cells Review Angiogenic Properties of NK Cells in Cancer and Other Angiogenesis-Dependent Diseases Dorota M. Radomska-Le´sniewska 1, Agata Białoszewska 1,* and Paweł Kami ´nski 2 1 Center for Biostructure Research, Department of Histology and Embryology, Medical University of Warsaw, 02-004 Warsaw, Poland; [email protected] 2 Department of Gynecology and Gynecological Oncology, Military Institute of Medicine, 04-349 Warsaw, Poland; [email protected] * Correspondence: [email protected] Abstract: The pathogenesis of many serious diseases, including cancer, is closely related to distur- bances in the angiogenesis process. Angiogenesis is essential for the progression of tumor growth and metastasis. The tumor microenvironment (TME) has immunosuppressive properties, which con- tribute to tumor expansion and angiogenesis. Similarly, the uterine microenvironment (UME) exerts a tolerogenic (immunosuppressive) and proangiogenic effect on its cells, promoting implantation and development of the embryo and placenta. In the TME and UME natural killer (NK) cells, which otherwise are capable of killing target cells autonomously, enter a state of reduced cytotoxicity or anergy. Both TME and UME are rich with factors (e.g., TGF-β, glycodelin, hypoxia), which support a conversion of NK cells to the low/non-cytotoxic, proangiogenic CD56brightCD16low phenotype. It is plausible that the phenomenon of acquiring proangiogenic and low cytotoxic features by NK cells is not only limited to cancer but is a common feature of different angiogenesis-dependent diseases (ADDs). In this review, we will discuss the role of NK cells in angiogenesis disturbances associated Citation: Radomska-Le´sniewska, D.M.; with cancer and other selected ADDs. Expanding the knowledge of the mechanisms responsible Białoszewska, A.; Kami´nski,P. for angiogenesis and its disorders contributes to a better understanding of ADDs and may have Angiogenic Properties of NK therapeutic implications. Cells in Cancer and Other Angiogenesis-Dependent Diseases. Keywords: NK cells; decidual NK cells; angiogenesis; proangiogenic factors; tumor microenvironment; Cells 2021, 10, 1621. https://doi.org/ endometriosis; rheumatoid arthritis; VEGF; TGF-β; hypoxia 10.3390/cells10071621 Academic Editor: Alessandro Poggi 1. Introduction Received: 30 May 2021 Angiogenesis, a new blood vessel formation from preexisting vasculature, is a normal Accepted: 26 June 2021 Published: 29 June 2021 and vital process in growth and development. Physiologically, angiogenesis regulates embryogenesis, the menstrual cycle, wound healing, and the formation of granulation Publisher’s Note: MDPI stays neutral tissue [1]. with regard to jurisdictional claims in Disturbances in neovascularization can lead to serious health consequences since the published maps and institutional affil- pathogenesis of many severe conditions is closely related to angiogenic disorders. These iations. conditions are called angiogenesis-dependent diseases (ADDs) and are characterized by a disturbed formation of new vessels, which affects their organization, structure, and function [2]. ADDs comprise conditions with excessive pathological angiogenesis, such as cancer, some eye diseases (e.g., age-related macular degeneration [AMD]), or chronic inflammatory disorders (e.g., rheumatoid arthritis [RA], psoriasis) and diseases with Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. insufficient angiogenesis (e.g., diabetes mellitus, stroke, atherosclerosis, hypertension, or This article is an open access article ischemic heart disease) [2,3]. distributed under the terms and Angiogenesis is a complex and multi-stage process usually induced by hypoxia, which conditions of the Creative Commons stimulates hypoxia-inducible factor-1 (HIF-1) leading to gene expression for proangiogenic Attribution (CC BY) license (https:// factors, such as the most powerful stimulator, vascular endothelial growth factor (VEGF), creativecommons.org/licenses/by/ and its receptor VEGFR-1/FLT-1 (Figure1)[ 4,5]. Many different kinds of cells participate 4.0/). in the regulation of angiogenesis, mainly by secreting various factors which control this Cells 2021, 10, 1621. https://doi.org/10.3390/cells10071621 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 26 Cells 2021, 10, 1621 2 of 25 cells participate in the regulation of angiogenesis, mainly by secreting various factors whichprocess control (Figure this1). process The diverse (Figure group 1). T ofhe angiogenesis diverse group regulating of angiogenesis cells includes regulating natural cells includeskiller (NK) natural cells, whichkiller (NK) are innate cells, lymphocyteswhich are innate (generally lymphocytes cytotoxic (generally ones) that cyt provideotoxic oprotectionnes) that