Potential Roles of Tumor Cell- and Stroma Cell-Derived Small Extracellular Vesicles in Promoting a Pro-Angiogenic Tumor Microenvironment

Extracellular vesicles (EVs) are produced and released by all cells and are present in all body fluids. They exist in a variety of sizes, however, small extracellular vesicles (sEVs), the EV subset with a size range from 30 to 150 nm, are of current interest. They are characterized by a distinct biogenesis and complex cargo composition, which reflects the cytosolic contents and cell-surface molecules of the parent cells. This cargo consists of proteins, nucleic acids, and lipids and is competent in inducing signaling cascades in recipient cells after surface interactions or in initiating the generation of a functional protein by delivering nucleic acids. Based on these characteristics, sEVs are now considered as important mediators of intercellular communication. One hallmark of sEVs is the promotion of angiogenesis. It was shown that sEVs interact with endothelial cells (ECs) and promote an angiogenic phenotype, ultimately leading to increased vascularization of solid tumors and disease progression. It was also shown that sEVs reprogram cells in the tumor microenvironment (TME) and act in a functionally cooperative fashion to promote angiogenesis by a paracrine mechanism involving the differential expression and secretion of angiogenic factors from other cell types. In this review, we will focus on the distinct functions of tumor-cell-derived sEVs (TEX) in promotion of angiogenesis and describe their potential as a therapeutic target for anti-angiogenic therapies. Also, we will focus on non-cancer stroma-cell-derived small extracellular vesicles and their potential role in stimulating a pro-angiogenic TME.

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P21 is a flexible, multi-functional protein. It governs various tumor cell activities, including autophagy. p21 is a possible radiotherapy target

10.31219/osf.io/ydkca ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Tumor Microenvironment ◽

Tumor Cell ◽

Radiation Exposure ◽

Future Study ◽

Regulatory Role ◽

Post Translational Modification ◽

Functional Protein ◽

Cellular Processes

p21 is a versatile protein with a lot of different functions. P21 controls several cellular processes in the tumor, including cell cycle, DNA repair, apoptosis, senescence, autophagy, and the tumor microenvironment, in response to radiation exposure. The fact that it is engaged in both of these processes makes things much more puzzling. As a result, truly grasping p21 continues to be a challenge. Researchers have begun to pay attention to p21 and consider it a potential radiotherapeutic target because of its robust regulatory role. The methods by which p21 performs contradictory tasks should be the focus of future study, as well as how to control its oncogenicity selectively. In biological systems, p21 can play a range of roles according to its many post-translational modification sites. The ability to strike a balance between p21's many functions might be the secret to successful radiotherapy.

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Lymphatic Control of the Tumor Immune Microenvironment

Blood ◽

10.1182/blood-2019-123389 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. SCI-46-SCI-46

Author(s):

Melody A. Swartz

Keyword(s):

T Cell ◽

Tumor Microenvironment ◽

Tumor Cell ◽

Cancer Immunotherapy ◽

T Cell Activation ◽

Immune Suppression ◽

Cell Activation ◽

Conflicts Of Interest ◽

Lymphatic Vessels ◽

Cell Types

Tumor engagement or activation of surrounding lymphatic vessels is well-known to correlate with tumor progression and metastasis in melanoma and many other cancers. We and others have identified several mechanisms by which the lymphatic growth factor VEGF-C and lymphangiogenesis can promote metastasis, including (i) increasing immune suppressive cell types and factors in the tumor microenvironment both directly and indirectly, (ii) inhibiting maturation of antigen-presenting cells and T cell activation, and (iii) driving changes in the stromal microenvironment that promote both cancer invasion and immune suppression. However, lymphatic activation also enhances communication with cells in the draining lymph node by antigen and cell transport, which may trigger the initiation of adaptive immune responses against the tumor. Under normal conditions, the potential anti-tumor effects are rendered 'dormant' by the pro-tumor immune suppression, and the tumor progresses. However, we are now observing that lymphangiogenic tumors are exceptionally responsive to immunotherapy, implying that the anti-tumor aspects can be unleashed when the overall balance of pro- and anti-tumor immune aspects is tipped enough towards the latter (e.g., upon tumor cell killing). On the mechanistic side, we are finding that 'lymphangiogenic potentiation' depends on tumor cell infiltration of both CD103+ dendritic cells and naïve T cells, driving local T cell education post-immunotherapy and antigen spreading. On the translational side, we are developing novel strategies to exploit lymphangiogenesis for cancer immunotherapy. Understanding the yin and yang of lymphatic activation in the tumor microenvironment and how it affects immunity may lead to exciting new translational strategies for cancer immunotherapy. Disclosures No relevant conflicts of interest to declare.

