Role of erythropoietin in the angiogenic activity of bone marrow endothelial cells of MGUS and multiple myeloma patients

Increasing evidences suggest several biological roles for erythropoietin and its receptor (Epo and EpoR), unrelated to erythropoiesis, including angiogenesis. Here, we detected the expression of EpoR in bone marrow-derived endothelial cells from monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) patients (MGECs and MMECs, respectively) and assessed whether Epo plays a role in MGECs- and MMECs-mediated angiogenesis. We show that EpoR is expressed by both MGECs and MMECs even though at a higher level in the first ones. Both EC types respond to rHuEpo in terms of cell proliferation, whereas other responses, including activation of JAK2/STAT5 and PI3K/Akt pathways, cell migration and capillarogenesis are enhanced by Epo in MGECs, but not in MMECs. In addition, the conditioned media of both Epo-treated cells induce a strong angiogenic response in vivo in the chorioallantoic membrane assay, comparable to that of vascular endothelial growth factor (VEGF). Overall, these data highlight the effect of Epo on MGECs- and MMECs-mediated angiogenesis: MGECs are more responsive to Epo treatment than MMECs, probably because over-angiogenic phenotype of MMECs is already activated by their autocrine/paracrine loops occurring in the "angiogenic switch" from MGUS

Immersive and Non-Immersive Virtual Reality for Pain and Anxiety Management in Pediatric Patients with Hematological or Solid Cancer: A Systematic Review

Invasive and painful procedures, which often induce feelings of anxiety, are necessary components of pediatric cancer treatment, and adequate pain and anxiety management during these treatments is of pivotal importance. In this context, it is widely recognized that a holistic approach, including pharmacological and non-pharmacological modalities, such as distraction techniques, should be the standard of care. Recent evidence suggested the use of virtual reality (VR) as an effective non-pharmacological intervention in pediatrics. Therefore, this systematic review aims to analyze previously published studies on the effectiveness of VR for the management of pain and/or anxiety in children and adolescents with hematological or solid cancer. Medline, SCOPUS, Web of Science, ProQuest, CINAHL, and The Cochrane Central Register of Controlled Trials were used to search for relevant studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Randomized controlled trial, crossover trial, cluster randomized trial, and quasi-experimental studies were included. Thirteen studies, published between 1999 and 2022, that fulfilled the inclusion criteria were included. Regarding the primary outcomes measured, pain was considered in five studies, anxiety in three studies, and the remaining five studies analyzed the effectiveness of VR for both pain and anxiety reduction. Our findings suggested a beneficial effect of VR during painful vascular access procedures. Limited data are available on the reduction of anxiety in children with cancer

Prognostic or predictive value of circulating cytokines and angiogenic factors for initial treatment of multiple myeloma in the GIMEMA MM0305 randomized controlled trial

Abstract Background Several new drugs are approved for treatment of patients with multiple myeloma (MM), but no validated biomarkers are available for the prediction of a clinical outcome. We aimed to establish whether pretreatment blood and bone marrow plasma concentrations of major cytokines and angiogenic factors (CAFs) of patients from a phase 3 trial of a MM treatment could have a prognostic and predictive value in terms of response to therapy and progression-free and overall survival and whether these patients could be stratified for their prognosis. Methods Blood and bone marrow plasma levels of Ang-2, FGF-2, HGF, VEGF, PDGF-β, IL-8, TNF-α, TIMP-1, and TIMP-2 were determined at diagnosis in MM patients enrolled in the GIMEMA MM0305 randomized controlled trial by an enzyme-linked immunosorbent assay (ELISA). These levels were correlated both reciprocally and with the type of therapy and patients’ characteristics and with a group of non-MM patients as controls. Results No significant differences were detected between the blood and bone marrow plasma levels of angiogenic cytokines. A cutoff for each CAF was established. The therapeutic response of patients with blood plasma levels of CAFs lower than the cutoff was better than the response of those with higher levels in terms of percentage of responding patients and quality of response. Conclusion FGF-2, HGF, VEGF, and PDGF-β plasma levels at diagnosis have predictive significance for response to treatment. The stratification of patients based on the levels of CAFs at diagnosis and their variations after therapy is useful to characterize different risk groups concerning outcome and response to therapy. Trial registration Clinical trial information can be found at the following link: NCT0106317

circPVT1 and PVT1/AKT3 show a role in cell proliferation, apoptosis, and tumor subtype-definition in small cell lung cancer

