Extracellular Vesicles and Integrins: Partners in Cancer Progression (original) (raw)
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Background: Extracellular vesicles (EVs) are lipid-bound particles that are naturally released from cells and mediate cell-cell communication. Integrin adhesion receptors are enriched in small EVs (SEVs) and SEV-carried integrins have been shown to promote cancer cell migration and to mediate organ-specific metastasis; however, how integrins mediate these effects is not entirely clear and could represent a combination of EV binding to extracellular matrix and cells. Methods: To probe integrin role in EVs binding and uptake, we employed a disintegrin inhibitor (DisBa-01) of integrin binding with specificity for αvβ3 integrin. EVs were purified from MDA-MB-231 cells conditioned media by serial centrifugation method. Isolated EVs were characterized by different techniques and further employed in adhesion, uptake and co-culture experiments. Results: We find that SEVs secreted from MDA-MB-231 breast cancer cells carry αvβ3 integrin and bind directly to fibronectin-coated plates, which is...
Cell Communication and Signaling, 2020
Background Extracellular vesicles (EVs) are lipid-bound particles that are naturally released from cells and mediate cell-cell communication. Integrin adhesion receptors are enriched in small EVs (SEVs) and SEV-carried integrins have been shown to promote cancer cell migration and to mediate organ-specific metastasis; however, how integrins mediate these effects is not entirely clear and could represent a combination of EV binding to extracellular matrix and cells. Methods To probe integrin role in EVs binding and uptake, we employed a disintegrin inhibitor (DisBa-01) of integrin binding with specificity for αvβ3 integrin. EVs were purified from MDA-MB-231 cells conditioned media by serial centrifugation method. Isolated EVs were characterized by different techniques and further employed in adhesion, uptake and co-culture experiments. Results We find that SEVs secreted from MDA-MB-231 breast cancer cells carry αvβ3 integrin and bind directly to fibronectin-coated plates, which is in...
Oncogene, 2013
The integrin α9β1 binds a number of extracellular matrix components to mediate cell adhesion, migration and tissue invasion. Although expressed in a variety of normal human cells including endothelium, it is also expressed in cancer cells. We have previously shown that α9β1 binds VEGF-A to facilitate angiogenesis, an important component of the tumor microenvironment. As α9β1 induces accelerated cancer cell migration, we wished to determine what role it played in cancer growth and metastasis. In this study, we show that α9β1 expression induces molecular changes consistent with epithelial-mesenchymal transition. In addition, we found that α9β1 forms a tri-partite protein complex with β-catenin and E-cadherin, which dissociates following integrin activation and subsequent src and β-catenin phosphorylation. These findings were consistent in cells in which: α9β1 was exogenously over-expressed, or when its expression was suppressed in cancer cells endogenously expressing α9β1. These in vi...
Tumor-derived extracellular vesicles require β1 integrins to promote anchorage-independent growth
iScience
The b1 integrins, known to promote cancer progression, are abundant in extracellular vesicles (EVs). We investigated whether prostate cancer (PrCa) EVs affect anchorage-independent growth and whether b1 integrins are required for this effect. Specifically using a cell-line-based genetic rescue and an in vivo PrCa model, we show that gradient-purified small EVs (sEVs) from either cancer cells or blood from tumor-bearing TRAMP (transgenic adenocarcinoma of the mouse prostate) mice promote anchorage-independent growth of PrCa cells. In contrast, sEVs from cultured PrCa cells harboring a short hairpin RNA to b1, from wild-type mice or from TRAMP mice carrying a b1 conditional ablation in the prostatic epithelium (b1 pcÀ/À), do not. We find that sEVs, from cancer cells or TRAMP blood, are functional and co-express b1 and sEV markers; in contrast, sEVs from b1 pcÀ/À / TRAMP or wild-type mice lack b1 and sEV markers. Our results demonstrate that b1 integrins in tumor-cell-derived sEVs are required for stimulation of anchorage-independent growth.
