scholarly journals Innate extracellular vesicles from melanoma patients suppress β-catenin in tumor cells by miRNA-34a

2019 ◽  
Vol 2 (2) ◽  
pp. e201800205 ◽  
Author(s):  
Jung-Hyun Lee ◽  
Jochen Dindorf ◽  
Martin Eberhardt ◽  
Xin Lai ◽  
Christian Ostalecki ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Clinical Stage ◽  
Tumor Resection ◽  
Cell Activity ◽  
Tumor Development ◽  
Dependent Manner ◽  
Primary Surgery ◽  
Melanoma Patients

Upon tumor development, new extracellular vesicles appear in circulation. Our knowledge of their relative abundance, function, and overall impact on cancer development is still preliminary. Here, we demonstrate that plasma extracellular vesicles (pEVs) of non-tumor origin are persistently increased in untreated and post-excision melanoma patients, exhibiting strong suppressive effects on the proliferation of tumor cells. Plasma vesicle numbers, miRNAs, and protein levels were elevated two- to tenfold and detected many years after tumor resection. The vesicles revealed individual and clinical stage-specific miRNA profiles as well as active ADAM10. However, whereas pEV from patients preventing tumor relapse down-regulated β-catenin and blocked tumor cell proliferation in an miR-34a–dependent manner, pEV from metastatic patients lost this ability and stimulated β-catenin–mediated transcription. Cancer-induced pEV may constitute an innate immune mechanism suppressing tumor cell activity including that of residual cancer cells present after primary surgery.

scholarly journals Liver cells and PBMC secrete Tumor-suppressive Plasma Extracellular Vesicles in Melanoma patients

2019 ◽  
Author(s):  
Jung-Hyun Lee ◽  
Martin Eberhardt ◽  
Katja Blume ◽  
Julio Vera ◽  
Andreas S. Baur
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Mononuclear Cells ◽  
Clinical Stage ◽  
Cell Activity ◽  
Liver Cells ◽  
Immune Defense ◽  
Cellular Origin ◽  
Melanoma Patients

SummaryBefore and after surgery melanoma patients harbor elevated levels of extracellular vesicles in plasma (pEV), but their cellular origin is obscure. Here we suggest that these pEV are secreted in part by tumor cells, but particularly by liver and peripheral blood mononuclear cells (PBMC), which strongly suppressed tumor cell activity. As the cellular origin of pEV is difficult to determine, we mimicked the interaction of tumor cells with liver cells and PBMC in vitro, and compared newly secreted EV-associated miRNAs and protein factors with those detected in melanoma patient’s pEV. The results identified factors that could be associated either with tumor cell activity or the counteracting immune system and liver cells. Notably, the presence/absence of these factors correlated with the clinical stage and tumor relapse. Our study provides new insights into the innate immune defense against tumor cells and implies that residual tumor cells may be more active than previously thought.Summary blurbPlasma extracellular vesicles (pEV) in melanoma patients are a mix of cancer cell-suppressive vesicles from liver cells and PBMC, but derive also from residual cancer cells.

scholarly journals Could Extracellular Vesicles Contribute to Generation or Awakening of “Sleepy” Metastatic Niches?

2021 ◽  
Vol 9 ◽  
Author(s):  
Alberto Hernández-Barranco ◽  
Laura Nogués ◽  
Héctor Peinado
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Residual Disease ◽  
Tumor Development ◽  
Extracellular Vesicle ◽  
Primary Tumors ◽  
Favorable Conditions ◽  
Cell Dormancy

Pre-metastatic niches provide favorable conditions for tumor cells to disseminate, home to and grow in otherwise unfamiliar and distal microenvironments. Tumor-derived extracellular vesicles are now recognized as carriers of key messengers secreted by primary tumors, signals that induce the formation of pre-metastatic niches. Recent evidence suggests that tumor cells can disseminate from the very earliest stages of primary tumor development. However, once they reach distal sites, tumor cells can persist in a dormant state for long periods of time until their growth is reactivated and they produce metastatic lesions. In this new scenario, the question arises as to whether extracellular vesicles could influence the formation of these metastatic niches with dormant tumor cells? (here defined as “sleepy niches”). If so, what are the molecular mechanisms involved? In this perspective-review article, we discuss the possible influence of extracellular vesicles in early metastatic dissemination and whether they might play a role in tumor cell dormancy. In addition, we comment whether extracellular vesicle-mediated signals may be involved in tumor cell awakening, considering the possibility that extracellular vesicles might serve as biomarkers to detect early metastasis and/or minimal residual disease (MRD) monitoring.

