstrate the feasibility of LDRT for therapy of COVID-19-related pneumonia; no conclusions on the efficacy have been reached due to poor accrual.

Characterization of three sialidases from Danio rerio.

Zebrafish encodes several sialidases belonging to the NEU3 group, the plasma membrane-associated member of the family with high specificity toward ganglioside substrates. Neu3.1, Neu3.2 and Neu 3.3 have been expressed in E. coli and purified using the pGEX-2T expression system. Although all the enzymes are expressed by bacterial cells, Neu3.1 formed insoluble aggregates that hampered its purification. Neu3.2 and Neu3.3 formed oligomers as demonstrated by gel filtration chromatography experiments. Actually, the first formed a trimer whereas the second a pentamer. Intriguingly, despite relevant degree of sequence identity and similarity, the two enzymes showed peculiar substrate specificities toward gangliosides other than GM3, two glycoproteins and two forms of sialyllactose. Using molecular modelling and the crystal structure of the human cytosolic sialidase NEU2 as a template, the 3D models of the sialidases from zebrafish have been generated. As expected, the 3D models showed the typical six blade beta-propeller typical of sialidases, with an overall highly conserved active site architecture. The differences among the three zebrafish enzymes and human NEU2 are mainly located in the loops connecting the antiparallel beta strands of the propeller core. These portions of the proteins are probably responsible for the differences observed in substrate specificities, as well as in the different subcellular localization and aggregation features observed in solution. Finally, the in silico analysis of RNA-Seq data evidenced a peculiar expression profile of the three genes during embryogenesis, suggesting different roles of these sialidases during development.

ß-Galactosylceramidase Promotes Melanoma Growth via Modulation of Ceramide Metabolism.

Disturbance of sphingolipid metabolism may represent a novel therapeutic target in metastatic melanoma, the most lethal form of skin cancer. ß-Galactosylceramidase (GALC) removes ß-galactose from galactosylceramide and other sphingolipids. In this study, we show that downregulation of galcb, a zebrafish ortholog of human GALC, affects melanoblast and melanocyte differentiation in zebrafish embryos, suggesting a possible role for GALC in melanoma. On this basis, the impact of GALC expression in murine B16-F10 and human A2058 melanoma cells was investigated following its silencing or upregulation. Galc knockdown hampered growth, motility, and invasive capacity of B16-F10 cells and their tumorigenic and metastatic activity when grafted in syngeneic mice or zebrafish embryos. Galc-silenced cells displayed altered sphingolipid metabolism and increased intracellular levels of ceramide, paralleled by a nonredundant upregulation of Smpd3, which encodes for the ceramide-generating enzyme neutral sphingomyelinase 2. Accordingly, GALC downregulation caused SMPD3 upregulation, increased ceramide levels, and inhibited the tumorigenic activity of human melanoma A2058 cells, whereas GALC upregulation exerted opposite effects. In concordance with information from melanoma database mining, RNAscope analysis demonstrated a progressive increase of GALC expression from common nevi to stage IV human melanoma samples that was paralleled by increases in microphthalmia transcription factor and tyrosinase immunoreactivity inversely related to SMPD3 and ceramide levels. Overall, these findings indicate that GALC may play an oncogenic role in melanoma by modulating the levels of intracellular ceramide, thus providing novel opportunities for melanoma therapy. SIGNIFICANCE: Data from zebrafish embryos, murine and human cell melanoma lines, and patient-derived tumor specimens indicate that ß-galactosylceramidase plays an oncogenic role in melanoma and may serve as a therapeutic target.

Author Correction: A novel homozygous mutation in GAD1 gene described in a schizophrenic patient impairs activity and dimerization of GAD67 enzyme.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Lack of specific T- and B-cell clonal expansions in multiple sclerosis patients with progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a rare, potentially devastating myelin-degrading disease caused by the JC virus. PML occurs preferentially in patients with compromised immune system, but has been also observed in multiple sclerosis (MS) patients treated with disease-modifying drugs. We characterized T and B cells in 5 MS patients that developed PML, 4 during natalizumab therapy and one after alemtuzumab treatment, and in treated patients who did not develop the disease. Results revealed that: i) thymic and bone marrow output was impaired in 4 out 5 patients at the time of PML development; ii) T-cell repertoire was restricted; iii) clonally expanded T cells were present in all patients. However, common usage or pairings of T-cell receptor beta variable or joining genes, specific clonotypes or obvious "public" T-cell response were not detected at the moment of PML onset. Similarly, common restrictions were not found in the immunoglobulin heavy chain repertoire. The data indicate that no JCV-related specific T- and B-cell expansions were mounted at the time of PML. The current results enhance our understanding of JC virus infection and PML, and should be taken into account when choosing targeted therapies.

