Normalizing Tumor Vasculature: History
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Subjects: Oncology
Contributor:
Jim Petrik

A basic requirement of tumorigenesis is the development of a vascular network to support the metabolic requirements of tumor growth and metastasis. Tumor vascular formation is regulated by a balance between promoters and inhibitors of angiogenesis. Typically, the pro-angiogenic environment created by the tumor is extremely aggressive, resulting in the rapid vessel formation with abnormal, dysfunctional morphology. The altered morphology and function of tumor blood and lymphatic vessels has numerous implications including poor perfusion, tissue hypoxia, and reduced therapy uptake. Targeting tumor angiogenesis as a therapeutic approach has been pursued in a host of different cancers. Although some preclinical success was seen, there has been a general lack of clinical success with traditional anti-angiogenic therapeutics as single agents. Typically, following anti-angiogenic therapy, there is remodeling of the tumor microenvironment and widespread tumor hypoxia, which is associated with development of therapy resistance. A more comprehensive understanding of the biology of tumor angiogenesis and insights into new clinical approaches, including combinations with immunotherapy, are needed to advance vascular targeting as a therapeutic area. 

  • hypoxia
  • angiogenesis
  • vascular normalization

1. Introduction

1.1. Sprouting Angiogenesis in Normal Physiology

Angiogenesis is the complex and highly regulated formation and maturation of vasculature from pre-existing vessels throughout the body. Typically, the process is kept quiescent through a balance of growth factors and inhibitors. Normal human processes that necessitate angiogenesis in the adult include placentation in the pregnant uterus, formation of the endometrium in the menstrual cycle, growth of the mammary gland in preparation for lactation, and supply of granulation tissue for wound healing [1][2][3]. In any of these situations, angiogenesis consists of a series of events including removal of structural pericytes in the area of the developing sprout, degradation of the capillary basement membrane, migration and proliferation of the endothelial cells comprising the new sprout, nascent tube formation, and vascular stabilization [4].
The presence of angiogenic stimuli such as hypoxia, mechanical stress, or inflammation leads to the release of growth factors, as summarized in Figure 1. These signaling events ultimately lead to the activation of cellular effectors, which aim to form the nascent vessel [4]. Upon effector stimulation, smooth muscle cells called pericytes located at intervals along the capillary wall are first removed from the sprouting area of a mother vessel. VEGF stimulation triggers intricate calcium oscillations within endothelial cells allowing for the selection of an endothelial cell distinguished by specialized filopodia, called a tip cell [5]. The tip cell guides the developing sprout through chemotaxis, following angiogenic stimuli secreted by the target tissue requiring increased perfusion [5]. As tip cells are highly influenced by even minute fluctuations in growth factor signaling, a loss of growth factor balance in this system may lead to disorganized vasculature. The tip cell releases matrix metalloproteases (MMP), which degrade basement membrane components in its path [6]. A second group of specialized endothelial cells, called stalk cells, are highly proliferative and interact with tip cells through delta-notch signaling to elongate the nascent sprout [7]. At a point of anastomoses between the tip cell of another nascent vessel or stabilized vessel, junctional adhesion proteins are deposited at the contact site of the two tip cells. A lumen is formed through cell membrane invagination or cord hollowing, forming a functional vascular network [8]. Circulating endothelial progenitor cells also contribute to the nascent vessels, which are haphazardly branched and in need of organization. Local differences in blood flow and pressure lead to the elimination of poorly perfused branches (pruning) or recycling of their component endothelial cells to areas of significant flow [9][10]. Conversely, highly perfused sprouts are stabilized through deposition of basement membrane, reduced endothelial cell activity, tightening of cell junctions, and recruitment of pericytes [10].
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Figure 1. Hypoxia induced by the growing tumor mass triggers an “angiogenic switch” within the tumor microenvironment, resulting in a crude version of angiogenesis.

