Tumor-derived microvesicles modulate the establishment of metastatic melanoma in a phosphatidylserine-dependent manner

Lima, Luize Gonçalves; Chammas, Roger; Monteiro, Robson Q.; Moreira, M E C; Barcinski, Marcello A.

doi:10.1016/j.canlet.2009.03.041

Cited by 224 publications

(187 citation statements)

References 37 publications

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“…This suggests that the benefit of chemotherapy, radiotherapy, and other treatments that trigger tumor cell apoptosis is undermined by the increase in local tumor immunosuppression caused by phosphatidylserine exposed on dying tumor cells and their microvesicles (25,43,45). Here, we show that treatment of tumor-bearing mice with a phosphatidylserinetargeting antibody counteracts the tumor immunosuppression caused by chemotherapy and activates innate tumor immunity.…”

Section: Discussionmentioning

confidence: 74%

Phosphatidylserine-Targeting Antibody Induces M1 Macrophage Polarization and Promotes Myeloid-Derived Suppressor Cell Differentiation

Yin

Huang

Lynn

et al. 2013

Cancer Immunology Research

132

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Multiple tumor-derived factors are responsible for the accumulation and expansion of immune-suppressing myeloid-derived suppressor cells (MDSC) and M2-like tumor-associated macrophages (TAM) in tumors. Here, we show that treatment of tumor-bearing mice with docetaxel in combination with the phosphatidylserine-targeting antibody 2aG4 potently suppressed the growth and progression of prostate tumors, depleted M2-like TAMs, and MDSCs, and increased the presence of M1-like TAMs and mature dendritic cells in the tumors. In addition, the antibody markedly altered the cytokine balance in the tumor microenvironment from immunosuppressive to immunostimulatory. In vitro studies confirmed that 2aG4 repolarized TAMs from an M2-to an M1-like phenotype and drove the differentiation of MDSCs into M1-like TAMs and functional dendritic cells. These data suggest that phosphatidylserine is responsible for the expansion of MDSCs and M2-like TAMs in tumors, and that bavituximab, a phosphatidylserine-targeting antibody currently in clinical trials for cancer, could reverse this process and reactivate antitumor immunity. Cancer Immunol Res; 1(4); 256-68. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 74%

Phosphatidylserine-Targeting Antibody Induces M1 Macrophage Polarization and Promotes Myeloid-Derived Suppressor Cell Differentiation

Yin

Huang

Lynn

et al. 2013

Cancer Immunology Research

132

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“…Lipid rafts were previously hypothesized to have a role in the initial 'pinching' events, because the microvesicles released from activated neutrophils contained high levels of cholesterol and pharmacological depletion of cellular cholesterol inhibits microvesicle shedding (Del Conde et al, 2005;Pilzer et al, 2005). Similarly, as stated above, phosphatidylserine has been found to be exposed on the extracellular leaflet of shed vesicles (Lima et al, 2009;Muralidharan-Chari et al, 2009a). This topological reversal may serve several purposes.…”

Section: Impact Of Membrane Lipidsmentioning

confidence: 86%

“…In this regard, not all plasma-membrane proteins are incorporated into shed vesicles (Muralidharan-Chari et al, 2009a). Phosphatidylserine is relocated to the outer membrane leaflet, specifically at sites on the cell surface where microvesicle shedding occurs, while the topology of membrane proteins remains intact (Hugel et al, 2005;Lima et al, 2009;Muralidharan-Chari et al, 2009a) (see Fig. 1).…”

Section: Microvesicles and Exosomes Are Distinct Vesicle Populationsmentioning

confidence: 99%

Microvesicles: mediators of extracellular communication during cancer progression

Muralidharan‐Chari

Clancy

Sedgwick

et al. 2010

Journal of Cell Science

830

765

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SummaryMicrovesicles are generated by the outward budding and fission of membrane vesicles from the cell surface. Recent studies suggest that microvesicle shedding is a highly regulated process that occurs in a spectrum of cell types and, more frequently, in tumor cells. Microvesicles have been widely detected in various biological fluids including peripheral blood, urine and ascitic fluids, and their function and composition depend on the cells from which they originate. By facilitating the horizontal transfer of bioactive molecules such as proteins, RNAs and microRNAs, they are now thought to have vital roles in tumor invasion and metastases, inflammation, coagulation, and stem-cell renewal and expansion. This Commentary summarizes recent literature on the properties and biogenesis of microvesicles and their potential role in cancer progression.