scholarly journals Biochemical and Anti-Triple Negative Metastatic Breast Tumor Cell Properties of Psammaplins

Marine Drugs ◽  
2018 ◽  
Vol 16 (11) ◽  
pp. 442 ◽  
Author(s):  
Yu-Dong Zhou ◽  
Jun Li ◽  
Lin Du ◽  
Fakhri Mahdi ◽  
Thuy Le ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Breast Tumor ◽  
Triple Negative ◽  
Hdac Inhibitors ◽  
Metastatic Breast ◽  
Dependent Manner ◽  
Breast Tumor Cells ◽  
Metastatic Breast Tumor

Breast tumors reprogram their cellular metabolism, nutrient uptake, and utilization-associated biochemical processes. These processes become further transformed as genetically predisposed metastatic breast tumor cells colonize specific organs. Breast tumor cells often metastasize to the brain, bone, lung and liver. Massagué and colleagues isolated organotropic subclones and established organ-specific gene signatures associated with lung-, bone-, and brain-specific metastatic triple-negative breast cancer (TNBC) MDA-MB-231 cells. Using these genetically characterized metastatic subclones specific to lung (LM4175), bone (BoM1833), and brain (BrM-2a), we evaluated marine natural products for the ability to differentially suppress metastatic breast cancer cells in a target organ-dependent manner. Psammaplin-based histone deacetylase (HDAC) inhibitors were found to differentially inhibit HDAC activity, induce activation of hypoxia-inducible factor-1 (HIF-1), and disrupt organotropic metastatic TNBC subclone growth. Further, psammaplins distinctly suppressed the outgrowth of BoM1833 tumor spheroids in 3D-culture systems. Similar results were observed with the prototypical HDAC inhibitor trichostatin A (TSA). These organotropic tumor cell-based studies suggest the potential application of HDAC inhibitors that may yield new directions for anti-metastatic breast tumor research and drug discovery.

Synergy of nanodiamond-doxorubicin conjugates and PD-L1 blockade effectively turns tumor associated macrophages against tumor cells

2021 ◽  
Author(s):  
Huazhen Xu ◽  
Tongfei Li ◽  
Chao Wang ◽  
Yan Ma ◽  
Yan Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Lung Cancer Cells ◽  
Dependent Manner ◽  
Tumor Associated Macrophages ◽  
M1 Type

Abstract Background: Tumor-associated macrophages (TAM) are the most abundant stromal cells in the tumor microenvironment. Turning the TAM against their host tumor cells is an intriguing therapeutic strategy particularly attractive for patients with immunologically “cold” tumors. This concept was mechanistically demonstrated on in vitro human and murine lung cancer cells and their corresponding TAM models through combinatorial use of nanodiamond-doxorubicin conjugates (Nano-DOX) and a PD-L1 blocking agent BMS-1. Nano-DOX are an agent previously proved to be able to stimulate tumor cells’ immunogenicity and thereby reactivate the TAM into the anti-tumor M1 phenotype. Results: Nano-DOX were first shown to stimulate the tumor cells and the TAM to release the cytokine HMGB1 which, regardless of its source, acted through the RAGE/NF-κB pathway to induce PD-L1 in the tumor cells and PD-L1/PD-1 in the TAM. Interestingly, Nano-DOX also induced NF-κB-dependent RAGE expression in the tumor cells and thus reinforced HMGB1’s action thereon. Then, BMS-1 was shown to enhance Nano-DOX-stimulated M1-type activation of TAM both by blocking Nano-DOX-induced PD-L1 in the TAM and by blocking tumor cell PD-L1 ligation with TAM PD-1. The TAM with enhanced M1-type repolarization both killed the tumor cells and suppressed their growth. BMS-1 could also potentiate Nano-DOX’s action to suppress tumor cell growth via blocking of Nano-DOX-induced PD-L1 therein. Finally, Nano-DOX and BMS-1 achieved synergistic therapeutic efficacy against in vivo tumor grafts in a TAM-dependent manner. Conclusions: PD-L1/PD-1 upregulation mediated by autocrine and paracrine activation of the HMGB1/RAGE/NF-κB signaling is a key response of lung cancer cells and their TAM to stress, which can be induced by Nano-DOX. Blockade of Nano-DOX-induced PD-L1, both in the cancer cells and the TAM, achieves enhanced activation of TAM-mediated anti-tumor response.

scholarly journals Immunoselection of tumor cell variants by mice suppressed with ultraviolet radiation.

