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 Thyroid tumor cells-fibroblasts crosstalk: role of extracellular vesicles

2020 ◽  
Vol 9 (6) ◽  
pp. 506-518 ◽  
Author(s):  
Rocío del Carmen Bravo-Miana ◽  
Ana Belén Della Vedova ◽  
Ana Lucía De Paul ◽  
María Mónica Remedi ◽  
María Laura Guantay ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Tumor Stroma ◽  
Thyroid Tumor ◽  
Thyroid Cell ◽  
Thyroid Cells ◽  
Cd147 Expression

Tumor-stroma crosstalk leads to a tumor-promoting microenvironment. In this milieu, extracellular vesicles (EVs) are protagonists in cell-cell communication. Despite thyroid cancer being the most common endocrine malignancy, the contribution of the tumor microenvironment to thyroid cancer progression is still largely underexplored. We focused on the role of thyroid tumor cell-fibroblast interaction and EVs as mediators of tumor-stroma interplay, in the promotion of thyroid tumor aggressiveness. Thyroid tumor (TPC-1, 8505c) or non-tumor thyroid cells (NThyOri) were co-cultured with human fibroblasts (Fb). Thyroid cell migration was investigated by the wound-healing assay and actin-network staining. Cell-CD147 expression was characterized by flow cytometry. EVs, obtained by ultracentrifugation of conditioned media (CMs), were characterized by transmission electron-microscopy and CD81 and CD147 expression. Metalloproteinases (MMPs) were evaluated by zymography in CMs. A migratory phenotype was triggered in thyroid tumor cells treated with CMs from Fb or from Fb-thyroid tumor cell co-cultures. Fb-thyroid cell co-cultures induced the secretion of proMMP9 and proMMP2 and led to a significant MMP2 activation in CMs. Fb, thyroid cells and Fb-thyroid cell co-cultures released EVs, and remarkably, EVs released by Fb-thyroid tumor cell co-cultures induced the secretion of proMMP2 and the expression of MMP2 from normal Fb. A significant CD147 expression was demonstrated in Fb-thyroid tumor cell-derived EVs. These findings reveal the role of Fb and thyroid tumor cell-Fb interaction in the promotion of a microenvironment suitable for thyroid tumor progression. Moreover, they highlight, for the first time, the role of thyroid tumor cell-Fb interaction in the production of specialized EVs.

scholarly journals Hepatocyte-tumor cell interaction in vitro. I. Conditions for rosette formation and inhibition by anti-H-2 antibody.

1980 ◽  
Vol 151 (4) ◽  
pp. 984-989 ◽  
Author(s):  
V Schirrmacher ◽  
R Cheingsong-Popov ◽  
H Arnheiter
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Metastatic Tumor ◽  
Cell Interaction ◽  
Rosette Formation ◽  
Normal Cells ◽  
Neuraminidase Treatment

Murine hepatocytes, isolated by an in situ collagenase-perfusion technique and cultured in Petri dishes, were shown to form rosettes with liver-metastasizing syngeneic tumor cells. Pretreatment of the tumor cells with neuraminidase generally increased the binding, whereas pretreatment of the liver cells with neuraminidase abolished the binding completely. The tumor-cell binding may be mediated by the previously described lectin-like receptor of hepatocytes that also was sensitive to neuraminidase treatment and that bound desialylated cells better than normal cells. Anti-H-2 sera could efficiently inhibit the rosette formation of metastatic tumor cells with the hepatocytes, which points to a possible role of H-2 molecules in this interaction of neoplastic and normal cells.

scholarly journals The Role of Extracellular Vesicles in Cancer: Cargo, Function, and Therapeutic Implications

Cells ◽  
2018 ◽  
Vol 7 (8) ◽  
pp. 93 ◽  
Author(s):  
James Jabalee ◽  
Rebecca Towle ◽  
Cathie Garnis
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Tumor Stroma ◽  
Therapeutic Implications ◽  
Membrane Bound ◽  
Immune Destruction ◽  
And Function ◽  
Cargo Molecule

Extracellular vesicles (EVs) are a heterogeneous collection of membrane-bound structures that play key roles in intercellular communication. EVs are potent regulators of tumorigenesis and function largely via the shuttling of cargo molecules (RNA, DNA, protein, etc.) among cancer cells and the cells of the tumor stroma. EV-based crosstalk can promote proliferation, shape the tumor microenvironment, enhance metastasis, and allow tumor cells to evade immune destruction. In many cases these functions have been linked to the presence of specific cargo molecules. Herein we will review various types of EV cargo molecule and their functional impacts in the context of oncology.