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“…4 Cancer cells may also exhibit apoptotic 'mimicry' through secretion of mobile membrane-enclosed vesicles like microvesicles (MVs) or exosomes. MVs and exosomes can be rich in PTS on their outer membrane leaflet (thereby allowing PTS-mediated phagocytosis) 127 and can carry cancer antigens 127 or even MHC-peptide complexes 128 such that the combination of these two can cause TGF-b-dependent immunosuppression 127 and subsequent tolerization towards the cancer antigens.…”

Section: Open Questionsmentioning

confidence: 99%

Danger signalling during cancer cell death: origins, plasticity and regulation

et al. 2013

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Accumulating data indicates that following anti-cancer treatments, cancer cell death can be perceived as immunogenic or tolerogenic by the immune system. The former is made possible due to the ability of certain anti-cancer modalities to induce immunogenic cell death (ICD) that is associated with the emission of damage-associated molecular patterns (DAMPs), which assist in unlocking a sequence of events leading to the development of anti-tumour immunity. In response to ICD inducers, activation of endoplasmic reticulum (ER) stress has been identified to be indispensable to confer the immunogenic character of cancer cell death, due to its ability to coordinate the danger signalling pathways responsible for the trafficking of vital DAMPs and subsequent anti-cancer immune responses. However, in recent times, certain processes apart from ER stress have emerged (e.g., autophagy and possibly viral response-like signature), which have the ability to influence danger signalling. In this review, we discuss the molecular nature, emerging plasticity in the danger signalling mechanisms and immunological impact of known DAMPs in the context of immunogenic cancer cell death. We also discuss key effector mechanisms modulating the interface between dying cancer cells and the immune cells, which we believe are crucial for the therapeutic relevance of ICD in the context of human cancers, and also discuss the influence of experimental conditions and animal models on these. The ultimate outcome of an immune response to cancer cell death (i.e., anti-tumourigenic, pro-tumourigenic or autoimmunity or different combinations of these) tends to be complex and may depend on a number of factors like the type of the cancer cells that die and their in vivo location, the type of cell death pathway they follow to die, the types of immune cells that phagocytose them or interact with them and, last but not the least, whether a cancer antigen is recognized or not. Tolerogenicity towards cell death, as happens predominantly when cancer cells undergo physiological apoptosis (after treatment with most anti-cancer therapies), depends on a number of factors including the presence of immunosuppressive factors, absence or inactivation of DAMPs, induction of tolerogenic dendritic cells (DCs), 'suboptimal' activation of CD8 þ T cells only and apoptotic 'mimicry'.Accentuated immunogenicity exhibited by cancer cells undergoing immunogenic cell death (ICD; after treatment with selected anti-cancer therapies), depends on a number of factors like emission of DAMPs (i.e., surface exposure of certain chaperones, secretion or release of certain nucleotides and endokines), presence of immunostimulatory factors, induction of DC maturation (both phenotypic and functional) and optimal activation of CD4 þ ab, CD8 þ ab and gd T-cell responses. Certain DAMPs are actively trafficked during ICD by danger signalling pathways, which are instigated and regulated by a complex interplay between endoplasmic reticulum (ER) stress, reactive oxygen species (ROS) production and cert...

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Tumor-derived microvesicles modulate the establishment of metastatic melanoma in a phosphatidylserine-dependent manner

Cited by 224 publications

References 37 publications

Phosphatidylserine-Targeting Antibody Induces M1 Macrophage Polarization and Promotes Myeloid-Derived Suppressor Cell Differentiation

Phosphatidylserine-Targeting Antibody Induces M1 Macrophage Polarization and Promotes Myeloid-Derived Suppressor Cell Differentiation

Microvesicles: mediators of extracellular communication during cancer progression

Danger signalling during cancer cell death: origins, plasticity and regulation

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