Extracellular vesicles (EVs) represent a heterogeneous group of membranous structures shed by all kinds of cell types, which are released into the surrounding microenvironment or spread to distant ...sites through the circulation. Therefore, EVs are key mediators of the communication between tumor cells and the surrounding microenvironment or the distant premetastatic niche due to their ability to transport lipids, transcription factors, mRNAs, non-coding regulatory RNAs, and proteins. Multiple myeloma (MM) is a hematological neoplasm that mostly relies on the bone marrow (BM). The BM represents a highly supportive niche for myeloma establishment and diffusion during the formation of distant bone lesions typical of this disease. This review represents a survey of the most recent evidence published on the role played by EVs in supporting MM cells during the multiple steps of metastasis, including travel and uptake at distant premetastatic niches, MM cell engraftment as micrometastasis, and expansion to macrometastasis thanks to EV-induced angiogenesis, release of angiocrine factors, activation of osteolytic activity, and mesenchymal cell support. Finally, we illustrate the first evidence concerning the dual effect of MM-EVs in promoting both anti-tumor immunity and MM immune escape, and the possible modulation operated by pharmacological treatments.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Despite novel therapies, relapse of multiple myeloma (MM) is virtually inevitable. Amplification of chromosome 1q, which harbors the inflammation-responsive RNA editase adenosine deaminase acting on ...RNA (ADAR)1 gene, occurs in 30-50% of MM patients and portends a poor prognosis. Since adenosine-to-inosine RNA editing has recently emerged as a driver of cancer progression, genomic amplification combined with inflammatory cytokine activation of ADAR1 could stimulate MM progression and therapeutic resistance. Here, we report that high ADAR1 RNA expression correlates with reduced patient survival rates in the MMRF CoMMpass data set. Expression of wild-type, but not mutant, ADAR1 enhances Alu-dependent editing and transcriptional activity of GLI1, a Hedgehog (Hh) pathway transcriptional activator and self-renewal agonist, and promotes immunomodulatory drug resistance in vitro. Finally, ADAR1 knockdown reduces regeneration of high-risk MM in serially transplantable patient-derived xenografts. These data demonstrate that ADAR1 promotes malignant regeneration of MM and if selectively inhibited may obviate progression and relapse.
Multiple myeloma (MM) is an incurable hematologic neoplasm, whose poor prognosis is deeply affected by the propensity of tumor cells to localize in the bone marrow (BM) and induce the pro-tumorigenic ...activity of normal BM cells, leading to events associated with tumor progression, including tumor angiogenesis, osteoclastogenesis, and the spread of osteolytic bone lesions. The interplay between MM cells and the BM niche does not rely only on direct cell-cell interaction, but a crucial role is also played by MM-derived extracellular vesicles (MM-EV). Here, we demonstrated that the oncogenic NOTCH receptors are part of MM-EV cargo and play a key role in EV pro-tumorigenic ability. We used in vitro and in vivo models to investigate the role of EV-derived NOTCH2 in stimulating the protumorigenic behaviour of endothelial cells and osteoclast progenitors. Importantly, MM-EV can transfer NOTCH2 between distant cells and increase NOTCH signaling in target cells. MM-EV stimulation increases endothelial cell angiogenic ability and osteoclast differentiation in a NOTCH2 dependent way. Indeed, interfering with NOTCH2 expression in MM cells may decrease the amount of NOTCH2 also in MM-EV and affect their angiogenic and osteoclastogenic potential. Finally, we demonstrated that the pharmacologic blockage of NOTCH activation by b-Secretase inhibitors may hamper the biological effect of EV derived by MM cell lines and by the BM of MM patients. These results provide the first evidence that targeting the NOTCH pathway may be a valid therapeutic strategy to hamper the pro-tumorigenic role of EV in MM as well as other tumors.