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 Aspirin inhibits platelets from reprogramming breast tumor cells and promoting metastasis

2019 ◽  
Vol 3 (2) ◽  
pp. 198-211 ◽  
Author(s):  
Kelly E. Johnson ◽  
Julia R. Ceglowski ◽  
Harvey G. Roweth ◽  
Jodi A. Forward ◽  
Mason D. Tippy ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Cell Invasion ◽  
Breast Tumor ◽  
Tumor Metastasis ◽  
Tumor Cell Invasion ◽  
Akt Pathway ◽  
Breast Tumor Cells ◽  
Invasive Capacity ◽  
Platelet Releasate

Abstract It is now recognized that compounds released from tumor cells can activate platelets, causing the release of platelet-derived factors into the tumor microenvironment. Several of these factors have been shown to directly promote neovascularization and metastasis, yet how the feedback between platelet releasate and the tumor cell affects metastatic phenotype remains largely unstudied. Here, we identify that breast tumor cells secrete high levels of interleukin 8 (IL-8, CXCL8) in response to platelet releasate, which promotes their invasive capacity. Furthermore, we found that platelets activate the Akt pathway in breast tumor cells, and inhibition of this pathway eliminated IL-8 production. We therefore hypothesized inhibiting platelets with aspirin could reverse the prometastatic effects of platelets on tumor cell signaling. Platelets treated with aspirin did not activate the Akt pathway, resulting in reduced IL-8 secretion and impaired tumor cell invasion. Of note, patients with breast cancer receiving aspirin had lower circulating IL-8, and their platelets did not increase tumor cell invasion compared with patients not receiving aspirin. Our data suggest platelets support breast tumor metastasis by inducing tumor cells to secrete IL-8. Our data further support that aspirin acts as an anticancer agent by disrupting the communication between platelets and breast tumor cells.

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.

Tenascin-C modulates tumor stroma and monocyte/macrophage recruitment but not tumor growth or metastasis in a mouse strain with spontaneous mammary cancer

1999 ◽  
Vol 112 (12) ◽  
pp. 1855-1864 ◽  
Author(s):  
J.F. Talts ◽  
G. Wirl ◽  
M. Dictor ◽  
W.J. Muller ◽  
R. Fassler
Keyword(s):  
Extracellular Matrix ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Mouse Strain ◽  
Extracellular Matrix Proteins ◽  
Tumor Stroma ◽  
Mammary Tumors ◽  
Matrix Proteins ◽  
Metastatic Tumors ◽  
Tenascin C

The local growth of tumors and their ability to metastasize are crucially dependent on their interactions with the surrounding extracellular matrix. Tenascin-C (TNC) is an extracellular matrix protein which is highly expressed during development, tissue repair and cancer. Despite the high levels of TNC in the stroma of primary and metastatic tumors, the function of TNC is not known. In the present study we have crossed TNC-null mice with a mouse strain where both female and male mice spontaneously develop mammary tumors followed by metastatic disease in the lungs. We report that the absence of TNC had no effect on the temporal occurrence of mammary tumors and their metastatic dissemination in lungs. Furthermore, the number and size of tumors, the number and size of metastatic foci in the lungs, the proliferation rate and apoptosis of tumor cells and tumor angiogenesis were not altered in the absence of TNC. Histological examination revealed that the tumor organisation, however, was modulated by TNC. In the presence of TNC both primary as well as metastatic tumors were organised in large tumor cell nests surrounded by thick layers of extracellular matrix proteins. In the absence of TNC these tumor cell nests were smaller but still separated from each other by extracellular matrix proteins. In addition, the TNC-null stromal compartment contained significantly more monocytes/macrophages than tumor stroma from TNC wild-type mice. Using in vitro coculture experiments we show that TNC-null tumor cells were still able to activate the TNC gene in fibroblasts which express low basal levels of TNC. Altogether these data indicate that TNC has a very limited role during the spontaneous development and growth of mamary tumors and their metastasis to the lungs.