The multifaceted role of extracellular vesicles in metastasis: Priming the soil for seeding
International Journal of Cancer, 2017
Extracellular vesicles (EVs), including exosomes, play a key role in inter and intracellular communication, promoting the proliferation and invasion of recipient cells to support tumor growth and metastasis. Metastasis comprises multiple steps that first include the detachment of tumor cells through epithelial to mesenchymal transition (EMT), allowing the physical dissemination to distant organs. Thereafter, cancer-derived exosomes are still critical components for preparing the tumor microenvironment by (i) enabling tumor cells to escape from the immunological surveillance and (ii) arranging the pre-metastatic site for the engraftment of detached cancer cells. In this review, we discuss the multifaceted role of EVs in the multiple steps of metastasis. Future research directions draw attention to EVs as biological targets for cancer diagnosis, prognosis and therapy. However, due to their significant role in cell communication, they may become a valuable drug delivery system. Epithelial-mesenchymal transition (EMT) is a hallmark of cancer progression and metastasis. Accumulating evidence indicates that extracellular vesicles, especially exosomes, play an important role in this process. 1 Exosomes have been associated with the initiation, development and prognosis of different types of cancer including pancreatic, 2 lung, 3 breast 4 and prostate cancer. 5 These extracellular vesicles (EVs) are capable of transferring oncogenic proteins and nucleic acids that modulate the activity of recipient cells and play decisive roles in tumorigenesis, growth, progression, drug resistance and metastasis. 6-11 Metastases are responsible for approximately 90% of all cancer-related deaths. Although the death rate is elevated, metastasis is a poorly understood phenomenon of cancer pathogenesis. 12 The establishment of a metastatic niche requires a complete series of distinct steps, which include invasion through the basement membrane, extravasation into the bloodstream, dissemination through circulation to the distal tissue parenchyma, and adaptation to the new microenvironment. 13,14 The EMT must occur prior to physical dissemination of cancer cells to distant organs by which epithelial cells acquire mesenchymal characteristics showing reduced intercellular adhesion and increased motility, 15 endowing the incipient cancer cells with invasive and metastatic properties, 16 a key event for tumor progression. However, the EMT switch may not be sufficient to describe all types of migratory phenotypes observed within carcinoma cells, but may represent one subtype of invasive behavior important for metastasis. The EMT complex may be influenced by different pathways and has many potential mechanisms of regulation by miRNA that can influence multiple steps in cancer cell metastasis; miR-NAs are well-established as key regulators of the EMT program in epithelial cells. 17 The exosomes from tumor cells
The αvβ6 integrin in cancer cell‐derived small extracellular vesicles enhances angiogenesis
Journal of Extracellular Vesicles
Prostate cancer (PrCa) cells crosstalk with the tumour microenvironment by releasing small extracellular vesicles (sEVs). sEVs, as well as large extracellular vesicles (LEVs), isolated via iodixanol density gradients from PrCa cell culture media, express the epithelial-specific αvβ6 integrin, which is known to be induced in cancer. In this study, we show sEV-mediated protein transfer of αvβ6 integrin to microvascular endothelial cells (human microvascular endothelial cells 1-HMEC1); we demonstrate that de novo αvβ6 integrin expression is not caused by increased mRNA levels. Incubation of HMEC1 with sEVs isolated from PrCa PC3 cells that express the αvβ6 integrin results in a highly significant increase in the number of nodes, junctions and tubules. In contrast, incubation of HMEC1 with sEVs isolated from β6 negative PC3 cells, generated by shRNA against β6, results in a reduction in the number of nodes, junctions and tubules, a decrease in survivin levels and an increase in a negative regulator of angiogenesis, pSTAT1. Furthermore, treatment of HMEC1 with sEVs generated by CRISPR/Cas9-mediated down-regulation of β6, causes up-regulation of pSTAT1. Overall, our findings suggest that αvβ6 integrin in cancer sEVs regulates angiogenesis during PrCa progression.
