Characterization of tumor-derived mesenchymal stem cells potentially differentiating into cancer-associated fibroblasts in lung cancer

PurposeThe goal of this study was to understand if mesenchymal stem cells isolated from lung tumor tissue (T-MSCs) may differentiate into cancer associated fibroblasts (CAFs), that promote neoplastic progression, angiogenesis and metastasis in the epithelial solid tumors, mimicking the tumor microenvironmental influence.MethodsMSCs were been obtained from healthy (Control, C-MSCs) and tumor (T-MSCs) tissue of one patient who underwent a lobectomy for a lung adenocarcinoma pT1bN0. Isolated cells were characterized for the presence of molecular markers (identified by routine diagnostic characterization in differentiated tumoral cells), stemness properties, and CAF-related markers expression. Subsequently, cells were co-cultured with a lung adenocarcinoma cell line (A549 cells) to evaluate the effects on proliferation, oncogene expression and IL6 secretion.ResultsC- and T-MSCs did not present EGFR mutations unlike tumor tissue and showed a stem-like immunophenotype, characterized by the ability to differentiate towards osteo-, chondro- and adipogenic lineages. The expression of markers referred to CAFs (-SMA, HI-1, MMP11, VEGF, CXCL12, TGF-1, TGF-RII, IL6, TNF) was significantly higher in T-MSCs than in C-MSCs. The co-cultures with A549 cells led to the over-expression of selected oncogenes and to the increase of IL6 secretion in T-MSCs but not in C-MSCs.ConclusionsMSCs isolated from tumor tissue displayed distinct properties compared to MSCs isolated from healthy tissue, suggesting T-MSCs differentiation towards a CAF-related phenotype under the influence of the tumoral microenvironment

Effects of somatostatin and its analogues on progenitor mesenchymal cells isolated from human pituitary adenomas

Purpose: Progenitor mesenchymal cells (PMCs) have been found also in epithelial tumors and may derive from cancer stem cells (CSCs) by EMT mechanism. In this scenario, the effects of traditionally drugs on PMCs become of primary concern for therapeutic approaches. Previously, we isolated PMCs from acromegalic (GHomas) and not-functioning pituitary adenomas (NFPAs). Here we evaluate: (1) the role of EMT on their origin; (2) the presence of the somatostatin receptors (SSTR1-5); (3) the effects of somatostatin (SST) and its analogues (SSAs) on PMCs proliferation, apoptosis and SSTR1-5 expression. Methods: PMCs were isolated from GHomas and NFPAs; the expression of E-CADHERIN and TGFβRII (referred to EMT), the expression of the SSTR1-5 as well as the proliferation and apoptosis were tested before and after drugs administration. Results: Results show a decrease of E-CADHERIN and an increase of TGFβRII, confirming an EMT involvement; SSTR1-5 are more expressed by PMCs from GHomas than from NFPAs. SST and SSAs administration does not affect cell proliferation and SSTR1-5 expression on PMCs from NFPAs while in PMCs from GHomas, cell proliferation showed a marked decrease and a corresponding increase in the expression of SSTR1-2. Apoptosis rate and EMT were not affected by drugs administration. Conclusions: Results indicate as EMT may be related to the presence of PMCs on pituitary tumors; SSAs, currently used in the management of human GHomas, exert anti-proliferative effect also in PMCs that, because of their derivation from CSCs, may be a new meaningful target for drugs treatment

Risk of cardiovascular toxicities and hypertension in nonmetastatic castration-resistant prostate cancer patients treated with novel hormonal agents: a systematic review and meta-analysis