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

Journal of Functional Biomaterials ◽

10.3390/jfb11020022 ◽

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.

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Tumor-Derived Extracellular Vesicles: A Means of Co-opting Macrophage Polarization in the Tumor Microenvironment

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.746432 ◽

2021 ◽

Vol 9 ◽

Author(s):

Theodore Reed ◽

Jeffrey Schorey ◽

Crislyn D’Souza-Schorey

Keyword(s):

Tumor Microenvironment ◽

Extracellular Vesicles ◽

Immune Modulation ◽

Macrophage Polarization ◽

Cell Types ◽

Heterogeneous Population ◽

Functional Plasticity ◽

Bioactive Proteins ◽

Membrane Bound ◽

Almost All

Extracellular vesicles (EVs) are a heterogeneous population of membrane-bound parcels of bioactive proteins, nucleic acids, and lipids released from almost all cell types. The diversity of cargo packaged into EVs proffer the induction of an array of effects on recipient cells. EVs released from tumor cells have emerged as a vital means of communication and immune modulation within the tumor microenvironment (TME). Macrophages are an important contributor to the TME with seemingly paradoxical roles promoting either pro- or anti-tumoral immune function depending on their activated phenotypes. Here, we discuss the influence of tumor-derived extracellular vesicles on the functional plasticity of macrophages in tumor progression.

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Exosomes and Their Role in Cancer Progression

Frontiers in Oncology ◽

10.3389/fonc.2021.639159 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yang Liu ◽

Ke Shi ◽

Yong Chen ◽

Xianrui Wu ◽

Zheng Chen ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Cell ◽

Tumor Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Immune Escape ◽

Research Progress ◽

Chemotherapeutic Drugs ◽

Other Substances

Exosomes from extracellular vesicles can activate or inhibit various signaling pathways by transporting proteins, lipids, nucleic acids and other substances to recipient cells. In addition, exosomes are considered to be involved in the development and progression of tumors from different tissue sources in numerous ways, including remodeling of the tumor microenvironment, promoting angiogenesis, metastasis, and invasion, and regulating the immune escape of tumor cells. However, the precise molecular mechanisms by which exosomes participate in these different processes remains unclear. In this review, we describe the research progress of tumor cell-derived exosomes in cancer progression. We also discuss the prospects of the application of exosomes combined with nanoengineered chemotherapeutic drugs in the treatment of cancer.

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Extracellular Vesicles: A New Perspective in Tumor Therapy

BioMed Research International ◽

10.1155/2018/2687954 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Yan-Zi Sun ◽

Jun-Shan Ruan ◽

Zong-Sheng Jiang ◽

Ling Wang ◽

Shao-Ming Wang

Keyword(s):

Cell Growth ◽

Tumor Microenvironment ◽

Tumor Cell ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Immune Therapy ◽

Tumor Therapy ◽

Critical Role ◽

Mesenchymal Transition

In recent years, the study of extracellular vesicles has been booming across various industries. Extracellular vesicles are considered one of the most important physiological endogenous carriers for the specific delivery of molecular information (nucleonic acid, cytokines, enzymes, etc.) between cells. It has been discovered that they perform a critical role in promoting tumor cell growth, proliferation, tumor cell invasion, and metastatic ability and regulating the tumor microenvironment to promote tumor cell communication and metastasis. In this review, we will discuss (1) the mechanism of extracellular vesicles generation, (2) their role in tumorigenesis and cancer progression (cell growth and proliferation, tumor microenvironment, epithelial-mesenchymal transition (EMT), invasion, and metastasis), (3) the role of extracellular vesicles in immune therapy, (4) extracellular vesicles targeting in tumor therapy, and (5) the role of extracellular vesicles as biomarkers. It is our hope that better knowledge and understanding of the extracellular vesicles will offer a wider range of effective therapeutic targets for experimental tumor research.

