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Metformin reverts the secretion of CXCL8 induced by TNF-α in primary cultures of human thyroid cells: An additional indirect anti-tumor effect of the drug
No full textCONTEXT:
Metformin displays both direct and indirect anti-tumor effects. CXCL8 is a crucial downstream mediator of Nuclear-Factor-κB signaling related to the growth and progression of thyroid cancers. Targeting CXCL8 results in prolonged survival and reduced metastatic spread in in-vivo animal models of thyroid tumors.
OBJECTIVE:
This study aimed to evaluate whether metformin inhibits the secretion of CXCL8 induced by Tumor-Necrosis-Factor-α (TNF-α) in primary cultures of normal and tumor human thyroid cells as well as in thyroid cancer cell lines.
METHODS:
Normal human thyrocytes, papillary thyroid cancer cells, and thyroid cancer cell lines (TPC-1 and BCPAP) were stimulated with TNF-α (10 ng/mL) alone or in combination with metformin (0.01, 0.1, 1, 2.5, 5, and 10mM). CXCL8 levels were measured in the cell supernatants after 24 hours.
RESULTS:
Metformin significantly and dose-dependently inhibited the TNF-α-induced CXCL8 secretion in both normal thyrocytes (ANOVA: F = 42.04; P < .0001) and papillary thyroid cancer cells (ANOVA: F = 21.691; P < .0001) but not in TPC-1 and BCPAP cell lines.
CONCLUSION:
Metformin inhibits the TNF-α-induced CXCL8 secretion in primary cultures of normal thyroid cells and differentiated thyroid cancer cells at least of the most frequent poorly aggressive phenotype. The recruitment of neutrophils within the thyroid gland is a crucial metastasis-promoting factor, and it depends on the amount of CXCL8 produced by both tumor cells and by the more abundant normal thyroid cells exposed to TNF-α. Thus, the here-reported inhibiting effect of metformin on TNF-α-induced CXCL8 secretion could be considered as a further indirect anticancer property of the drug
Expanding the therapeutic spectrum of metformin: From diabetes to cancer
No full textINTRODUCTION:
Metformin, an oral hypoglycemic agent, was introduced in the clinical practice for the treatment of type 2 diabetes mellitus more than a half-century ago. Over the years, several studies demonstrated that diabetic patients treated with metformin have a lower incidence of cancer, raising the hypothesis that the spectrum of clinical applications of the drug could be expanded also to cancer therapy. Following these initial findings, a large number of studies were performed aimed at elucidating the effects of metformin on different types of tumor, at explaining its direct and indirect anti-cancer mechanisms and at identifying the molecular pathways targeted by the drug. Several clinical trials were also performed aimed at evaluating the potential anti-cancer effect of metformin among diabetic and non-diabetic patients affected by different types of cancer. While the results of several clinical studies are encouraging, a considerable number of other investigations do not support a role of metformin as an anti-cancer agent, and highlight variables possibly accounting for discrepancies.
AIM:
We hereby review the results of in vitro and in vivo studies addressing the issue of the anti-cancer effects of metformin.
CONCLUSIONS:
If in vitro data appear solid, the results provided by in vivo studies are somehow controversial. In this view, larger studies are needed to fully elucidate the role of metformin on cancer development and progression, as well as the specific clinical settings in which metformin could become an anti-cancer drug
Per-polyfluoroalkyl substances (PFAS) as thyroid disruptors: is there evidence for multi-transgenerational effects?