Small cell lung cancer (SCLC) is treated as a homogeneous disease, although the expression of NEUROD1, ASCL1, POU2F3, and YAP1 identifies distinct molecular subtypes. The MYC oncogene, amplified in SCLC, was recently shown to act as a lineage-specific factor to associate subtypes with histological classes. Indeed, MYC-driven SCLCs show a distinct metabolic profile and drug sensitivity. To disentangle their molecular features, we focused on the co-amplified PVT1, frequently overexpressed and originating circular (circRNA) and chimeric RNAs. We analyzed hsa_circ_0001821 (circPVT1) and PVT1/AKT3 (chimPVT1) as examples of such transcripts, respectively, to unveil their tumorigenic contribution to SCLC. In detail, circPVT1 activated a pro-proliferative and anti-apoptotic program when over-expressed in lung cells, and knockdown of chimPVT1 induced a decrease in cell growth and an increase of apoptosis in SCLC in vitro. Moreover, the investigated PVT1 transcripts underlined a functional connection between MYC and YAP1/POU2F3, suggesting that they contribute to the transcriptional landscape associated with MYC amplification. In conclusion, we have uncovered a functional role of circular and chimeric PVT1 transcripts in SCLC; these entities may prove useful as novel biomarkers in MYC-amplified tumors.</p

The Landscape of lncRNAs in Multiple Myeloma: Implications in the &ldquo;Hallmarks of Cancer&rdquo;, Clinical Perspectives and Therapeutic Opportunities

Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that are not translated into proteins. Nowadays, lncRNAs are gaining importance as key regulators of gene expression and, consequently, of several biological functions in physiological and pathological conditions, including cancer. Here, we point out the role of lncRNAs in the pathogenesis of multiple myeloma (MM). We focus on their ability to regulate the biological processes identified as &ldquo;hallmarks of cancer&rdquo; that enable malignant cell transformation, early tumor onset and progression. The aberrant expression of lncRNAs in MM suggests their potential use as clinical biomarkers for diagnosis, patient stratification, and clinical management. Moreover, they represent ideal candidates for therapeutic targeting

Different Adaptive Responses to Hypoxia in Normal and Multiple Myeloma Endothelial Cells

Background/Aims: Hypoxia is a powerful stimulator of angiogenesis under physiological as well as pathological conditions. Normal endothelial cells (EC), such as human umbilical vein EC (HUVEC), are relatively affected by hypoxic insult in terms of cell survival. In contrast, EC from tumors are particularly resistant to hypoxia-induced cell death. Previous reports have shown that EC in bone marrow from multiple myeloma (MM) patients had a hypoxic phenotype, even under normoxic conditions. The aim of this study was to evaluate whether HUVEC and MMEC adapt differently to hypoxia. Methods: Cell proliferation was assessed by the CyQUANT assay. Cdc25A, p21, Bax, Bcl-xl, BNIP3, glucose transporter (GLUT)-1, monocarboxylate transporter (MCT)-4 and carbonic anhydrase (CA)IX mRNA expression was determined by qRT-PCR. HIF-1α, BNIP3, Beclin-1, LC3B, livin, Bax, Bcl-xl, p21, p62 and β-actin protein expression was analyzed by western blot. Apoptosis was determined by TUNEL assay. Silencing of BNIP3 was achieved by stealth RNA system technology. Results: While HUVEC survival was reduced after prolonged hypoxic exposure, MMEC were completely unaffected. This difference was also significant in terms of livin, cdc25A and p21 expression. Hypoxia induced apoptosis and inhibited autophagy in HUVEC, but not in MMEC, where hypoxic treatment resulted in a more sustained adaptive response. In fact, MMEC showed a more significant increase in the expression of genes regulated transcriptionally by hypoxia-inducible factor (HIF)-1α. Interestingly, they showed higher expression of BNIP3 than did HUVEC, indicating a more pronounced autophagic (and pro-survival) phenotype. The potential role of BNIP3 in EC survival was confirmed by BNIP3 siRNA experiments in HUVEC, where BNIP3 inhibition resulted in reduced cell survival and increased apoptosis. Conclusion: These findings provide further information on how hypoxia may affect EC survival and could be important for a better understanding of EC physiology under normal and pathological conditions, such as in multiple myeloma