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MEKK1 Regulates Chemokine Expression in Mammary Fibroblasts: Implications for the Breast Tumor Microenvironment

Frontiers in Oncology ◽

10.3389/fonc.2021.609918 ◽

2021 ◽

Vol 11 ◽

Author(s):

Saverio Gentile ◽

Najmeh Eskandari ◽

Michael A. Rieger ◽

Bruce D. Cuevas

Keyword(s):

Gene Expression ◽

Cell Migration ◽

Tumor Microenvironment ◽

Tumor Cell ◽

Breast Tumor ◽

Cell Function ◽

Breast Tumor Cell ◽

Tumor Cell Migration ◽

Stroma Cell

Breast tumors contain both transformed epithelial cells and non-transformed stroma cells producing secreted factors that can promote metastasis. Previously, we demonstrated that the kinase MEKK1 regulates cell migration and gene expression, and that transgene-induced breast tumor metastasis is markedly inhibited in MEKK1-deficient mice. In this report, we examined the role of MEKK1 in stroma cell gene expression and the consequent effect on breast tumor cell function. Using a heterotypic cell system to quantify the effect of stroma cells on breast tumor cell function, we discovered that MEKK1−/− fibroblasts are significantly less effective at inducing tumor cell invasion than MEKK1+/+ fibroblasts. Expression array analysis revealed that both baseline and tumor cell-induced expression of the chemokines CCL3, CCL4, and CCL5 were markedly reduced in MEKK1−/− mammary fibroblasts. By focusing on the role of MEKK1 in CCL5 regulation, we discovered that MEKK1 kinase activity promotes CCL5 expression, and inactive mutant MEKK1 strongly inhibits CCL5 transcription. CCL5 and the other MEKK1-dependent chemokines are ligands for the GPCR CCR5, and we show that the CCR5 antagonist Maraviroc strongly inhibits fibroblast-induced tumor cell migration. Finally, we report that fibroblast growth factor 5 (FGF-5) is secreted by MDA-MB 231 cells, that FGF-5 activates MEKK1 effectors ERK1/2 and NFκB in fibroblasts, and that chemical inhibition of NFκB inhibits CCL5 expression. Our results suggest that MEKK1 contributes to the formation of a breast tumor microenvironment that supports metastasis by promoting expression of stroma cell chemokine genes in response to tumor cell-induced paracrine signaling.

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Exosomes: Emerging Diagnostic and Therapeutic Targets in Cutaneous Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21239264 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9264

Author(s):

Abdul Q. Khan ◽

Sabah Akhtar ◽

Kirti S. Prabhu ◽

Lubna Zarif ◽

Rehan Khan ◽

...

Keyword(s):

Nucleic Acids ◽

Signaling Pathways ◽

Extracellular Vesicles ◽

Skin Diseases ◽

Cell Types ◽

Trigger Factors ◽

Disease Pathogenesis ◽

Human Organ ◽

Factors Affecting ◽

Multiple Signaling

Skin is the largest human organ and is continuously exposed to various exogenous and endogenous trigger factors affecting body homeostasis. A number of mechanisms, including genetic, inflammatory and autoimmune ones, have been implicated in the pathogenesis of cutaneous diseases. Recently, there has been considerable interest in the role that extracellular vesicles, particularly exosomes, play in human diseases, through their modulation of multiple signaling pathways. Exosomes are nano-sized vesicles secreted by all cell types. They function as cargo carriers shuttling proteins, nucleic acids, lipids etc., thus impacting the cell-cell communications and transfer of vital information/moieties critical for skin homeostasis and disease pathogenesis. This review summarizes the available knowledge on how exosomes affect pathogenesis of cutaneous diseases, and highlights their potential as future targets for the therapy of various skin diseases.

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