1982 ◽  
Vol 156 (4) ◽  
pp. 1025-1041 ◽  
Author(s):  
J L Urban ◽  
J M Holland ◽  
M L Kripke ◽  
H Schreiber
Keyword(s):  
Ultraviolet Radiation ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Nude Mice ◽  
Tumor Development ◽  
Phenotypic Change ◽  
Athymic Nude Mice ◽  
Induced Tumors ◽  
Progressive Growth ◽  
Parental Tumor

It has previously been shown that mice exposed to ultraviolet radiation (UV) fail to reject highly immunogenic UV-induced tumors, which are regularly rejected by normal mice. The present study shows, however, that this immunosuppresion is incomplete, as UV-treated mice can still mount certain tumor-specific immune responses and reject smaller inocula of tumor cells that regularly grow progressively in athymic nude mice. Furthermore, all tumor cell lines that were reisolated from the tumor mass resulting from one tumor passage through UV-treated recipients heritably lost a tumor-specific determinant present on the parental tumor cells used for transplantation, and a large percentage of these reisolated variant tumors had changed to progressively growing tumors, in that they were no longer rejected by normal mice. In contrast, none of the tumors reisolated from passage through athymic nude mice or anti-idiotypically suppressed mice showed this change in antigenicity and progressive growth behavior. Thus, it appears that the phenotypic change in tumors reisolated from UV-treated mice was caused by immunoselection, and that the tumor-specific immunity in these mice apparently restrained the outgrowth of the parental tumor cells despite the partial immunosuppression. Because of the regularity at which tumor variants arose in the UV-treated mice after tumor transplantation, it appears that the partial immunosuppression caused by UV-treatment may have favored the outgrowth of antigenic variants from the parental tumor cell population, possibly by allowing more time for the generation of tumor variants. A similar immunoselection process might be part of tumor progression during tumor development and preferentially occur in cancer-bearing individuals showing concomitant tumor immunity.

scholarly journals Cytotoxic Effects of Plant Sap-Derived Extracellular Vesicles on Various Tumor Cell Types

2020 ◽  
Vol 11 (2) ◽  
pp. 22
Author(s):  
Kimin Kim ◽  
Hye Ju Yoo ◽  
Jik-Han Jung ◽  
Ruri Lee ◽  
Jae-Kyung Hyun ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Biological Activities ◽  
Cell Types ◽  
Skin Tumor ◽  
Cytotoxic Effects ◽  
Chemical Structures ◽  
Dendropanax Morbifera ◽  
Plant Sap

Edible plants have been widely used in traditional therapeutics because of the biological activities of their natural ingredients, including anticancer, antioxidant, and anti-inflammatory properties. Plant sap contains such medicinal substances and their secondary metabolites provide unique chemical structures that contribute to their therapeutic efficacy. Plant extracts are known to contain a variety of extracellular vesicles (EVs) but the effects of such EVs on various cancers have not been investigated. Here, we extracted EVs from four plants—Dendropanax morbifera, Pinus densiflora, Thuja occidentalis, and Chamaecyparis obtusa—that are known to have cytotoxic effects. We evaluated the cytotoxic effects of these EVs by assessing their ability to selectively reduce the viability of various tumor cell types compared with normal cells and low metastatic cells. EVs from D. morbifera and P. densiflora sap showed strong cytotoxic effects on tumor cells, whereas those from T. occidentalis and C. obtusa had no significant effect on any tumor cell types. We also identified synergistic effect of EVs from D. morbifera and P. densiflora saps on breast and skin tumor cells and established optimized treatment concentrations. Our findings suggest these EVs from plant sap as new candidates for cancer treatment.