No full textIntroductionThe environmental spread of pollutants has led to a persistent exposure of living beings to multiple chemicals, by now become ubiquitous in the surrounding environment. Environmental exposure to these substances has been reported to cause multi- and/or transgenerational health effects. Per- and Polyfluorinated Substances (PFAS) raise great concern, given their known effects both as endocrine disruptors and potential carcinogens. The multi/trans-generational effects of different endocrine disruptors have been investigated by several studies, and harmful effects observed also for PFAS.Areas coveredThis review examines the current data on the multi-trans-generational effects of PFAS, with a focus on their impact on the thyroid axis. The aim is to determine if there is evidence of potential multi-trans-generational effects of PFAS on the thyroid and/or if more research is needed.Expert opinionPFAS exposure impacts thyroid homeostasis and can cross the placental barrier. In addition PFAS have shown multi-transgenerational effects in laboratory experiences and animal models, but thyroid disruptive effects of PFAS were also investigated only in a small number of these studies. Efforts are needed to study the adverse effects of PFAS, as not all PFAS are regulated and removal strategies are still being developed
The multifaceted anti-cancer effects of BRAF-inhibitors
No full textThe BRAF gene is commonly involved in normal processes of cell growth and differentiation. The BRAF (V600E) mutation is found in several human cancer, causing an increase of cell proliferation due to a modification of the ERK/MAPK-signal cascade. In particular, BRAFV600E mutation is found in those melanoma or thyroid cancer refractory to the common therapy and with a more aggressive phenotype. BRAF V600E was found to influence the composition of the so-called tumour microenvironment modulating both solid (immune-cell infiltration) and soluble (chemokines) mediators, which balance characterize the ultimate behaviour of the tumour, making it more or less aggressive. In particular, the presence of BRAFV600E mutation would be associated with a change of this balance to a more aggressive phenotype of the tumour and a worse prognosis. The investigation of the possible modulation of those components of tumour microenvironment is nowadays object of several studies as a new potential target therapy in those more complicated cases. At present several clinical trials both in melanoma and thyroid cancer are using BRAF-inhibitors with encouraging results, which are derived also from numerous in vitro pre-clinical studies aimed at evaluate the possible modulation of immune-cell density and of specific pro-tumorigenic chemokine secretion (CXCL8 and CCL2) by several BRAF-inhibitors in the context of melanoma and thyroid cancer. This review will encompass in vitro and in vivo studies which investigated the modulation of the tumour microenvironment by BRAF-inhibitors, highlighting also the most recent clinical trials with a specific focus on melanoma and thyroid cancer
DIAGNOSIS OF ENDOCRINE DISEASE: IgG4-related thyroid autoimmune disease
No full textIgG4-related disease (IgG4-RD) is fibro-inflammatory, immune-mediated, systemic disease recognized as a defined clinical condition only in 2001. The prevalence of IgG4-RD is 6/100 000, but it is likely to be underestimated due to insufficient awareness of the disease. The diagnostic approach is complex because of the heterogeneity of clinical presentation and because of rather variable diagnostic criteria. Indeed, high concentrations of IgG4 in tissue and serum are not a reliable diagnostic marker. The spectrum of IgG4-RD also includes well-known thyroid diseases including Riedel's thyroiditis, Hashimoto's thyroiditis and its fibrotic variant, Graves' disease and Graves' orbitopathy. Results from clinical studies indicate that a small subset of patients with the above-mentioned thyroid conditions present some features suggestive for IgG4-RD. However, according to more recent views, the use of the term thyroid disease with an elevation of IgG4 rather than IgG4-related thyroid diseases would appear more appropriate. Nevertheless, the occurrence of high IgG4 levels in patients with thyroid disease is relevant due to peculiarities of their clinical course
The interplay between subclinical hypothyroidism and poor sleep quality: A systematic review