Background: With hormonal agents quickly expanding as novel therapeutic options in nonmetastatic castration-resistant prostate cancer (nmCRPC), the toxicity profile of enzalutamide, apalutamide, and darolutamide should be kept in mind. Methods: We performed an updated meta-analysis with the aim to analyze the risk of treatment-related cardiovascular (CV) events, any grade, and grade 3–4 (G3-4) hypertension in nmCRPC patients treated with enzalutamide, apalutamide, and darolutamide plus androgen deprivation therapy (ADT) versus ADT plus placebo in randomized controlled trials (RCTs). Results were compared by calculating Relative Risk (RR) with 95% confidence intervals (CIs); RRs were combined with Mantel-Haenszel method. Results: Three RCTs involving 4110 patients were available for the meta-analysis. According to our results, the addition of novel hormonal agents was associated with a significantly increased risk of CV events (RR = 1.71; 95% CI 1.29–2.27) and G3-4 hypertension (RR = 1.53; 95% CI 1.19–1.97). In addition, a trend toward a higher risk of any grade hypertension was reported in the experimental arm. Conclusions: The use of enzalutamide, apalutamide, and darolutamide in nmCRPC patients implies a careful benefit-risk assessment. Real-world, large-cohort studies are warranted to confirm the findings of our meta-analysis

Role of mesenchymal stem cells in the pathogenesis of psoriasis: current perspectives

Anna Campanati*, Veronica Consales*, Monia Orciani, Katia Giuliodori, Giulia Ganzetti, Ivan Bobyr, Giulia Sorgentoni, Roberto di Primio, Annamaria Offidani Dermatological Clinic, Department of Clinical and Molecular Sciences, Polytechnic Marche University, Ancona, Italy *These authors contributed equally to this work Abstract: Mesenchymal stem cells (MSCs) are multipotent nonhematopoietic stromal cells studied for their properties and importance in management of several skin diseases. This review collects and analyzes the emerging published data, which describe the function of MSCs in the pathogenesis of psoriasis. Keywords: mesenchymal stem cells, pathogenesis of psoriasis, revie

Adjuvant therapy in renal cell carcinoma-is pharmacogenomics assessment another element to select our patients?

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Incidence of grade 3–4 adverse events, dose reduction, and treatment discontinuation in castration-resistant prostate cancer patients receiving PARP inhibitors: a meta-analysis

Background: PARP inhibitors (PARPi) have recently emerged as a new treatment option for several solid tumors, including metastatic castration-resistant prostate cancer (mCRPC). However, several grade 3–4 adverse events have been reported during PARPi administration, leading to limitations in treatment adherence. Methods: Herein, we conducted a meta-analysis aimed at analyzing the incidence rate of commonly reported grade 3–4 adverse events, dose reduction, and treatment discontinuation in mCRPC patients treated with PARPi monotherapy. Results: Incidence rate with 95% confidence intervals (CIs) of grade 3–4 toxicities, dose reduction, and treatment discontinuation were calculated. Six trials involving 752 mCRPC patients were available for the meta-analysis. According to our results, anemia was the most frequently observed grade 3–4 toxicity (24.1%), and dose reduction (26.9%) and treatment discontinuation (14.1%) were common events during PARPi treatment. Conclusions: Clinicians should carefully consider these risks, especially taking into account that the use of PARPi in mCRPC patients is expected to rise in the near future

The role of obesity in renal cell carcinoma patients: Clinical-pathological implications

Obesity is a well-known risk factor for renal cell carcinoma (RCC) development. However, the RCC–obesity link has not been fully addressed when considering a comprehensive scenario starting from pathogenetic aspects through pathological issues up to the outcome of medical treatment. We therefore conducted an electronic PubMed search using keywords “obesity”, “body mass index”, “overweight”, “renal cell carcinoma/kidney cancer”, “medical treatment”, “targeted therapy”, and “immunotherapy/immune checkpoint inhibitors”. The selected data supported a crosstalk between adipose tissue (adipocytes and other white adipose tissue cells) and cancer cells inducing several signaling pathways that finally stimulated angiogenesis, survival, and cellular proliferation. Accurate sampling of renal sinus fat correlated with a prognostic value. Retrospective clinical evidence in metastatic RCC patients with higher body mass index (BMI) and treated with targeted therapies and/or immune checkpoint inhibitors showed advantageous survival outcomes. Therefore, obesity may influence the course of RCC patients, although the interplay between obesity/BMI and RCC warrants a large prospective confirmation. We are therefore still far from determining a clear role of obesity as a prognostic/predictive factor in metastatic RCC patients undergoing targeted therapy and immunotherapy