1.2. Tumor Control of Angiogenesis

In many ways, tumors can be considered functional organs as opposed to a group of aberrant cells. The tumor stroma includes mesenchymal-derived cells, inflammatory cells, and vascular cells, albeit in an irregular fashion that has been modified by the tumor to tailor to its survival needs [11][12]. Tumors are therefore capable of inducing angiogenesis by co-opting the same pro-angiogenic program. Small tumors devoid of vasculature are often observed in solid tumor types—their oxygen and nutrient demands being supplied by passive diffusion from nearby vessels [13]. However, as tumors grow beyond 2 mm2, the tumor core becomes increasingly hypoxic and the process of angiogenesis begins to fuel oxygen and nutrient demands [14]. This moment has been termed “the angiogenic switch” in which tumor cells respond to low oxygen perfusion by releasing many of the angiogenic factors represented in Figure 1 [15]. Cellular responses to low oxygen are primarily regulated by DNA-binding transcription factors known as hypoxia inducible factors (HIF). HIFs are heterodimeric proteins that consist of a constitutively expressed HIF-1ß subunit and an oxygen-regulating subunit (HIF-1α or HIF-2α) [16][17]. These alpha subunits are composed of an amino terminal basic Helix-Loop-Helix (bHLH) necessary for DNA binding to hypoxia response elements (HRE), transactivation domains (N-TAD and C-TAD) that are vital for activation of HIF target genes, PAS-A and PAS-B domains for protein-protein dimerization, and an oxygen-dependent degradation domain (ODDD). Redundancy in HIF-1α stabilization is evident as a secondary lysine residue within the ODDD can be acetylated by an acetyl transferase enzyme called arrest-defective-1 (ARD-1) to favour degradation of HIF-1α [18]. The expression of ARD-1 is decreased in hypoxia, resulting in stabilized HIF-1α under this condition [18].
Under normoxic conditions, the prolyl hydroxylase domain (PHD) uses oxygen as a rate-limiting substrate and iron as a cofactor to hydroxylate two proline residues within the ODDD [18]. Hydroxylated HIF-1α becomes associated with Von Hippel Lindau factor (pVHL) and elongins B and C, cullin-2 (cul-2) and rbx1 co-factors, forming a complex with E3 ubiquitin ligase activity (HIF-1α-VBC complex) [19]. However, under hypoxic conditions, HIF-1α is stabilized through limited PHD activity. This allows generation and accumulation of non-hydroxylated HIF-1α. Further, HIF-1α stability is controlled by ubiquitin ligases that are PHD enzymes themselves, as well as pVHL-interacting deubiquitinating enzyme (VDU2), which acts to destabilize ubiquitin ligases on HIF-1α [18]. Given the significantly short half-life of HIF-1α (<1 min in a perfused lung), it is constantly being degraded at physiological oxygen levels in normal cells and is subject to tight regulation should oxygen levels decline [20]. In contrast, the median oxygenation of an untreated tumor falls between approximately 0.3% and 4.2%, with most untreated tumors exhibiting median oxygen levels <2% [21]. This level of hypoxia triggers the release and stabilization of HIF-1α while also inducing oncogenic mechanisms that further derail the HIF pathway and make tumors less dependent on oxygen [21]. Tumor-induced mutations in the binding pocket of pVHL have been shown to disrupt HIF-1α interactions and thereby disassemble the E3 ubiquitin ligase (VEC) complex [22]. More directly, in lung cancer, TP53 mutants have been shown to exert a gain of function on HIF-1, leading to heightened expression of hypoxia-response genes [23]. HIF-1α is capable of binding directly to the tumor suppressor, favouring mouse double minute 2 homolog (Mdm2) ubiquitination and proteosomal degradation of HIF-1α, which is not possible in TP53 mutants or knockouts [24]. Several studies have shown that HIF expression is abrogated upon phosphoinositide 3-kinase (PI3K) pathway inhibition regardless of oxygen levels [25][26]. Similarly, HIF-1 is upregulated by AKT in human gastric cancer, breast cancer, and non-small cell lung cancer [27][28].