Mebendazole as a Candidate for Drug Repurposing in Oncology: An Extensive Review of Current Literature.

Anticancer treatment efficacy is limited by the development of refractory tumor cells characterized by increased expression and activity of mechanisms promoting survival, proliferation, and metastatic spread. The present review summarizes the current literature regarding the use of the anthelmintic mebendazole (MBZ) as a repurposed drug in oncology with a focus on cells resistant to approved therapies, including so called "cancer stem cells". Mebendazole meets many of the characteristics desirable for a repurposed drug: good and proven toxicity profile, pharmacokinetics allowing to reach therapeutic concentrations at disease site, ease of administration and low price. Several in vitro studies suggest that MBZ inhibits a wide range of factors involved in tumor progression such as tubulin polymerization, angiogenesis, pro-survival pathways, matrix metalloproteinases, and multi-drug resistance protein transporters. Mebendazole not only exhibits direct cytotoxic activity, but also synergizes with ionizing radiations and different chemotherapeutic agents and stimulates antitumoral immune response. In vivo, MBZ treatment as a single agent or in combination with chemotherapy led to the reduction or complete arrest of tumor growth, marked decrease of metastatic spread, and improvement of survival. Further investigations are warranted to confirm the clinical anti-neoplastic activity of MBZ and its safety in combination with other drugs in a clinical setting.

Overexpression of sialidase NEU3 increases the cellular radioresistance potential of U87MG glioblastoma cells.

The plasma membrane-associated sialidase NEU3 is known to play important roles in different physiological and pathophysiological processes such as proliferation, cellular differentiation and tumorigenesis. Up-regulation of NEU3 has been associated to several tumors and recently it was demonstrated that its down-modulation in glioblastoma cells promotes cell invasiveness. To date, no information concerning the possible role played by NEU3 in relation to tumor radioresistance is available. Here we show that overexpression of NEU3 in glioblastoma U87MG cells activates PI3K/Akt signaling pathway resulting in an increased radioresistance capacity and in an improved efficiency of double strand DNA-repair mechanisms after irradiation. Our results demonstrate for the first time that NEU3 contributes to the radioresistance features of U87MG cells, bringing to evidence a novel rand peculiar role of the enzyme in cancer biology.

A novel homozygous mutation in GAD1 gene described in a schizophrenic patient impairs activity and dimerization of GAD67 enzyme.

Recently, by whole exome sequencing of schizophrenia (SCZ) patients, we identified a subject that was homozygous for a novel missense substitution (c.391 A > G) in the glutamate acid decarboxylase 1 (GAD1) gene. GAD1 encodes for GAD67 enzyme, catalyzing the production of gamma-aminobutyric acid (GABA) from L-glutamic acid. Here, we studied the impact of this mutation on GAD67 activity, dimerization and subcellular localization. Biochemical assay revealed that c.391 A > G reduces GAD67 enzymatic activity by ~30%, probably due to the impaired homodimerization of homozygous mutants as highlighted by proximity ligation assays. The mutational screening of 120 genes of the "GABAergic system" in a cohort of 4,225 SCZ cases and 5,834 controls (dbGaP: phs000473.v1.p2), did not identify other cases that were homozygous for ultra-rare variants in GAD1, but highlighted an increased frequency of cases that were homozygous for rare variants in genes of the GABA system (SCZ: 0.14% vs. Controls: 0.00%; p-value = 0.0055). In conclusion, this study demonstrates the functional impact of c.391 A > G variant and its biological effect makes it a good candidate as risk variant for SCZ. This study also supports an involvement of ultra-rare variants in GABAergic genes in the etiopathogenesis of SCZ.

Exploring the Role of Enzalutamide in Combination with Radiation Therapy: An In Vitro Study.

BACKGROUND/AIM: Androgen receptor plays a key role in prostate cancer development and is a causative agent of its radio-resistance. The present study investigated the potential radio-sensitizing effect of enzalutamide, a second-generation anti-androgen, in human prostate cancer cells. MATERIALS AND METHODS: The radio-sensitizing effect of enzalutamide was assessed in the androgen-dependent LNCaP cells and the androgen-independent PC3 cells by clonogenic assay and γ-H2AX assay. RESULTS: Enzalutamide-treated LNCaP cells showed a significant decrease of cell survival at all radiation doses tested. An increased number of γ-H2AX-positive nuclei was observed, suggesting a possible impairment of the DNA repair machinery. Conversely, enzalutamide did not exhibit a significant radio-sensitizing effect on PC3 cells. CONCLUSION: The combination of enzalutamide with ionizing radiation significantly improves radio-sensitivity of hormone-dependent LNCaP cells. Translated in the clinical practice, our results may help to find additional strategies to improve effectiveness of radiotherapy.