Emerging Roles for von Willebrand Factor in Cancer Cell Biology

2017 ◽  
Vol 44 (02) ◽  
pp. 159-166 ◽  
Author(s):  
Roger Preston ◽  
Tracy Robson ◽  
James O'Donnell ◽  
Jamie O'Sullivan
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Von Willebrand Factor ◽  
Cell Biology ◽  
Tumor Metastasis ◽  
Human Tumor ◽  
Advanced Tumor Stage ◽  
Von Willebrand ◽  
Willebrand Factor

Abstractvon Willebrand factor (VWF) is a complex multimeric plasma glycoprotein that plays critical roles in normal hemostasis. However, additional novel roles for VWF in modulating cancer cell biology, and in particular tumor metastasis, have recently been reported. Markedly elevated plasma VWF levels were associated with advanced tumor stage and metastatic disease. These observations have raised the question of whether VWF may be involved in regulating tumor progression. Interestingly, novel findings indicate that VWF is expressed by a variety of tumor cells of nonendothelial origin. Critically, tumor cells that exhibit de novo acquired VWF expression demonstrate enhanced binding to endothelial cells (EC) and platelets, and increased extravasation through EC barriers. Furthermore, in vitro studies have shown that VWF can bind a variety of different tumor cells mediated by specific receptors expressed on the tumor cell surface. The concept that VWF is important in modulating tumor metastasis is further supported by in vivo experiments demonstrating that antibody-mediated VWF inhibition significantly attenuated murine metastasis. Intriguingly, however, VWF binding to specific human tumor cell lines results in apoptosis. In this study, the authors provide an overview of recent advances supporting a role for VWF in regulating multiple aspects of cancer cell biology.

scholarly journals Microbial Antigen-Presenting Extracellular Vesicles Derived from Genetically Modified Tumor Cells Promote Antitumor Activity of Dendritic Cells

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 57
Author(s):  
Tomoko Ito ◽  
Kikuya Sugiura ◽  
Aya Hasegawa ◽  
Wakana Ouchi ◽  
Takayuki Yoshimoto ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antitumor Activity ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Ternary Complex ◽  
Binary Complex ◽  
Mouse Bone Marrow ◽  
Bacterial Antigen ◽  
Tumor Vaccines ◽  
Antigen Presenting

Tumor-derived extracellular vesicles (EVs), as tumor vaccines, carry tumor-associated antigens (TAAs), and were expected to transfer TAAs to antigen-presenting cells. However, treatment with tumor-derived EVs exhibited no obvious antitumor effect on the established tumors, likely due to their immuno-suppressive functions, and also to the poor immunogenicity of TAAs. In order to improve the immune stimulating properties, EVs expressing a highly immunogenic bacterial antigen, 6 kDa early secretory antigenic target (ESAT-6), from Mycobacterium tuberculosis were prepared by genetically modifying the parent tumor cells with a plasmid coding for ESAT-6. Cultured B16 tumor cells were transfected with a ternary complex system consisting of pDNA, polyethylenimine (PEI), and chondroitin sulfate. The cells that were transfected with the ternary complex secreted EVs with a higher number of ESAT-6 epitopes than those transfected by a conventional DNA/PEI binary complex, due to the low cytotoxicity, and durable high expression efficiency of the ternary complex systems. The EVs presenting the ESAT-6 epitope (ESAT-EV) were collected and explored as immune modulatory agents. Dendritic cells (DCs) were differentiated from mouse bone marrow cells and incubated with ESAT-EV. After incubating with the EVs for one day, the DCs expressed a significantly higher level of DC maturation marker, CD86. The DCs treated with ESAT-EV showed a significantly improved antitumor activity in tumor-bearing mice.

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.

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