scholarly journals Analysis of the thrombotic and fibrinolytic activities of tumor cell–derived extracellular vesicles

2018 ◽  
Vol 2 (10) ◽  
pp. 1054-1065 ◽  
Author(s):  
Ludovic Durrieu ◽  
Alamelu Bharadwaj ◽  
David M. Waisman
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Recipient Cell ◽  
Key Points ◽  
Generating Capacity

Key Points Microvesicles, but not exosomes, from tumor cells have thrombotic activity. Tumor derived–exosomes can confer increased plasmin-generating capacity to a recipient cell.

scholarly journals Tumor Extracellular Vesicles Regulate Macrophage-Driven Metastasis through CCL5

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3459
Author(s):  
Daniel C. Rabe ◽  
Nykia D. Walker ◽  
Felicia D. Rustandy ◽  
Jessica Wallace ◽  
Jiyoung Lee ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Tumor Metastasis ◽  
Tumor Stroma ◽  
Metastatic Tumor ◽  
Mouse Bone Marrow ◽  
Metastatic Phenotype ◽  
Immune Infiltrate ◽  
Phenotype Analysis

Purpose: To understand how tumor cells alter macrophage biology once they are recruited to triple-negative breast cancer (TNBC) tumors by CCL5. Method: Mouse bone marrow derived macrophage (BMDMs) were isolated and treated with recombinant CCL5 protein alone, with tumor cell conditioned media, or with tumor extracellular vesicles (EVs). Media from these tumor EV-educated macrophages (TEMs) was then used to determine how these macrophages affect TNBC invasion. To understand the mechanism, we assayed the cytokine secretion from these macrophages to determine how they impact tumor cell invasion. Tumor CCL5 expression was varied in tumors to determine its role in regulating macrophage biology through EVs. Results: Tumor EVs are a necessary component for programming naïve macrophages toward a pro-metastatic phenotype. CCL5 expression in the tumor cells regulates both EV biogenesis/secretion/cargo and macrophage EV-education toward a pro-metastatic phenotype. Analysis of the tumor EV-educated macrophages (TEMs) showed secretion of a variety of factors including CXCL1, CTLA-4, IFNG, OPN, HGF, TGFB, and CCL19 capable of remodeling the surrounding tumor stroma and immune infiltrate. Injection of tumor cells with macrophages educated by metastatic tumor cell EVs into mice increased tumor metastasis to the lung. Conclusion: These results demonstrate that tumor-derived EVs are key mediators of macrophage education and likely play a more complex role in modulating tumor therapeutic response by regulating the tumor immune infiltrate.

scholarly journals Intercellular transfer of mitochondrial DNA carrying metastasis-enhancing pathogenic mutations from high- to low-metastatic tumor cells and stromal cells via extracellular vesicles

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Keizo Takenaga ◽  
Nobuko Koshikawa ◽  
Hiroki Nagase
Keyword(s):  
Mitochondrial Dna ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Stromal Cells ◽  
Metastatic Tumor ◽  
Dependent Manner ◽  
Intercellular Transfer ◽  
Pathogenic Mutations ◽  
Metastatic Cells

