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Pasquier et al. J Transl Med (2020) 18:52 https://doi.org/10.1186/s12967-020-02244-9 Journal of Translational Medicine REVIEW Open Access Angiocrine endothelium: from physiology to cancer Jennifer Pasquier1,2*, Pegah Ghiabi2, Lotf Chouchane3,4,5, Kais Razzouk1, Shahin Rafi3 and Arash Rafi1,2,3 Abstract The concept of cancer as a cell-autonomous disease has been challenged by the wealth of knowledge gathered in the past decades on the importance of tumor microenvironment (TM) in cancer progression and metastasis. The sig- nifcance of endothelial cells (ECs) in this scenario was initially attributed to their role in vasculogenesis and angiogen- esis that is critical for tumor initiation and growth. Nevertheless, the identifcation of endothelial-derived angiocrine factors illustrated an alternative non-angiogenic function of ECs contributing to both physiological and pathological tissue development. Gene expression profling studies have demonstrated distinctive expression patterns in tumor- associated endothelial cells that imply a bilateral crosstalk between tumor and its endothelium. Recently, some of the molecular determinants of this reciprocal interaction have been identifed which are considered as potential targets for developing novel anti-angiocrine therapeutic strategies. Keywords: Angiocrine, Endothelium, Cancer, Cancer microenvironment, Angiogenesis Introduction of blood vessels in initiation of tumor growth and stated Metastatic disease accounts for about 90% of patient that in the absence of such angiogenesis, tumors can- mortality. Te difculty in controlling and eradicating not expand their mass or display a metastatic phenotype metastasis might be related to the heterotypic interaction [7]. Based on this theory, many investigators assumed of tumor and its microenvironment [1]. Te role of the tumor endothelium as the ultimate target for tumor tumor type specifc microenvironment (TM) has been therapy through prevention of neo-vascularization. widely described in tumor initiation, maintenance and However, strategies aimed at targeting tumor angiogen- progression [2–4]. However efective targeting of TM in esis have mostly failed at clinical trial stage [8], indicat- cancer therapy is not fully appreciated. ing an alternative function for ECs in regulation of tumor Te vascular system comprises a vast network of capil- progression. lary endothelial cells (ECs) that interconnect arteries and Te contribution of tumor endothelium to many hall- veins and create heterogenous vascular beds throughout marks of cancer has already been reviewed by Hanahan body. Te formation of these vascular networks and their and Coussens [2] and is beyond the scope of this review. interaction with the surrounding cells is the prerequisite In summary, the ECs infer a proliferative advantage to of organ development and tissue regeneration [5, 6]. Sim- cancer cells in many ways such as neo-angiogenesis and ilarly, neo-angiogenesis is considered as a critical process provision of blood supply and nutrients, production of for establishing tumor vasculature that ensures tumor paracrine factors, metabolic regulation, modulation of survival and expansion. Folkman originally proposed tumor invasiveness, and resisting cellular apoptosis [5, the term “angiogenic switch” to imply the essential role 9–13]. Tis review will describe the emerging role of endothelial transmembrane and secretory growth fac- tors and trophogens, referred to as angiocrine factors, as *Correspondence: [email protected] 1 Nice Breast Institute, 57 bld de la Californie, 06000 Nice, France essential players in physiological processes and tumor Full list of author information is available at the end of the article growth [5]. We will describe the concept of angiocrine © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Pasquier et al. J Transl Med (2020) 18:52 Page 2 of 17 switch referring to the secreted and membrane bound In this model the activation of ECs by neighboring leu- endothelial factors that participate to the cross talk with kemia cells also triggers production of stem cell promot- cancer cells in association with their role in nutrients and ing angiocrine factors such as epidermal growth factors oxygen delivery (angiogenic switch). We will review the (EGFs) and fbroblast growth factors (FGFs) [33] enrich- data demonstrating that endothelial angiocrine reper- ing leukemia stem cells [34]. Similar fndings by Cao et al. toire is heterogenous and organ or tumor type specifc. [35] showed participation of lymphoma-derived FGF4 Our aim is to describe the ECs’ angiocrine role in devel- in priming of a Jagged1 vascular niche that reciprocally opmental processes and illustrate how these mecha- reinforced lymphoma propagation and chemoresistance. nisms are hijacked by tumor cells. We will review the Jagged1-dependent tumor cells stimulated a transient role of endothelial contexture in drug resistance, immune mesenchymal shift in a subset of tumor ECs in a notch response, and tumor metabolic regulation. Finally, we and TGFβ-mediated manner [15]. Te mesenchymal will discuss new therapeutic approaches disrupting angi- ECs (ECsMes) maintain their endothelial identity while ocrine endothelium. acquiring improved angiocrine and angiogenic proper- ties. Although diferent from endothelial-to-mesenchy- Normal versus tumor endothelium: is there any angiocrine mal transition (EndMT) phenomenon implicated in the switch? enrichment of cancer-associated fbroblasts (CAFs) [36], Te importance of angiogenesis in initiation and devel- this might potentially represent selective activation of opment of tumors was postulated by Folkman in the con- tumor endothelium leading to the generation of a pro- text of an angiogenic switch with neovascularization [14]. tumoral angiocrine endothelium. While tumor vessels displayed an abnormal structure, the existence of a tumor specifc endothelium compared EC angiocrine role in organ development versus tumor to normal endothelium was revealed by gene expression progression alterations in tumor-associated ECs [15–19]. In addi- In addition to the primary role of ECs in vasculogenesis tion to genetic alterations, infammation and hypoxia, in and angiogenesis, accumulating evidence shows that the vicinity of ECs trigger the production of endothelial ECs contribute to complex patterning occurring dur- cytokines promoting tissue repair and tumor growth [20, ing organogenesis [7]. Te participation of vascular ECs 21]. Tumor endothelial cells usually display an activated in organ formation and regeneration has been described state (discussed below) associated to a change of mem- in a recent review by our group [6]. Te involvement of brane bound and secretory elements referred here as angiocrine factors in many physiological body processes angiocrine switch. Trough the angiocrine switch that and their role in stem and progenitor cells regulation occurs early in tumor development, ECs establish a pro- suggested their potential involvement in tumor progres- tumoral niche that serves an alternative duty than the sion and phenotypic plasticity [37–42] (Fig. 2). Here we previously described angiogenic switch. Hence, the acti- provide an overview of the ECs angiocrine role in organ vated tumor ECs play a distinctive role in enhancement development in light of the angiocrine role in tumor pro- of tumorigenicity independent of its function as oxygen gression mediated by secretion/expression of endothe- and nutrient transporters. lial-specifc angiocrine factors described above (Table 1). In a recent review by Friedl and Alexander, a model has been proposed in which tumor and its microenvi- Brain ronment induces reciprocal changes in their phenotypes Endothelial cells from dorsal aorta secrete BMPs induc- and functions (spatiotemporal plasticity) by processing ing mesenchymal SDF1 and neuregulin-1 expression, signals they receive from their environment (reciproc- resulting in the attraction of sympatho-adrenal progeni- ity) [22–25]. Te interactions occurring in TM are similar tors [43]. BMP signaling from ECs also governs progen- to normal tissue development and remodeling processes itor’s segregation through neuregulin-ErbB signaling, and mediated by soluble factors or cell-to-cell contacts forming the adrenal medulla and sympathetic gangli- [3, 4, 26, 27] (Fig. 1). For instance, tumor-derived infam- ons. Brain capillaries’ ECs activate quiescent Neural matory cytokines stimulate the expression of notch stem cells (NSC) through jagged-1 and EphrinB2 path- ligands

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