The key role of extracellular vesicles in the metastatic process
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Extracellular vesicles (EVs), including exosomes, have a key role in the paracrine communication between organs and compartments. EVs shuttle virtually all types of biomolecules such as proteins, lipids, nucleic acids, metabolites and even pharmacological compounds. Their ability to transfer their biomolecular cargo into target cells enables EVs to play a key role in intercellular communication that can regulate cellular functions such as proliferation, apoptosis and migration. This has led to the emergence of EVs as a key player in tumor growth and metastasis through the formation of "tumor niches" in target organs. Recent data have also been shown that EVs may transform the microenvironment of primary tumors thus favoring the selection of cancer cells with a metastatic behavior. The release of EVs from resident non-malignant cells may contribute to the metastatic processes as well. However, cancer EVs may induce malignant transformation in resident mesenchymal stem cells, suggesting that the metastatic process is not exclusively due to circulating tumor cells. In this review, we outline and discuss evidence-based roles of EVs in actively regulating multiple steps of the metastatic process and how we can leverage EVs to impair metastasis.
Extracellular vesicles: their role in cancer biology and epithelial-mesenchymal transition
The Biochemical journal, 2017
Cell-cell communication is critical across an assortment of physiological and pathological processes. Extracellular vesicles (EVs) represent an integral facet of intercellular communication largely through the transfer of functional cargo such as proteins, messenger RNAs (mRNAs), microRNA (miRNAs), DNAs and lipids. EVs, especially exosomes and shed microvesicles, represent an important delivery medium in the tumour micro-environment through the reciprocal dissemination of signals between cancer and resident stromal cells to facilitate tumorigenesis and metastasis. An important step of the metastatic cascade is the reprogramming of cancer cells from an epithelial to mesenchymal phenotype (epithelial-mesenchymal transition, EMT), which is associated with increased aggressiveness, invasiveness and metastatic potential. There is now increasing evidence demonstrating that EVs released by cells undergoing EMT are reprogrammed (protein and RNA content) during this process. This review summ...
Integrin trafficking and its role in cancer metastasis
Cancer and Metastasis Reviews, 2007
Enhanced levels of expression of certain integrins, and a consequent increase in specific integrin signals, have been linked to cancer cell progression. Dysfunctional integrin signaling is thought to be involved, at least in part, in mediating the detachment of tumor cells from neighboring cells while providing enhanced survival and proliferative capabilities which allow such disseminating tumor cells to grow in new, foreign, microenvironments. Cell biologists have known for some time that integrin heterodimers are endocytosed from the plasma membrane in to the cytoplasm with some of this receptor later being exocytosed back to the cell surface; a cellular mechanism referred to as 'trafficking'. Although extensive research within the integrin field has elucidated key signal transduction pathways as being involved in integrin-mediated cellular behavior, both in normal and transformed cells, it is only relatively recently that the importance of integrin trafficking in modulating cellular function has been demonstrated. This review aims to identify the major trafficking molecules found to play a functional role in cancer cell behavior with special emphasis on the importance of integrin trafficking during neoplastic cell migration and invasion; vital components of the metastatic process.
Horizontal Transfer of Malignant Traits and the Involvement of Extracellular Vesicles in Metastasis
Cells
Metastases are responsible for the vast majority of cancer deaths, yet most therapeutic efforts have focused on targeting and interrupting tumor growth rather than impairing the metastatic process. Traditionally, cancer metastasis is attributed to the dissemination of neoplastic cells from the primary tumor to distant organs through blood and lymphatic circulation. A thorough understanding of the metastatic process is essential to develop new therapeutic strategies that improve cancer survival. Since Paget’s original description of the “Seed and Soil” hypothesis over a hundred years ago, alternative theories and new players have been proposed. In particular, the role of extracellular vesicles (EVs) released by cancer cells and their uptake by neighboring cells or at distinct anatomical sites has been explored. Here, we will outline and discuss these alternative theories and emphasize the horizontal transfer of EV-associated biomolecules as a possibly major event leading to cell tran...