MicroRNA-Mediated Metabolic Shaping of the Tumor Microenvironment

The metabolism of cancer cells is generally very different from what is found in normal counterparts. However, in a tumor mass, the continuous crosstalk and competition for nutrients and oxygen among different cells lead to metabolic alterations, not only in cancer cells, but also in the different stromal and immune cells of the tumor microenvironment (TME), which are highly relevant for tumor progression. MicroRNAs (miRs) are small non-coding RNAs that silence their mRNA targets post-transcriptionally and are involved in numerous physiological cell functions as well as in the adaptation to stress situations. Importantly, miRs can also be released via extracellular vesicles (EVs) and, consequently, take part in the bidirectional communication between tumor and surrounding cells under stress conditions. Certain miRs are abundantly expressed in stromal and immune cells where they can regulate various metabolic pathways by directly suppressing enzymes or transporters as well as by controlling important regulators (such as transcription factors) of metabolic processes. In this review, we discuss how miRs can induce metabolic reprogramming in stromal (fibroblasts and adipocytes) and immune (macrophages and T cells) cells and, in turn, how the biology of the different cells present in the TME is able to change. Finally, we debate the rebound of miR-dependent metabolic alterations on tumor progression and their implications for cancer management

Bisphosphonates study on effect of implant-bone interface

Fil: Brunengo, Ignacio. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Virga, María Carolina. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra Farmacología y Terapéutica B; Argentina.Fil: Aguzzi, Alejandra. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra Farmacología y Terapéutica A; Argentina.Fil: Sosa, Federico. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Marion, Gustavo Carlos. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Prostodoncia III A; Argentina.Introduction: The success of any dental implant depends on a number of parameters including general health conditions, biocompatibility of implant materials, the nature of the surface of the microscopic and macroscopic implant, the surgical procedure and the quality and quantity of bone maxilla. Objective: to evaluate the alkaline phosphatase (AP) levels to analyze the therapeutic response to treatment with bisphosphonates administered subcutaneously in experimental animals. Materials and Methods: The pharmaceutical formulations were prepared with a dosage for Alendronate (AL) of 0.5 mg / kg weight, and pamidronate (PA) of 0.6 mg / Kg . Control (C) was saline. The effect was evaluated in normal male Wistar rats, which were divided into three groups, one control and two problems. We designed a class IV titanium microimplant dimensions 1 mm diameter by 2 mm to place in rat tibia after a drilling operation with strawberry No.6 manual rotation. AP in blood was measured to analyze bone level changes. Comparison of the data was performed by analysis of variance of two criteria (treatments and treatment times: 0, 15, 30, 60 and 90 days). Differences were considered significant if p <0.05. Results: The average value obtained in pubertal rats was 1425 IU / I, and in normal adult rats taken as a parameter for estimating the bone marker normal values in rats was 51.03 IU / l. The data showed that the experimental groups at 15 days 1.37 higher PA than AL; 30 days PA is 1.12 higher than Al, at 60 days 1, 14 and 90 days increased 1.07 higher. Conclusions: The experimental model healthy male rats subcutaneously weekly treatment with AL and PA for 12 weeks resulted in significant variations in mineral concentrations in blood, revealing an inhibitory action on osteoclast activity by the drugs studied .Fil: Brunengo, Ignacio. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Virga, María Carolina. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra Farmacología y Terapéutica B; Argentina.Fil: Aguzzi, Alejandra. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra Farmacología y Terapéutica A; Argentina.Fil: Sosa, Federico. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Marion, Gustavo Carlos. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Prostodoncia III A; Argentina.Otras Ciencias Médica

Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation

Unbalanced immune responses to pathogens can be life-threatening although the underlying regulatory mechanisms remain unknown. Here, we show a hypoxia-inducible factor 1α–dependent microRNA (miR)–210 up-regulation in monocytes and macrophages upon pathogen interaction. MiR-210 knockout in the hematopoietic lineage or in monocytes/macrophages mitigated the symptoms of endotoxemia, bacteremia, sepsis, and parasitosis, limiting the cytokine storm, organ damage/dysfunction, pathogen spreading, and lethality. Similarly, pharmacologic miR-210 inhibition improved the survival of septic mice. Mechanistically, miR-210 induction in activated macrophages supported a switch toward a proinflammatory state by lessening mitochondria respiration in favor of glycolysis, partly achieved by downmodulating the iron-sulfur cluster assembly enzyme ISCU. In humans, augmented miR-210 levels in circulating monocytes correlated with the incidence of sepsis, while serum levels of monocyte/macrophage-derived miR-210 were associated with sepsis mortality. Together, our data identify miR-210 as a fine-tuning regulator of macrophage metabolism and inflammatory responses, suggesting miR-210–based therapeutic and diagnostic strategies

Blood Vessel Proximity Shapes Cancer Cell Metabolism

Cancer cells are highly heterogeneous, and their features markedly vary within different areas of the tumor microenvironment. In this issue, Kumar et al. (2019) identified perivascular tumor cells, derived from mouse glioblastoma xenografts, as the fraction that displays the highest mTOR-dependent anabolic metabolism, aggressiveness, and resistance to therapy.status: publishe

Risk factors in the development of dysphonia in childhood

Aim: Childhood dysphonia has an estimated incidence of 6–24%. Dysphonia may adversely impact the child’s communicative effectiveness, social and educational development, self-esteem and participation in school group activities. It is commonly believed that children become dysphonic due to vocal misuse behaviors, however there are no consistent data in the few studies published on this topic. Our aim was to evaluate the influence of some potential risk factors on the development of childhood dysphonia. Sources and methods: 33 consecutive dysphonic children with vocal folds nodules underwent a phoniatric examination in the Phoniatric Unit of the “Azienda Policlinico Umberto I Hospital” of Rome. The mean age was 10 years (Ds ± 2 ys). Several risk factor were examined, such as temperament, ENT pathologies, number of siblings, sport practices, scouting, extended school, singing activities, environmental noise in classrooms. Data were compared with a control group of 33 matched children without voice pathologies. Results: the incidence of allergy, sport practices and extended school was found significantly higher in the group of dysphonic children compared with the control group. Furthermore also a prevalence of extrovert and anxious personality in dysphonic children was found. Conclusions: data from our study on risk factors, that act in the development of dysphonia in childhood, stress the relevance of both personality and behavioral factors. It would be useful to encourage the diffusion of information to show the risks related to voice abuse in children, in order to prevent the development of pediatric dysphonia. It would also be necessary to develop instruments specifically designed to examine personality dispositions in dysphonic children

Mir-214 and mir-148b targeting inhibits dissemination of melanoma and breast cancer

miR-214 and miR-148b have been proposed to antagonize the effects of each other in enabling or blocking metastasis, respectively. In this study, we provide evidence deepening their role and interrelationship in the process of metastatic dissemination. Depleting miR-214 or elevating miR-148b blocked the dissemination of melanoma or breast cancer cells, an effect that could be accentuated by dual alteration. Mechanistic investigations indicated that dual alteration suppressed passage of malignant cells through the blood vessel endothelium by reducing expression of the cell adhesion molecules ITGA5 and ALCAM. Notably, transendothelial migration in vitro and extravasation in vivo impaired by singly alternating miR-214 or miR-148b could be overridden by overexpression of ITGA5 or ALCAM in the same tumor cells. In clinical specimens of primary breast cancer or metastatic melanoma, we found a positive correlation between miR-214 and ITGA5 or ALCAM along with an inverse correlation of miR-214 and miR-148b in the same specimens. Our findings define an antagonistic relationship of miR-214 and miR-148b in determining the dissemination of cancer cells via tumor–endothelial cell interactions, with possible implications for microRNA-mediated therapeutic interventions aimed at blocking cancer extravasation. Cancer Res; 76(17); 1–12. 2016 AACR

ESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3

An interactive crosstalk between tumor and stroma cells is essential for metastatic melanoma progression. We evidenced that ESDN/DCBLD2/CLCP1 plays a crucial role in endothelial cells during the spread of melanoma. Precisely, increased extravasation and metastasis formation was revealed in ESDN-null mice injected with melanoma cells, even if the primary tumor growth, vessel permeability, and angiogenesis were not enhanced. Interestingly, improved adhesion of melanoma cells to ESDN-depleted endothelial cells was observed, due to the presence of higher levels of E-selectin transcripts/proteins in ESDN-defective cells. In accordance with these results, anticorrelation was observed between ESDN and E-selectin in human endothelial cells. Most importantly, our data revealed that cimetidine, an E-selectin inhibitor, was able to block cell adhesion, extravasation, and metastasis formation in ESDN-null mice, underlying a major role of ESDN in E-selectin transcription upregulation, which according to our data may presumably be linked to STAT3. Based on our results, we propose a protective role for ESDN during the spread of melanoma and reveal its therapeutic potential

Macrophage-derived glutamine boosts satellite cells and muscle regeneration

Muscle regeneration is sustained by infiltrating macrophages and the consequent activation of satellite cells1-4. Macrophages and satellite cells communicate in different ways1-5, but their metabolic interplay has not been investigated. Here we show, in a mouse model, that muscle injuries and ageing are characterized by intra-tissue restrictions of glutamine. Low levels of glutamine endow macrophages with the metabolic ability to secrete glutamine via enhanced glutamine synthetase (GS) activity, at the expense of glutamine oxidation mediated by glutamate dehydrogenase 1 (GLUD1). Glud1-knockout macrophages display constitutively high GS activity, which prevents glutamine shortages. The uptake of macrophage-derived glutamine by satellite cells through the glutamine transporter SLC1A5 activates mTOR and promotes the proliferation and differentiation of satellite cells. Consequently, macrophage-specific deletion or pharmacological inhibition of GLUD1 improves muscle regeneration and functional recovery in response to acute injury, ischaemia or ageing. Conversely, SLC1A5 blockade in satellite cells or GS inactivation in macrophages negatively affects satellite cell functions and muscle regeneration. These results highlight the metabolic crosstalk between satellite cells and macrophages, in which macrophage-derived glutamine sustains the functions of satellite cells. Thus, the targeting of GLUD1 may offer therapeutic opportunities for the regeneration of injured or aged muscles.status: publishe

Stroma-derived miR-214 coordinates tumor dissemination

Abstract Background Tumor progression is based on a close interaction between cancer cells and Tumor MicroEnvironment (TME). Here, we focus on the role that Cancer Associated Fibroblasts (CAFs), Mesenchymal Stem Cells (MSCs) and microRNAs (miRs) play in breast cancer and melanoma malignancy. Methods We used public databases to investigate miR-214 expression in the stroma compartment of primary human samples and evaluated tumor formation and dissemination following tumor cell injections in miR-214 overexpressing (miR-214over) and knock out (miR-214ko) mice. In addition, we dissected the impact of Conditioned Medium (CM) or Extracellular Vesicles (EVs) derived from miR-214-rich or depleted stroma cells on cell metastatic traits. Results We evidence that the expression of miR-214 in human cancer or metastasis samples mostly correlates with stroma components and, in particular, with CAFs and MSCs. We present data revealing that the injection of tumor cells in miR-214over mice leads to increased extravasation and metastasis formation. In line, treatment of cancer cells with CM or EVs derived from miR-214-enriched stroma cells potentiate cancer cell migration/invasion in vitro. Conversely, dissemination from tumors grown in miR-214ko mice is impaired and metastatic traits significantly decreased when CM or EVs from miR-214-depleted stroma cells are used to treat cells in culture. Instead, extravasation and metastasis formation are fully re-established when miR-214ko mice are pretreated with miR-214-rich EVs of stroma origin. Mechanistically, we also show that tumor cells are able to induce miR-214 production in stroma cells, following the activation of IL-6/STAT3 signaling, which is then released via EVs subsequently up-taken by cancer cells. Here, a miR-214-dependent pro-metastatic program becomes activated. Conclusions Our findings highlight the relevance of stroma-derived miR-214 and its release in EVs for tumor dissemination, which paves the way for miR-214-based therapeutic interventions targeting not only tumor cells but also the TME