Notch signaling is a well-known key player in the communication between adjacent cells during organ development, when it controls several processes involved in cell differentiation. Notch-mediated ...communication may occur through the interaction of Notch receptors with ligands on adjacent cells or by a paracrine/endocrine fashion, through soluble molecules that can mediate the communication between cells at distant sites. Dysregulation of Notch pathway causes a number of disorders, including cancer. Notch hyperactivation may be caused by mutations of Notch-related genes, dysregulated upstream pathways, or microenvironment signals. Cancer cells may exploit this aberrant signaling to "educate" the surrounding microenvironment cells toward a pro-tumoral behavior. This may occur because of key cytokines secreted by tumor cells or it may involve the microenvironment through the activation of Notch signaling in stromal cells, an event mediated by a direct cell-to-cell contact and resulting in the increased secretion of several pro-tumorigenic cytokines. Up to now, review articles were mainly focused on Notch contribution in a specific tumor context or immune cell populations. Here, we provide a comprehensive overview on the outcomes of Notch-mediated pathological interactions in different tumor settings and on the molecular and cellular mediators involved in this process. We describe how Notch dysregulation in cancer may alter the cytokine network and its outcomes on tumor progression and antitumor immune response.
Multiple myeloma is still incurable due to an intrinsic aggressiveness or, more frequently, to the interactions of malignant plasma cells with the bone marrow (BM) microenvironment. Myeloma cells ...educate BM cells to support neoplastic cell growth, survival, acquisition of drug resistance resulting in disease relapse. Myeloma microenvironment is characterized by Notch signaling hyperactivation due to the increased expression of Notch1 and 2 and the ligands Jagged1 and 2 in tumor cells. Notch activation influences myeloma cell biology and promotes the reprogramming of BM stromal cells. In this work we demonstrate,
and by using a zebrafish multiple myeloma model, that Jagged inhibition causes a decrease in both myeloma-intrinsic and stromal cell-induced resistance to currently used drugs, i.e. bortezomib, lenalidomide and melphalan. The molecular mechanism of drug resistance involves the chemokine system CXCR4/SDF1α. Myeloma cell-derived Jagged ligands trigger Notch activity in BM stromal cells. These, in turn, secrete higher levels of SDF1α in the BM microenvironment increasing CXCR4 activation in myeloma cells, which is further potentiated by the concomitant increased expression of this receptor induced by Notch activation. Consistently with the augmented pharmacological resistance, SDF1α boosts the expression of BCL2, Survivin and ABCC1. These results indicate that a Jagged-tailored approach may contribute to disrupting the pharmacological resistance due to intrinsic myeloma cell features or to the pathological interplay with BM stromal cells and, conceivably, improve patients' response to standard-of-care therapies.
Long non-coding RNA NEAT1 is the core structural component of the nuclear paraspeckle (PS) organelles and it has been found to be deregulated in multiple myeloma (MM) patients. Experimental evidence ...indicated that NEAT1 silencing negatively impacts proliferation and viability of MM cells, both in vitro and in vivo, suggesting a role in DNA damage repair (DDR). In order to elucidate the biological and molecular relevance of NEAT1 upregulation in MM disease we exploited the CRISPR/Cas9 synergistic activation mediator genome editing system to engineer the AMO-1 MM cell line and generate two clones that para-physiologically transactivate NEAT1 at different levels. NEAT1 overexpression is associated with oncogenic and prosurvival advantages in MM cells exposed to nutrient starvation or a hypoxic microenvironment, which are stressful conditions often associated with more aggressive disease phases. Furthermore, we highlighted the NEAT1 involvement in virtually all DDR processes through, at least, two different mechanisms. On one side NEAT1 positively regulates the posttranslational stabilization of essential PS proteins, which are involved in almost all DDR systems, thus increasing their availability within cells. On the other hand, NEAT1 plays a crucial role as a major regulator of a molecular axis that includes ATM and the catalytic subunit of DNA-PK kinase proteins, and their direct targets pRPA32 and pCHK2. Overall, we provided novel important insightsthe role of NEAT1 in supporting MM cells adaptation to stressful conditions by improving the maintenance of DNA integrity. Taken together, our results suggest that NEAT1, and probably PS organelles, could represent a potential therapeutic target for MM treatment.
