Microparticles in Cancer
Total Page：16
File Type：pdf, Size：1020Kb
Microparticles in Cancer Janusz Rak, M.D., Ph.D.1 ABSTRACT Microparticles (MP) are vesicular structures released from cells upon activation, malignant transformation, stress, or death. MP may be derived from the plasma membrane (shed microvesicles), produced by endosomal pathway (exosomes), or arise from membrane blebs of apoptotic cells. The terms microparticles or microvesicles (MV) are often used as general and interchangeable descriptors of all cellular vesicles, but a more rigorous terminology is still to be established. The cargo of MP/MV consists of proteins, lipids, and nucleic acids (DNA, mRNA, microRNA), all of which may be transferred horizontally between cells. In cancer, oncogenic pathways drive production of MP/MV, and oncopro- teins may be incorporated into the cargo of MV (oncosomes). Oncogenic pathways may also stimulate production of MP/MV harboring tissue factor and involved in cancer coagulopathy. In addition, the cargo of MV may include several receptors, antigens, bioactive molecules, and other species capable of stimulating tumor progression, immu- notolerance, invasion, angiogenesis, and metastasis. MP emanate not only from tumor cells but also from platelets, endothelium, and inflammatory cells. Indeed, circulating MP/MV harbor molecular information related to cancer-related processes and may serve as a reservoir of prognostic and predictive biomarkers to monitor genetic tumor progression, angiogenesis, thrombosis, and responses to targeted therapeutics. KEYWORDS: Microparticles, cancer, oncogenes, tissue factor, microvesicles, exosomes, coagulation, angiogenesis CELLULAR MICROPARTICLES AS UNITS activation of intracellular signaling networks,1,2 in either OF BIOLOGICAL INFORMATION one or two directions,3 thereby changing the cellular In a multicellular organism, biological functions are behavior. In addition to these canonical processes, a executed by assemblies of cells whose actions must be seemingly direct uptake of factors, enzymes, and par- coordinated by intercellular communication. In this ticles has also been described in several instances and regard, the exchange of signals is usually ascribed to found to trigger rearrangements of the intracellular specific molecules (soluble or immobilized) and their machinery.4–7 Numerous pathways of (uni)molecular corresponding cognate receptors. Such exchange may intercellular communication have been characterized to This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. entail a direct cell-to-cell contact (adhesion, juxtacrine date8 and documented to act as important players in interactions) or release and gradient forming soluble health and disease, including cancer.9–11 (paracrine) mediators, which may also circulate in blood In addition to their participation in the intercel- and body fluids and act in a regional or systemic lular networks of the (uni)molecular messages just men- (endocrine) manner. Such information translates into tioned, cells may also compose and receive more complex 1Montreal Children’s Hospital Research Institute, McGill University, Nigel S. Key, M.D., and Hau C. Kwaan, M.D., Ph.D. Montreal, Quebec, Canada. Semin Thromb Hemost 2010;36:888–906. Copyright # 2010 by Address for correspondence and reprint requests: Janusz Rak, Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY M.D., Ph.D., Montreal Children’s Hospital Research Institute, 10001, USA. Tel: +1(212) 584-4662. McGill University, 4060 Sainte Catherine West, Montreal, QC DOI: http://dx.doi.org/10.1055/s-0030-1267043. H3Z 2Z3, Canada (e-mail: [email protected]). ISSN 0094-6176. Microparticles in Thrombosis and Hemostasis; Guest Editors, 888 MICROPARTICLES IN CANCER/RAK 889 (multi)molecular signals, packaged in fragments of ways, often somewhat independently from one another. plasma membrane, or specialized extracellular organelles This distinctiveness was attached to procoagulant and of a vesicular (microvesicles),12,13 tubular (nanotubes),14 regulatory MP that emerged relatively early from studies or filopodial (cytoneme)15 nature. These structures serve on hemostasis and vascular biology.26,30,32–35 In contrast, to transmit their protein, lipid, or nucleic acid cargo MV were studied in the field of neurobiology and through a process often referred to as trogocytosis, or immunomodulation,13,36,37 and EXSM have entered cellular synapse.16,17 This mode of intercellular contact the scene largely in the course of studies on cellular allows the transmission of both soluble and insoluble differentiation,19 endosomal trafficking and receptor (e.g., membrane bound) entities, in a preprogrammed, recycling.38–40 What adds to the confusion is that the combinatorial and efficient