Exosomes Secreted by HeLa Cells Shuttle on Their Surface the Plasma Membrane-Associated Sialidase NEU3.

Sialidases are glycohydrolases that remove terminal sialic acid residues from oligosaccharides, glycolipids, and glycoproteins. The plasma membrane-associated sialidase NEU3 is involved in the fine-tuning of sialic acid-containing glycans directly on the cell surface and plays relevant roles in important biological phenomena such as cell differentiation, molecular recognition, and cancer transformation. Extracellular vesicles are membranous structures with a diameter of 0.03-1 µm released by cells and can be detected in blood, urine, and culture media. Among extracellular vesicles, exosomes play roles in intercellular communication and maintenance of several physiological and pathological conditions, including cancer, and could represent a useful diagnostic tool for personalized nanomedicine approaches. Using inducible expression of the murine form of NEU3 in HeLa cells, a study of the association of the enzyme with exosomes released in the culture media has been performed. Briefly, NEU3 is associated with highly purified exosomes and localizes on the external leaflet of these nanovesicles, as demonstrated by enzyme activity measurements, Western blot analysis, and dot blot analysis using specific protein markers. On the basis of these results, it is plausible that NEU3 activity on exosome glycans enhances the dynamic biological behavior of these small extracellular vesicles by modifying the negative charge and steric hindrance of their glycocalyx. The presence of NEU3 on the exosomal surface could represent a useful marker for the detection of these nanovesicles and a tool for improving our understanding of the biology of these important extracellular carriers in physiological and pathological conditions.

Genomic and biochemical characterization of sialic acid acetylesterase (siae) in zebrafish.

Sialic acid acetylesterase (SIAE) removes acetyl moieties from the carbon 9 and 4 hydroxyl groups of sialic acid and recently a debate has been opened on its association to autoimmunity. Trying to get new insights on this intriguing enzyme we have studied siae in zebrafish (Danio rerio). In this teleost siae encodes for a polypeptide with a high degree of sequence identity to human and mouse counterparts. Zebrafish Siae behavior upon transient expression in COS7 cells is comparable to human enzyme concerning pH optimum of enzyme activity, subcellular localization and glycosylation. In addition, and as already observed in case of human SIAE, the glycosylated form of the enzyme from zebrafish is released into the culture media. During embryogenesis, in situ hybridization experiments demonstrate that siae transcript is always detectable during development, with a more specific expression in the central nervous system, in pronephric ducts and liver in the more advanced stages of the embryo development. In adult fish an increasing amount of siae mRNA is detectable in heart, eye, muscle, liver, brain, kidney and ovary. These results provide novel information about Siae and point out zebrafish as animal model to better understand the biological role(s) of this rather puzzling enzyme in vertebrates, regarding immune system function and the development of central nervous system.

Pro-lymphangiogenic properties of IFN-γ-activated human dendritic cells.

Dendritic cells (DCs) play a crucial role in the initiation of adaptive immune responses. In addition, through the release of pro- and anti-angiogenic mediators, DCs are key regulators of blood vessel remodeling, a process that characterizes inflammation. Less information is available on the role of DCs in lymphangiogenesis. This study reports that human DCs produce VEGF-C, a cytokine with potent pro-lymphangiogenic activity when stimulated with IFN-γ. DC-derived VEGF-C was biologically active, being able to promote tube-like structure formation in cultures of human lymphatic endothelial cells (LECs). DCs co-cultured with IL-15-activated NK cells produced high levels of VEGF-C, suggesting a role for NK-DC cross-talk in peripheral lymphoid and non-lymphoid tissues in inflammation-associated lymphangiogenesis. Induction of VEGF-C by IFN-γ was detected also in other myeloid cells, such as blood-purified CD1c(+) DCs, CD14(+) monocytes and in monocyte-derived macrophages. In all these cell types, VEGF-C was found associated with the cell membrane by low affinity, heparan sulphate-mediated, interactions. Therefore, human DCs should be considered as new players in inflammation-associated lymphangiogenesis.