Published OnlineFirst December 12, 2019; DOI: 10.1158/0008-5472.CAN-19-3351 CANCER RESEARCH | CONTROVERSY AND CONSENSUS Beyond Angiogenesis: Exploiting Angiocrine Factors to Restrict Tumor Progression and Metastasis Mahak Singhal1,2,3 and Hellmut G. Augustin1,2,4 ABSTRACT ◥ Looking beyond tumor angiogenesis, the past decade has wit- thelial cell–derived angiocrine signals orchestrate a favorable nessed a fundamental change of paradigm with the discovery that the immune milieu to facilitate metastatic growth. Here, we discuss vascular endothelium does not just respond to exogenous cytokines, recent advances in the field of tumor microenvironment research but exerts active “angiocrine” gatekeeper roles, controlling their and propose angiocrine signals as promising targets of future mech- microenvironment in an instructive manner. While vascular niches anism-driven antimetastatic therapies, which may prove useful to host disseminated cancer cells and promote their stemness, endo- synergistically combine with chemotherapy and immunotherapy. Introduction to this day. It is poorly understood why antiangiogenic drugs synergize with chemotherapy. Regression of intratumoral blood vessels should, if The limited diffusion distance of oxygen into tissues (100–150 mm) anything, reduce the delivery of cytotoxic drugs to a tumor. To restricts the growth of tumor cells away from blood vessels. This reconcile for this apparent discrepancy of preclinical concept from biophysical phenomenon led Judah Folkman in 1971 to postulate that clinical reality, Rakesh Jain proposed that antiangiogenic drugs may tumor growth may be angiogenesis-dependent and, conversely, that not necessarily drive all intratumoral blood vessels in regression, but inhibition of tumor neovascularization could restrain tumor growth to preferentially the highly irregular, tortuous, and poorly functioning microscopic size in an avascular dormant state. Intense research in the immature microvasculature. As a result, the more mature vasculature following two decades resulted in the identification of pleiotropic and may persist, resulting in a “normalizing” effect of the remaining, better specific growth factors capable of inducing tumor neoangiogenesis. perfused vasculature. This reduces intratumoral fluid pressure and Notably, VEGF was identified by Napoleone Ferrara in 1989 as the eventually leads to enhanced drug delivery. While the concepts of most specific, hierarchically high master inducer of the angiogenic vascular normalization are today widely accepted, the actual relative cascade. Blocking reagents to the VEGF–VEGF receptor signaling axis contribution of vessel normalization and vessel regression toward the were developed soon thereafter and, in line with Folkman's hypothesis, efficacy of antiangiogenic drugs in human tumors continues to be proved highly potent to suppress the growth of xenografted tumors in poorly understood, which is a major bottleneck to rationally advance mice. Concurrently, bevacizumab, a humanized anti-VEGF antibody, the clinical efficacy of approved antiangiogenic drugs, for example, by in combination with chemotherapy, prolonged the overall survival of combination with second-generation antiangiogenic drugs. patients with metastatic colorectal carcinoma, paving the way for the Beyond acting as responsive cell population executing exogenously FDA approval of the first antiangiogenic therapy. While the most stimulated programs, such as angiogenic or inflammatory activation, remarkable efficacy of preclinical trials could not similarly translate in endothelial cells have in the last decade been recognized as a highly man, drugs targeting the VEGF/VEGFR axis have received FDA dynamic cell population that serves as a source of instructive signals for approval as first-line therapy in combination with chemotherapy for neighboring cells. For example, endothelial cells may control embry- multiple types of cancer, leading on average to an extension of overall onic organogenesis even prior to the establishment of a functional survival in the range of 25%. circulatory system. Extrapolating these developmental findings into Antiangiogenic drugs have now been in clinical use in the field of the adult, Shahin Rafii proposed in 2010 that organ-specific endothelial oncology for more than 15 years. Still, the precise mechanism-of- cells may actively shape the local tissue microenvironment by releasing action and their effect on the tumor microenvironment remain elusive a wide-array of paracrine/juxtacrine-acting growth factors. This novel type of instructive, vascular-controlled cell–cell communication was subsequently referred to as “angiocrine signaling.” These newly dis- 1European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidel- covered perfusion-independent molecular functions of the vascular berg University, Mannheim, Germany. 2Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), endothelium quickly emerged into the much broader concept of Heidelberg, Germany. 3Faculty of Biosciences, Heidelberg University, Heidel- organotypic vasculature wherein organ-specific angiocrine signals berg, Germany. 4German Cancer Consortium, Heidelberg, Germany. exert a vital role in maintaining physiologic tissue homeostasis and fl Corresponding Authors: Mahak Singhal, European Center for Angioscience, resolving pathologic challenges such as cancer and in ammation. Medical Faculty Mannheim, Heidelberg University, and German Cancer Now, nearly a decade since pioneering this bold concept, the eluci- Research Center Heidelberg, Im Neuenheimer Feld 280, D-69120 Heidelberg, dation of angiocrine signaling mechanisms has taken center stage in Germany. Phone: 4962-2142-1508; E-mail: [email protected]; and Hellmut G. vascular biology research, essentially affecting all organ disciplines Augustin, European Center for Angioscience, Medical Faculty Mannheim, and, most recently, also heavily impacting aging research. Heidelberg University, and German Cancer Research Center Heidelberg, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. Phone: 4962-2142-1500; In the context of tumor progression and metastasis, several unam- E-mail: [email protected] biguous pieces of evidence highlight the central roles of endothelial cells as an instructive component within the metastatic niche. Involv- Cancer Res 2020;80:1–4 ing multicellular cross-talk mechanisms, they orchestrate a conducive doi: 10.1158/0008-5472.CAN-19-3351 niche to allow single-seeded tumor cells to colonize a distant site. Ó2019 American Association for Cancer Research. Following an overview of our current understanding of angiocrine AACRJournals.org | OF1 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst December 12, 2019; DOI: 10.1158/0008-5472.CAN-19-3351 Singhal and Augustin signals in metastasis, this perspectives article will aim to identify key STAT3 or administration of CCL2-neutralizing antibody suppressed unanswered questions and discuss possible avenues to translate this metastatic outgrowth in an angiogenesis-independent manner (5, 6), novel knowledge into future therapeutic applications. thereby underlining a critical role of the vasculature in choreographing the metastatic immune landscape. Vascular niches house and nourish disseminated tumor cells Metastatic site endothelial cells with sustained activation of The unique anatomic position of blood vessels necessitates a NOTCH1 signaling have been described to exhibit a senescent phe- circulating tumor cell to closely interact with endothelial cells to arrive, notype characterized by the overexpression of a wide-array of chemo- home, and eventually survive at a metastatic site. Indeed, disseminated kines and the adhesion molecule VCAM1 (7). These molecular changes tumor cells may stay dormant in specialized vascular niches for long promoted the infiltration of myeloid-derived suppressor cells into the periods of time, possibly years, prior to giving rise to metastases. Latent metastatic niche and facilitated postsurgical metastasis. Concurrently, breast cancer cells frequently reside in bone and brain microvascular mice preconditioned with NOTCH1-blocking antibody displayed niches where endothelial cells, by enhanced expression of tumor- reduced metastatic burden in experimental metastasis assays. Con- suppressive TSP1, have been reported to promote sustained senes- versely, endothelial cells express nonsignaling chemokine-scavenging cence of seeded tumor cells (1). Intriguingly, while the secretome of the receptor DARC, which acts as a chemokine sink, thereby buffering resting mature vasculature maintained tumor cells in a quiescent state, potential surges in plasma chemokine levels. During tumor progression, activated endothelium conferred a tumor-promoting signature to endothelial cells overexpressed DARC to suppress chemokine bioavail- facilitate metastatic growth. Likewise, the resting lung vasculature has ability to eventually subside the host inflammatory response. been shown to express DARC, which is capable of inducing senescence Endothelial cells and hematopoietic cells share a common cellular in prostate cancer cells by physically interacting with KAI1 on tumor ancestry during development, called the “hemogenic endothelium.” cells (2). Concurrently, gene expression of both DARC and KAI1 has Secretion of cytokines such as SCF and CXCL12 as well as the been negatively associated with metastatic progression