Bone is the most common site of cancer metastasis and the spread of cancer cells to the bone is associated with poor prognosis, pain, increased risk of fractures, and hypercalcemia. The bone marrow ...microenvironment is an attractive place for tumor dissemination, due to the dynamic network of non-malignant cells. In particular, the alteration of the bone homeostasis favors the tumor homing and the consequent osteolytic or osteoblastic lesions. Extracellular vesicles (EVs) are reported to be involved in the metastatic process, promoting tumor invasion, escape from immune surveillance, extravasation, extracellular matrix remodeling, and metastasis, but the role of EVs in bone metastases is still unclear. Current results suggest the ability of tumor derived EVs in promoting bone localization and metastasis formation, altering the physiological balance between bone destruction and new bone depositions. Moreover, EVs from the bone marrow niche may support the onset of tumor metastasis. This review summarizes recent findings on the role of EVs in the pathological alterations of homeostasis that occur during bone metastasis to show novel potential EV-based therapeutic options to inhibit metastasis formation.
Notch is a multifaceted protein that plays a fundamental role in fetal development and tissue homeostasis by directing many cellular functions, including cell growth and differentiation, cell fate ...determination and regulation of stem cells maintenance. The Notch family consists of four receptors (Notch 1-4) and five ligands (Jagged1-2 and Delta-like 1-3-4) widely expressed in human tissues. Given the crucial contribution of Notch signaling in many physiological processes, it is not surprising that a variety of human malignancies is characterized by a dysregulation of one or more components of this pathway.
In this review, we are going to provide a broad overview on the role of Notch pathway in solid and hematological malignancies and a survey on possible Notch-directed therapeutic strategies.
We present the most recent findings indicating that Notch signaling dysregulation in human cancers may be due to genetic and epigenetic alterations or to the interactions with other oncogenic pathways. Furthermore, Notch activity may have an oncogenic or a tumor suppressor effect. Finally, we describe the latest preclinical and clinical studies concerning the different pharmacological approaches targeting Notch.
The provided evidence confirms the importance of Notch pathway in human malignancies indicating that a strong rationale exists for the development of a Notch-tailored therapy.
Both astronauts and patients affected by chronic movement-limiting pathologies face impairment in muscle and/or brain performance. Increased patient survival expectations and the expected longer ...stays in space by astronauts may result in prolonged motor deprivation and consequent pathological effects. Severe movement limitation can influence not only the motor and metabolic systems but also the nervous system, altering neurogenesis and the interaction between motoneurons and muscle cells. Little information is yet available about the effect of prolonged muscle disuse on neural stem cells characteristics. Our
study aims to fill this gap by focusing on the biological and molecular properties of neural stem cells (NSCs). Our analysis shows that NSCs derived from the SVZ of HU mice had shown a reduced proliferation capability and an altered cell cycle. Furthermore, NSCs obtained from HU animals present an incomplete differentiation/maturation. The overall results support the existence of a link between reduction of exercise and muscle disuse and metabolism in the brain and thus represent valuable new information that could clarify how circumstances such as the absence of load and the lack of movement that occurs in people with some neurological diseases, may affect the properties of NSCs and contribute to the negative manifestations of these conditions.
DIS3 gene mutations occur in approximately 10% of patients with multiple myeloma (MM); furthermore, DIS3 expression can be affected by monosomy 13 and del(13q), found in roughly 40% of MM cases. ...Despite the high incidence of DIS3 mutations and deletions, the biological significance of DIS3 and its contribution to MM pathogenesis remain poorly understood. In this study we investigated the functional role of DIS3 in MM, by exploiting a loss-of-function approach in human MM cell lines. We found that DIS3 knockdown inhibits proliferation in MM cell lines and largely affects cell cycle progression of MM plasma cells, ultimately inducing a significant increase in the percentage of cells in the G0/G1 phase and a decrease in the S and G2/M phases. DIS3 plays an important role not only in the control of the MM plasma cell cycle, but also in the centrosome duplication cycle, which are strictly co-regulated in physiological conditions in the G1 phase. Indeed, DIS3 silencing leads to the formation of supernumerary centrosomes accompanied by the assembly of multipolar spindles during mitosis. In MM, centrosome amplification is present in about a third of patients and may represent a mechanism leading to genomic instability. These findings strongly prompt further studies investigating the relevance of DIS3 in the centrosome duplication process. Indeed, a combination of DIS3 defects and deficient spindle-assembly checkpoint can allow cells to progress through the cell cycle without proper chromosome segregation, generating aneuploid cells which ultimately lead to the development of MM.
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