Microenvironment drug resistance in multiple myeloma: emerging new players

Marzo, Lucia Di; Desantis, Vanessa; Solimando, Antonio Giovanni; Ruggieri, Simona; Annese, Tiziana; Nico, Beatrice; Fumarulo, Ruggiero; Vacca, Angelo; Frassanito, Maria Antonia

doi:10.18632/oncotarget.10849

Cited by 143 publications

(157 citation statements)

References 117 publications

(156 reference statements)

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“…In cancer, secretion of exosomes often increases as tumors transit toward a more aggressive phenotype. The tumor-host crosstalk mediated by exosomes has multiple effects that can influence processes such as formation of the pre-metastatic niche, angiogenesis, host immune function as well as conferring anticancer drug resistance (Di Marzo et al, 2016; Peinado et al, 2012; Peinado et al, 2011; Wojtuszkiewicz et al, 2016; Zhang and Grizzle, 2011). Several members of the Rab protein family have been shown to control exosome formation and more recently it was reported that syndecan proteoglycans, through their interaction with the syntenin-ALIX complex, influence the biogenesis of exosomes (Baietti et al, 2012; Ostrowski et al, 2010; Peinado et al, 2011).…”

Section: Cellular Uptake and Trafficking Of Heparanasementioning

confidence: 99%

Heparanase: From basic research to therapeutic applications in cancer and inflammation

Vlodavsky¹,

Singh²,

Boyango³

et al. 2016

Drug Resistance Updates

187

229

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Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Heparanase expression is enhanced in almost all cancers examined including various carcinomas, sarcomas and hematological malignancies. Numerous clinical association studies have consistently demonstrated that upregulation of heparanase expression correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. In contrast, knockdown of heparanase or treatments of tumor-bearing mice with heparanase-inhibiting compounds, markedly attenuate tumor progression further underscoring the potential of anti-heparanase therapy for multiple types of cancer. Heparanase neutralizing monoclonal antibodies block myeloma and lymphoma tumor growth and dissemination; this is attributable to a combined effect on the tumor cells and/or cells of the tumor microenvironment. In fact, much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis and chemoresistance. The repertoire of the physiopathological activities of heparanase is expanding. Specifically, heparanase regulates gene expression, activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and non-enzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive inflammatory responses, tumor survival, growth, dissemination and drug resistance; but in the same time, may fulfill some normal functions associated, for example, with vesicular traffic, lysosomal-based secretion, stress response, and heparan sulfate turnover. Heparanase is upregulated in response to chemotherapy in cancer patients and the surviving cells acquire chemoresistance, attributed, at least in part, to autophagy. Consequently, heparanase inhibitors used in tandem with chemotherapeutic drugs overcome initial chemoresistance, providing a strong rationale for applying anti-heparanase therapy in combination with conventional anti-cancer drugs. Heparin-like compounds that inhibit heparanase activity are being evaluated in clinical trials for various types of cancer. Heparanase neutralizing monoclonal antibodies are being evaluated in pre-clinical studies, and heparanase-inhibiting small molecules are being developed based on the recently resolved crystal structure of the heparanase protein. Collectively, the emerging premise is that heparanase expressed by tumor cells, innate immune cells, activated endothelial cells as well as other cells of the tumor microenvironment is a master regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a prime target for therapy.

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Section: Cellular Uptake and Trafficking Of Heparanasementioning

confidence: 99%

Heparanase: From basic research to therapeutic applications in cancer and inflammation

Vlodavsky¹,

Singh²,

Boyango³

et al. 2016

Drug Resistance Updates

187

229

View full text Add to dashboard Cite

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“…Exosomes can contain protein, lipid, and DNA signatures in addition to mRNA and miRNAs, but only 2-5% of the RNAome is found in exosomes [29]. Exosomes mediate communication between cells by transferring their contents through fusion or endocytosis with their target cell [6]. Reticulocytes, dendritic cells, B cells, T cells, mast cells, epithelial cells, and tumor cells all release exosomes [30].…”

Section: Exosome Mediated Transfer Of Mirnas From Bmat To Myelomamentioning

confidence: 99%

“…The bone marrow microenvironment (BMME), an intricate and dynamic niche composed of extracellular matrix (ECM) proteins and cells of hematopoietic lineage, serves as an instrumental contributor to myeloma disease progression [4]. Understanding the mechanisms of crosstalk between bone marrow stromal cells (BMSCs) and myeloma cells is essential for developing therapeutic agents and protecting the quality of life of those living with myeloma [5, 6]. BMSCs, fibroblasts, macrophages, endothelial cells, bone marrow adipocytes, osteoblasts, and osteoclasts form a complex framework with ECM proteins, growth factors, and hypoxia to enable myeloma cell colonization [5].…”

Section: Introductionmentioning

confidence: 99%

“…Ensconced in RNA binding proteins or in micro vesicles such as exosomes, miRNAs circulate through biological fluids act as signaling molecules within their target cells by changing the expression of specific target genes [6]. Many miRNAs play an important role in bone homeostasis and skeletal development, and even serve as diagnostic and prognostic biomarkers in tumors [9]; both functions make them pertinent to myeloma [10].…”

Section: Introductionmentioning

confidence: 99%

“…The highly specific differential expression of miRNAs in tumors could one day aid in the diagnosis and treatment of cancer [11]. Additionally, miRNAs may mediate crosstalk between the BMME and myeloma cells [6]. In a study conducted by Lee et al, BMSCs were observed to deliver miRNA mimics carried by exosomes to glioma tumor cells, independent of cell to cell contact or gap junctions [13].…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA Transfer Between Bone Marrow Adipose and Multiple Myeloma Cells

Soley

Falank

Reagan

2017

Curr Osteoporos Rep

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Purpose of Review Multiple myeloma remains an incurable disease, largely due to the tumor-supportive role of the bone marrow microenvironment. Bone marrow adipose tissue (BMAT) is one component of the fertile microenvironment which is believed to contribute to myeloma progression and drug resistance, as well as participate in a vicious cycle of osteolysis and tumor growth. Recent Findings MicroRNAs (miRNAs) have recently emerged as instrumental regulators of cellular processes that enable the development and dissemination of cancer. This review highlights the intersection between two emerging research fields and pursues the scientific and clinical implications of miRNA transfer between BMAT and myeloma cells. Summary This review provides a concise and provocative summary of the evidence to support exosome-mediated transfer of tumor-supportive miRNAs. The work may prompt researchers to better elucidate the mechanisms by which this novel means of genetic communication between tumor cells and their environment could someday yield targeted therapeutics.

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