No full textBackground: The relationship between subclinical hypothyroidism (SHYPO) and sleep disturbances is still poorly investigated. This systematic review aims to critically appraise the existing literature to provide more insights in understanding whether SHYPO favors sleep disturbances or it is the sleep disturbance per se that affects the hypothalamus-pituitary-thyroid axis regulation. Methods: Original studies on sleep quality and duration in patients with SHYPO were searched in the PubMed/ MEDLINE, Embase, Web of Science and Scopus databases. Two reviewers independently screened articles for inclusion, extracted data, and assessed the quality of included studies. Results: Eight studies, including 2916 patients with SHYPO and 18,574 healthy controls, were retrieved. An overall agreement (7 out of 8 studies), about a positive correlation between decreased sleep quality and/or duration and SHYPO was observed. Five studies investigated sleep quality through self-reported surveys; only two studies explored both subjective and objective assessment of sleep quality with actigraphy (n n = 1) or polysomnography (n n = 1); finally, one study assessed subjective evaluation of sleep quality through a single question regarding the number of sleeping hours. A high level of heterogeneity among studies was manifest due to differences in population source, sleep measure assessment and criteria for diagnosing SHYPO. Discussion: Overall, the existing literature data suggest a link between SHYPO and sleep disturbances, but further studies on larger populations of patients with homogeneous study designs and outcomes are warranted
Editorial: Further advances in understanding the endocrine cancer microenvironment
No full textInflammation is a physiologic process occurring in response to tissue damage. Already in 1863, Virchow (1, 2), based on the observation that leukocytes infiltrate neoplastic tissues, hypothesized a relationship between inflammation and cancer. The demonstration that inflammation promotes tumor genome instability, cell growth, survival, invasion and angiogenesis has led to the current notion that inflammation is an essential component of malignancies (1) suggesting that it could represent a target for cancer therapy.
More recently, the term tumor microenvironment (TME) was used to include both cellular and soluble components which surround and infiltrate the tumor mass (3). The TME is composed of extracellular matrix and stromal cells, including fibroblasts, vessel cells (endothelial cells, pericytes, and smooth muscle cells), and inflammatory leukocytes (lymphocytes, macrophages, dendritic cells, mast cells, and neutrophils), while soluble mediators include a wide spectrum of chemokines, cytokines, and growth factors, which are secreted by both resident tumor and surrounding normal cells as well as by infiltrating immune cells (4–6).
It progressively became clear that both the phenotype and the number of infiltrating cells are strongly dependent upon specific chemokines secreted within the TME. Thus, chemokines rapidly became among the most extensively characterized molecules involved in the maintenance and progression of tumor-related inflammation (7).
In the five articles included in this Research Topic, different aspects of the most recent lines of research on the field of TME and cancer biology were addressed. The findings are here briefly overviewed with the final aim to provide a stimulating summary of the present knowledge
Effect of Pistacia palaestina Boiss. Essential Oil on Colorectal Cancer Cells: Inhibition of Proliferation and Migration
No full textColorectal cancer (CRC) is the third most common malignancy diagnosed worldwide and its management is still challenging; necessitating discovery of alternative agents. Natural compounds have historically been used in the treatment of CRC. Pistacia genus has recently received particular interest for its antitumor activity. The present study aimed to analyze the qualitative and quantitative composition of P. palaestina Boiss. fruit oil obtained from trees grown in Jordan, and to investigate its anticancer activity on CRC cells. The essential oil was obtained by hydro-distillation and solid phase micro-extraction (SPME). The composition of the essential oils were determined by gas chromatography-mass-spectrometry (GC/MS) and gas chromatography-flame ionization detector (GC/FID) analyses. The anticancer activity of P. palaestina fruit essential oil was investigated on HCT116 CRC cells. The cytotoxic activity was performed by MTT assay while the wound-healing assay was conducted to examine the potential anti-migratory activity of the fruit oil. The levels of CXCL8 were also measured in the cells' supernatant through ELISA. Monoterpene hydrocarbons were detected as the main constituents in the hydro-distilled and in the SPME detected oils with 96.1 % and 98.3 %, respectively. The MTT assay showed that P. palaestina fruit oil significantly reduced HCT116 cells viability and potentiated the anti-cancer activity of the traditional chemotherapy, 5-FU. An anti- migratory effect was observed on HCT116 cells after treatment with the fruit oil. P. palaestina significantly reduced CXCL8 levels, a chemokine contributing in CRC cells proliferation, and metastasis. The results of the study demonstrate P. palaestina as a promising alternative or adjuvant therapy for the treatment of CRC