Abstract Background Mitochondrial DNA (mtDNA) carrying certain pathogenic mutations or single nucleotide variants (SNVs) enhances the invasion and metastasis of tumor cells, and some of these mutations are homoplasmic in tumor cells and even in tumor tissues. On the other hand, intercellular transfer of mitochondria and cellular components via extracellular vesicles (EVs) and tunneling nanotubes (TNTs) has recently attracted intense attention in terms of cell-to-cell communication in the tumor microenvironment. It remains unclear whether metastasis-enhancing pathogenic mutant mtDNA in tumor cells is intercellularly transferred between tumor cells and stromal cells. In this study, we investigated whether mtDNA with the NADH dehydrogenase subunit 6 (ND6) G13997A pathogenic mutation in highly metastatic cells can be horizontally transferred to low-metastatic cells and stromal cells in the tumor microenvironment. Results When MitoTracker Deep Red-labeled high-metastatic Lewis lung carcinoma A11 cells carrying the ND6 G13997A mtDNA mutation were cocultured with CellLight mitochondria-GFP-labeled low-metastatic P29 cells harboring wild-type mtDNA, bidirectional transfer of red- and green-colored vesicles, probably mitochondria-related EVs, was observed in a time-dependent manner. Similarly, intercellular transfer of mitochondria-related EVs occurred between A11 cells and α-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs, WA-mFib), macrophages (RAW264.7) and cytotoxic T cells (CTLL-2). Intercellular transfer was suppressed by inhibitors of EV release. The large and small EV fractions (L-EV and S-EV, respectively) prepared from the conditioned medium by differential ultracentrifugation both were found to contain mtDNA, although only S-EVs were efficiently incorporated into the cells. Several subpopulations had evidence of LC3-II and contained degenerated mitochondrial components in the S-EV fraction, signaling to the existence of autophagy-related S-EVs. Interestingly, the S-EV fraction contained a MitoTracker-positive subpopulation, which was inhibited by the respiration inhibitor antimycin A, indicating the presence of mitochondria with membrane potential. It was also demonstrated that mtDNA was transferred into mtDNA-less ρ0 cells after coculture with the S-EV fraction. In syngeneic mouse subcutaneous tumors formed by a mixture of A11 and P29 cells, the mitochondria-related EVs released from A11 cells reached distantly positioned P29 cells and CAFs. Conclusions These results suggest that metastasis-enhancing pathogenic mtDNA derived from metastatic tumor cells is transferred to low-metastatic tumor cells and stromal cells via S-EVs in vitro and in the tumor microenvironment, inferring a novel mechanism of enhancement of metastatic potential during tumor progression.

scholarly journals 242 Pharmacologic tumor PD-L1 depletion with chlorambucil treats ovarian cancer and melanomas in a tumor PD-L1-dependent manner and renders αPD-L1-resistant tumors αPD-L1-sensitive

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A261-A261
Author(s):  
Haiyan Bai ◽  
Álvaro Padrón ◽  
Yilun Deng ◽  
Anand Kornepati ◽  
Srikanth Polusani ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cell ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Nk Cell ◽  
San Antonio ◽  
Cell Generation ◽  
List Type ◽  
Dependent Manner ◽  
Cell Content

BackgroundProgrammed cell death ligand-1 (PD-L1) overexpression in tumor cells inhibits T cells activity and delivers pathologic intracellular signals that can reduce cancer treatment responses in pre-clinicalmodels.1 2MethodsTo reduce tumor intracellular PD-L1-mediated pathology, we performed a drug screen that identified chlorambucil as a tumor cell PD-L1 depletion drug.ResultsChlorambucil depletes basal tumor PD-L1 expression through the ubiquitination proteasome pathway. In the tumor microenvironment, high chlorambucil doses treated orthotopic B16 melanoma and ID8agg ovarian cancer. Chlorambucil treatment efficacy was lost or reduced in PD-L1lo ID8agg and PD-L1KO B16 tumors, corroborated with in vitro data. These data suggest that chlorambucil anti-tumor activity of CAMB requires tumor PD-L1 expression, confirmed in PD-L1KO host challenge with CTRL tumor, which chlorambucil treated effectively. Chlorambucil rendered αPD-L1 resistant CTRL ID8agg and PD-L1lo B16 tumors αPD-L1 sensitive, preliminarily possibly due to tumor STING activation, and associated with enhanced tumor NK cell infiltration and central memory T cell generation. Chlorambucil also phenocopied genetic PD-L1KO by reducing tumor cell mTORC1 signals and stem cell content,3 suggesting additional treatment potential.ConclusionsChlorambucil could be a useful strategy to reprogram tumor PD-L1 signals and boost immune-based therapies especially for anti-PD-L1-resistant tumors.ReferencesClark CA et al. Tumor-intrinsic PD-L1 signals regulate cell growth, pathogenesis, and autophagy in ovarian cancer and melanoma. Cancer Res 2016;76:6964–6974.Juneja VR et al. PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity. J Exp Med 2017;214:895–904.Gupta HB et al. Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer. Signal Transduct Target Ther 2016;1:2095–9907.Ethics ApprovalWe received approval from the UT Health San Antonio Institutional Animal Care and Use Committee (IACUC) for each procedure that used mice. We conducted each experiment per the standards required by the UT Health San Antonio Department of Laboratory Animal Resources.

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