provide against protection viral infections against and viral tumor infections metastasis. and tumor NK cells metastasis. also modulate NK cells other also modulateaspects of other the immune aspects systemof the i throughmmune thesystem rapid through production the rapid of numerous production cytokines of numer- and ouschemokines. cytokines Out and of chemokines. the broad spectrum Out of the of NK broad cell spectrum subpopulations, of NK somecell subpopul were shownations to, soaffectme were angiogenesis shown to by affect VEGF, angiogenesis placenta growth by VEGF, factor placenta (PlGF), growth interleukin factor (IL)-8/CXCL8, (PlGF), inter- leukinIL-10, angiopoietin(IL)-8/CXCL8 (Ang)-1,, IL-10, andangiopoietin Ang-2 production (Ang)-1, [ 6and]. There Ang is-2 aproduction unique subset [6]. ofThere decidual is a uniqueNK (dNK) subset cells of known decidual to participateNK (dNK) incells vascularization known to participat during embryonice in vascularization and placental dur- ingdevelopment embryonic [ 7and]. Recently, placenta al d similarevelopment nurturing [7]. Recently, activity of a NKsimilar cells nurturing has been activity described of NKunder cells pathological has been described conditions, under predominantly pathological in different conditions, types predominantly of cancer, which in indicatesdifferent typethe relevances of cancer of, which NK cells indicates in the developmentthe relevance of ADDsNK cells [8 –in13 the]. A development better understanding of ADDs [8of– the13]. mechanismsA better understanding in which NK of cellsthe mechanisms regulate angiogenesis in which NK and cells its disordersregulate a mayngiogen be ofe- sistherapeutic and its disorders significance. may In be this of article,therapeutic we will sign summarizeificance. In the this current article, body we ofwill knowledge summa- rizeon NK the cell current biology, body with of knowledge a special focus on NK on the cell angiogenic biology, with properties a special of focus NK cells on inthe cancer angi- ogenicand other properties ADDs. of NK cells in cancer and other ADDs. Figure 1. StagesStages of of t thehe angiogenesis angiogenesis process process and its regulation. New New bl bloodood vessel vessel formation formation is is upregulated upregulated by by hypoxia, hypoxia, which stimulatesstimulates hypoxia-induciblehypoxia-induciblefactor-1 factor-1 (HIF-1) (HIF-1) leading leading to to the the vascular vascular endothelial endothelial growth growth factor factor (VEGF) (VEGF) expression. expres- sion. VEGF, fibroblast growth factor (FGF), transforming growth factor (TGF), platelet-derived growth factor (PDGF), VEGF, fibroblast growth factor (FGF), transforming growth factor (TGF), platelet-derived growth factor (PDGF), hepatocyte hepatocyte growth factor (HGF), placenta growth factor (PlGF), angiogenin, angiopoietin (Ang)-1, interleukin (IL)-8, IL- growth6, IL-17, factor matrix (HGF), metalloproteinases placenta growth (MMPs), factor (PlGF), and tumor angiogenin, necrosis angiopoietin factor (TNF) (Ang)-1, stimulate interleukin angiogenesis. (IL)-8, IL-6,Inhibitors IL-17, o matrixf neo- metalloproteinasesvascularization include (MMPs), angiostatin, and tumor endostatin, necrosis factor thrombospondin, (TNF) stimulate tissue angiogenesis. inhibitors Inhibitors of matrix of metalloproteinases neovascularization (TIMP), include angiostatin,interferon (IFN endostatin,)-α, IL-10, thrombospondin, IL-12, IL-18, IL-23, tissue IL-25, inhibitors IL-27, and of matrixAng-2. metalloproteinases The various kinds (TIMP),of cells participating interferon (IFN)- in theα, IL-10,regu- IL-12,lation IL-18,of angiogenesis, IL-23, IL-25, mainly IL-27, andby secreting Ang-2. The stim variousulatory kinds and/or of cellsinhibitory participating factors, in include the regulation endothelial of angiogenesis, cells, macrophages mainly by(MΦ) secreting, mast cells, stimulatory fibroblasts, and/or CD56 inhibitory+CD16- natural factors, killer include (NK) endothelial cells, T cells, cells, neutrophils, macrophages basophils, (MF), masteosinophils, cells, fibroblasts, and den- CD56dritic +cellsCD16 (DCs)− natural [7,14 killer–18]. (NK) cells, T cells, neutrophils, basophils, eosinophils, and dendritic cells (DCs) [7,14–18]. 2. NK NK Cell Cell Biology NK cells constituteconstitute upup toto 15%15% of of circulating circulating lymphocytes lymphocytes and and can can be be found found in variousin vari- ousorgans organs and and tissues. tissues. They They are aare subset a subset of a heterogeneousof a heterogeneous family family of innate of innate lymphoid lymphoid cells cells(ILCs) (ILCs) and originate and originate from commonfrom common lymphoid lymphoid progenitors progenitors which derivewhich fromderive