Metabolic control of hyaluronan synthases

Hyaluronan (HA) is a glycosaminoglycan composed by repeating units of D-glucuronic acid (GlcUA) and N-acetylglucosamine (GlcNAc) that is ubiquitously present in the extracellular matrix (ECM) where it has a critical role in the physiology and pathology of several mammalian tissues. HA represents a perfect environment in which cells can migrate and proliferate. Moreover, several receptors can interact with HA at cellular level triggering multiple signal transduction responses. The control of the HA synthesis is therefore critical in ECM assembly and cell biology; in this review we address the metabolic regulation of HA synthesis. In contrast with other glycosaminoglycans, which are synthesized in the Golgi apparatus, HA is produced at the plasma membrane by HA synthases (HAS1-3), which use cytoplasmic UDP-glucuronic acid and UDP-N-acetylglucosamine as substrates. UDP-GlcUA and UDP-hexosamine availability is critical for the synthesis of GAGs, which is an energy consuming process. AMP activated protein kinase (AMPK), which is considered a sensor of the energy status of the cell and is activated by low ATP:AMP ratio, leads to the inhibition of HA secretion by HAS2 phosphorylation at threonine 110. However, the most general sensor of cellular nutritional status is the hexosamine biosynthetic pathway that brings to the formation of UDP-GlcNAc and intracellular protein glycosylation by O-linked attachment of the monosaccharide \u3b2-N-acetylglucosamine (O-GlcNAcylation) to specific aminoacid residues. Such highly dynamic and ubiquitous protein modification affects serine 221 residue of HAS2 that lead to a dramatic stabilization of the enzyme in the membranes

Hyaluronan: Biosynthesis and signaling

Background Hyaluronan is a critical component of extracellular matrix with several different roles. Besides the contribution to the tissue hydration, mechanical properties and correct architecture, hyaluronan plays important biological functions interacting with different molecules and receptors. Scope of review The review addresses the control of hyaluronan synthesis highlighting the critical role of hyaluronan synthase 2 in this context as well as discussing the recent findings related to covalent modifications which influence the enzyme activity. Moreover, the interactions with specific receptors and hyaluronan are described focusing on the importance of polymer size in the modulation of hyaluronan signaling. Major conclusions Due to its biological effects on cells recently described, it is evident how hyaluronan is to be considered not only a passive component of extracellular matrix but also an actor involved in several scenarios of cell behavior. General significance The effects of metabolism on the control of hyaluronan synthesis both in healthy and pathologic conditions are critical and still not completely understood. The hyaluronan capacity to bind several receptors triggering specific pathways may represent a valid target for new approach in several therapeutic strategies. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties

Hyaluronan Produced by Smooth Muscle Cells Plays a Critical Role in Neointima Formation

Large body of evidence supports the idea that microenvironment plays a critical role in several pathologies including atherosclerosis and cancer. The amount of hyaluronan (HA) is involved in the microenvironment alterations and the concentration of this polymer reflects the progression of the diseases promoting neoangiogenesis, cell migration, and inflammation. The HA synthesis is regulated by several factors: UDP sugar precursors availability and the phosphorylation of synthetic enzyme HAS2 as well as specific drugs reducing the UDP precursors. The HAS2 phosphorylation is done by AMP kinase, a sensor of cell energy. When the cells have low energy, AMP kinase is activated and modifies covalently the regulatory enzymes, blocking all biosynthetic processes and activating the energy producing metabolism. It was recently reported that the hexosamine biosynthetic pathway (HBP) may increase the concentration of HA precursor UDP-N-acetylglucosamine (UDP-GlcNAc) leading to an increase of HA synthesis. We demonstrated that the increase of HA synthesis depends on the HAS2 post translational modification O-GlcNAcylation, which increases HA secretion modifying a residue different from the phosphorylation site of AMP kinase. In this report we highlighted the critical aspects of the post translational HAS2 regulation and its influence on HA synthesis

Are you planning to be a radiation oncologist? A survey by the young group of the Italian Association of Radiotherapy and Clinical Oncology (yAIRO)

Background and purpose The Young Section of the Italian Association of Radiotherapy and Clinical Oncology (yAIRO) circulated an online questionnaire survey among residents currently enrolled within Italian radiotherapy residency schools to investigate the profiles, motivations, knowledge of the radiotherapy discipline, organizations and the needs of younger members.Materials and Methods The survey was developed by the yAIRO steering committee and included questions about the demo-graphic characteristics of the residents (Profile A), the background of their clinical experience during the school of medicine and national residency admission test performance (Profile B) and the residents' knowledge of the scientific associations active in the field of radiotherapy (Profile C).Results Out of 400 residents actually in training, 134 responded to the questionnaire (response rate 33.5%). According to most of the residents, radiotherapy was not adequately studied during the medical school (n. 95; 71%) and an Internship in Radiotherapy was not mandatory (n. 99; 74%). Only a minority of the residents had chosen to complete a master's degree thesis in radiotherapy (n. 12; 9%). A low percentage of the residents stated that they were aware of the Italian Association of Radiotherapy and Clinical Oncology (AIRO), its young section (yAIRO) and the European Society for Radiotherapy and Oncology (ESTRO) when they were in School of Medicine (respectively, 11%, 7% and 13%).Conclusions The results of the survey require a profound reflection on the current teaching methods of Radiation Oncology in our country, highlighting the need for a better integration in the framework of the School of Medicine core curriculum

Axillary dissection in patients with preoperative positive nodal cytology: Genuine need or overtreatment?

Recent studies demonstrated the possibility to avoid axillary dissection (ALND) in selected patients with one or two metastatic nodes. Otherwise, patients with positive nodal ultrasound-guided fine-needle aspiration cytology (US-FNAC) currently undergo ALDN. The aim of this study is to quantify the nodal burden in patients with positive US-FNAC treated with ALND and to evaluate if clinical or pathological characteristics associated with low nodal involvement can be identified. This is a multicentric retrospective study involving 297 patients who underwent ALND because of a positive preoperative US-FNAC. A total of 157 patients showed bulky axillary lymph nodes at diagnosis, and 70% of them had three or more metastatic nodes. One hundred and forty patients had a clinically negative axilla and in 50% of them, 4 or more metastatic nodes were found with axillary dissection. Overall, the median number of metastatic nodes was 5. Favorable pathological characteristics of tumors were found in patients with only one or two metastatic nodes: smaller primary tumor, a lower proportion of grade 3, invasive lobular carcinomas and a higher proportion of low-Ki67 tumors. In the group of patients with clinically negative axilla and potentially meeting ACOSOG Z0011 criteria, 22 (31%) showed less than three metastatic axillary nodes. A preoperative positive axillary FNAC is associated with a metastatic nodal burden significantly higher than in patients with positive sentinel lymph node biopsy (SLNB). Nevertheless, about 30% of patients with cN0 axilla, positive axillary FNAC performed because of suspicious nodes on imaging, T1-2 primary tumor and breast-conserving surgery showed less than three metastatic axillary nodes, thus meeting ACOSOG Z0011 trial's criteria and therefore would be eligible for skipping ALND according to current guidelines