Functional and Biological Role of Endothelial Precursor Cells in Tumour Progression: A New Potential Therapeutic Target in Haematological Malignancies

It was believed that vasculogenesis occurred only during embryo life and that postnatal formation of vessels arose from angiogenesis. Recent findings demonstrate the existence of Endothelial Precursor Cells (EPCs), which take partin postnatal vasculogenesis. EPCs are recruited from the bone marrow under the stimulation of growth factors and cytokines and reach the sites of neovascularization in both physiological and pathological conditions such as malignancies where they contribute to the “angiogenic switch” and tumor progression. An implementation of circulating EPCs in the bloodstream of patients with haematological malignancies has been demonstrated. This increase is strictly related to the bone marrow microvessel density and correlated with a poor prognosis. The EPCs characterization is a very complex process and still under investigation. This literature review aims to provide an overview of the functional and biological role of EPCs in haematological malignancies and to investigate their potential as a new cancer therapeutic target

Antiangiogenic drugs as chemosensitizers in hematological tumors

Angiogenesis, the formation of new capillaries from preexisting blood vessels, plays an important role in cancer progression. When the tumor mass expands, the balance is shifted toward a pro-angiogenic milieu to maintain sustainable angiogenic processes. In this context, there is an up-regulation of several pro-angiogenic factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), placental growth factor (PlGF), platelet derived endothelial cell growth factor (PD-ECGF), angiopoietins (Angs), transforming growth factors (TGFs) -α and -β, and epidermal cell growth factor (EGF), which collectively activate the proliferation of circulating endothelial progenitor cells (EPCs) able to enter in the peripheral blood circulation, migrating to sites of angiogenesis. Hence, the number of antiangiogenic agents developed for cancer treatment has risen over the past years. To date, the most common approaches to the inhibition of the VEGF axis include the blockade of VEGF receptors (VEGFRs) or ligands by neutralizing antibodies, as well as the tyrosine kinase inhibitors (TKIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs). Here, we focus on the role of circulating EPCs, which mediate the cross-talk between cancer angiogenesis and neoplastic clone, as potential novel targets for antiangiogenic drugs with particular relevance for hematological malignancies

Role of Extracellular Vesicle-Based Cell-to-Cell Communication in Multiple Myeloma Progression

Multiple myeloma (MM) progression closely depends on the bidirectional crosstalk between tumor cells and the surrounding microenvironment, which leads to the creation of a tumor supportive niche. Extracellular vesicles (EVs) have emerged as key players in the pathological interplay between the malignant clone and near/distal bone marrow (BM) cells through their biologically active cargo. Here, we describe the role of EVs derived from MM and BM cells in reprogramming the tumor microenvironment and in fostering bone disease, angiogenesis, immunosuppression, drug resistance, and, ultimately, tumor progression. We also examine the emerging role of EVs as new therapeutic agents for the treatment of MM, and their potential use as clinical biomarkers for early diagnosis, disease classification, and therapy monitoring