manner, and while protect- term exosome has also been used to describe the intra- ing the signaling molecules from extracellular degrada- cellular ribonuclease complex, which is completely un- tion.18 As in the case with soluble mediators, the related to cellular vesiculation.41 vesicular material emitted by various cells may partic- Nonetheless, MP/MV have emerged as a long ipate in short-, medium-, and long-range communica- known but newly appreciated mode of biological regu- tion or in cellular defense and attack processes, whose lation, and they are increasingly implicated in various nature and scope still remains to be understood in a far important contexts, especially during vascular pathology, greater depth. immune responses, cellular differentiation, and other There is a marked biological diversity among physiologically and pathologically significant events.42– cellular vesicles in terms of their origin, structure, func- 45 Their role is also increasingly recognized in cancer, tion, and cargo. Therefore, several terms are used to including in such aspects of the disease as cancer coagul- describe them, including microparticles (MP), secretory opathy,26,30,34,46–50 activated stroma generation,51 tumor vesicles (SV), microvesicles (MV), ectosomes (ECSM) growth,22 establishment of the tumor stem cell niche,49 or exosomes (EXSM), and many more, depending on invasion,52 angiogenesis,53–58 metastasis,54,59–61 and im- the context in which they are studied and their particular mune responses/evasion.12,23,58,62–66 Moreover, distinct properties.13,18–26 In this article we collectively refer to molecular properties of MP present in the bloodstream vesicles released from various cellular sources, including and body fluids of cancer patients render them poten- cancer cells, as microparticles (MP) or microvesicles tially useful as a novel and unique source of disease- (MV), which are perhaps the most commonly used terms related information.23,62,67,68 Although this area still at the moment but not necessarily the most precise. remains to be explored more fully (e.g., as a source of Indeed, in this area a wider consensus as to the nomen- biomarkers), a considerable demand for such markers clature is still to be reached.13 Examples of confusing reflecting the natural complexity does seem to exist in differences in the usage of various terms include descrip- terms of individualized patient care, precise molecular tion as microvesicles (MV), as either a more general and diagnosis, and monitoring the effects of targeted thera- all-encompassing descriptor of all vesicles, micropar- pies.18 The crucial questions that perhaps should be ticles, and exosomes23,26 or in a more circumscribed addressed before MV/MP are fully understood and manner. In the latter case, MV are described as plasma utilized are those surrounding their biogenesis, biolog- membrane–derived structures produced by viable cells, ical roles, and their functional involvement in the patho- and often referred to as ectosomes.19 Still, in other genesis of cancer and other diseases. publications, microparticles (MP) are viewed mainly as products of cellular apoptosis,27 and there are sources in which this term is used interchangeably with MV and BIOGENESIS OF MICROPARTICLES ECSM.26 Because different studies use different criteria The properties of various MP are implicitly defined by to describe various microvesicles, their comparisons may their biogenesis. Cellular vesiculation has been appreci- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. be difficult and the nomenclature often inconsistent. ated and studied for several decades, but its exact Differences among various MV/MP in terms of mechanisms still remain surprisingly mysterious.20 In- their nature and nomenclature may, to some extent, be deed, the release of vesicular organelles was first de- derived from their cellular sources. In this regard some scribed by Wolf in 1967, who noted formation of a studies examined circulating MP for lineage/tissue-spe- particulate ‘‘dust’’ by activated blood platelets.33 In a cific markers to pinpoint their cells of origin. This series of pioneering studies Johnstone observed that resulted in the description of distinct MP emanating seemingly similar organelles (EXSM) were produced from platelets (PMP), monocytes (MMP), endothelial by differentiating reticulocytes, and were involved in cells (EMP), or tumor cells (TMP), which exhibit both the removal of ‘‘spent’’ transferrin receptors from the similarities and differences.20,26,28–31 The differential emerging red blood cells.19 Formation of vesicles was nomenclature of MP may also result from traditions also noticed in the case of cancer cells, in which their adopted by different research fields, in which