Vitamin D Reduces Thyroid Cancer Cells Migration Independently From the Modulation of CCL2 and CXCL8 Chemokines Secretion
No full textBackgroundVitamin D3 is largely involved in the regulation of calcium homeostasis. More recently, it was demonstrated that vitamin D exerts several beneficial effects against cancer progression through several mechanisms, including the reduction of cancer cells proliferation and migration. CXCL8 and CCL2 are two chemokines secreted by thyroid tumor cells. In the thyroid tumor microenvironment, these chemokines exert several pro-tumorigenic effects including the one to increase the metastatic potential. The aim of the present study was to investigate if vitamin D could modulate both thyroid cancer cell migration and their ability to secrete CCL2 and CXCL8. MethodsTPC-1 (RET/PTC rearranged) and 8505C (BRAFV600e mutated) thyroid cancer cell lines were treated with increasing concentrations of 1,25-OH-vitamin D3 (0-1,000 nM). Cell viability was assessed by WST-1 assay, cell migration was evaluated by transwell-migration chamber system, and CCL2 and CXCL8 levels were measured in the cell culture supernatants by ELISA. ResultsVitamin D did not affect cell viability but reduced, in a dose-dependent and significant manner, thyroid cancer cell migration (ANOVAs p < 0.05 for both TPC-1 and 8505C). Vitamin D differently modulated the secretion of CCL2 and CXCL8, by significantly inhibiting the secretion of CCL2 in both thyroid cancer cell lines and inhibiting the secretion of CXCL8 only in TPC-1 (ANOVAs p < 0.05). ConclusionsVitamin D treatment of thyroid cancer cell lines reduces cell migration independently from the inhibition of the secretion of pro-tumorigenic chemokines. Future studies specifically designed at clarifying the pathways involved in the different inhibitory effects of vitamin D on CCL2 and CXCL8 in thyroid cancer cells appear worthwhile
Inflamm-ageing: How cytokines and nutrition shape the trajectory of ageing
No full text: Population ageing is increasing in prevalence in most developed countries. Ageing is the decline of functional properties at the cellular, tissue, and organ level. Biochemical changes that occur in all organisms that experience biological ageing are referred to as the "Hallmarks of ageing". Inflammation is a common denominator of the hallmarks of ageing, being mechanistically involved in most age-related health consequences. Inflamm-ageing refers to age-related changes in the inflammatory and immune systems which somehow drive the ageing process towards healthy or unhealthy ageing. Current evidences, support that, reversing the age-related pro-inflammatory status of inflamm-ageing, is able to modulate most hallmarks of ageing. Inflamm-ageing is associated with increased levels of pro-inflammatory molecules (e.g. cytokines, chemokines), ultimately producing a chronic low-grade inflammatory state typically observed in older individuals. It is commonly accepted that, the balance between pro- and anti-inflammatory cytokines/chemokines is one of the factors determining whether healthy or unhealthy ageing occurs. Malnutrition and nutritional imbalances, are highly prevalent in the elderly, playing a role in driving the balance of pro- and anti-inflammatory immunoactive molecules. In particular, malnutrition is a major risk factor for sarcopenia, a phenomenon characterized by loss of muscle mass, which is often referred to as the biological basis for frailty. Given the close relationship between malnutrition and sarcopenia, there is also evidence for a link between malnutrition and frailty. Indeed, changes in cytokine/chemokine levels in elderly patients with malnutrition were demonstrated. The demonstration that specific cytokines play a role in modulating appetite and nutrient sensing and taste reception, provided further evidence for the existence of a link between inflamm-ageing, nutrition and cytokines in shaping the trajectory of ageing. The present review will overview current evidence supporting the role of specific circulating cytokines and chemokines in the relationship between ageing, inflammation, and malnutrition
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