1.3. Factors Contributing to Tumor Vascular Dysfunction

Tumors initiate the angiogenic process through activation of multiple factors including the most prominent angiogenic ligand, vascular endothelial growth factors (VEGF), and its receptors including VEGFR2 [29][30][31]. The VEGF family of proteins includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placenta growth factor (PIGF) [31]. VEGF-C and VEGF-D are studied as regulators of lymphangiogenesis, while VEGF-A is commonly referred to simply as VEGF due to its dominant role in angiogenesis. VEGF undergoes alternative splicing, leading to several isoforms that differ based on heparin binding affinity, localization to the extracellular matrix, or diffusive potential. The VEGF gene is transcriptionally regulated in response to HIF, and its levels must be tightly controlled to prevent aberrant angiogenesis [31]. Due to their control over HIF, tumor cells release exaggerated levels of VEGF to the extracellular space in response to hypoxia [32]. High concentrations of VEGF surrounding endothelial cells select for excess tip cells, which then contribute to irregular branching and tortuous vascular networks. The basement membrane of tumor vessels, which serves as a physical barrier for cancer cell metastasis to surrounding tissues, is often absent or thin due to chemical degradation by tumor-derived proteases [33][34]. The monolayer of endothelial cells is often disorganized and cells are plagued with abnormal gene expression profiles, karyotypic abnormalities, and chromosomal instability [35][36][37]. Compared with normal endothelial cells, tumor endothelial cells contain four times the amount of total RNA, indicating enhanced gene expression. Indeed, tumor endothelial cells have enhanced expression of VEGFR-1 and -2 and are therefore more responsive to VEGF stimulation [38]. Recently, tumor endothelial cells have been shown to have enhanced expression of markers of angiogenesis and stemness such as CD61, CD105, Sca-1, CD34, CD90, and ALDH [39][40]. These expression profiles contribute to the escalated angiogenic potential of tumor endothelial cells compared with normal endothelial cells, which facilitates the aberrant vascular arrangement seen in tumors [41]. Extracellular factors such as VEGF, PMA, TGF-ß, and cytochalasin B, which are overexpressed in the tumor microenvironment, have been shown to impact fenestration formation in endothelial cells [42][43]. Given that these plasma membrane microdomains are vital for the exchange of solutes and water at the interface of tissue and vasculature, tumor endothelial cells are often more porous compared with normal counterparts [43]. Abnormal VEGF signaling in tumor endothelial cells also leads to downregulation of connexin expression, causing gap junction dysfunction, increasing vascular fenestrations, and increasing vascular permeability [44][45][46]. In fact, VEGF was initially identified based on its ability to increase vascular permeability and extravasation of plasma proteins, such as fibrinogen [47].
Pericytes are specialized smooth muscle cells that are recruited to mature and stabilized vessels through release of PDGF-ß by ECs [48]. Mice deficient in PDGF-ß signaling lack pericytes and succumb to micro hemorrhaging, demonstrating the importance of these cells for proper vascular function [48][49]. Signals secreted by pericytes maintain EC survival by leading to enhanced expression of BCL-w antiapoptotic protein [49]. Pericytes therefore also shelter normal vessels from anti-angiogenic therapies, allowing for tumor-targeted action of these agents. Hypoxia and downstream angiogenic factors released by tumor cells disengage pericytes from endothelial cells as the initial step to the formation of the nascent vascular sprout. Therefore, tumor-associated vessels are largely devoid of pericytes or demonstrate weak connections between pericytes and endothelial cells, contributing to an immature vascular phenotype and facilitating continued angiogenesis [50].

1.4. Abnormal Vasculature Results in Limited Treatment Delivery

The abnormalities of the tumor vasculature result in poor tissue perfusion, which poses a physical barrier to therapy delivery to tumors. Of the number of delivery and uptake impediments, elevated interstitial pressure (IFP) is considered to be the most significant barrier to therapy access to the tumor [51][52][53]. The etiology of IFP elevation is multifactorial and involves high vascular permeability and mechanical compression of lymphatic blood vessels [54][55]. Disrupted vascular morphology with reduced pericyte coverage is associated with a loss of endothelial cell junction integrity and an activated endothelium, resulting in vessels that are leaky and extravasate fluid into the tumor environment, thereby increasing pressure within the tumor [56][57]. Combined with solid stress, in which accumulation of cancer cells, stromal cells, cancer-associated fibroblasts (CAFs), and their associated extracellular matrix create high mechanical pressure within the tumor, IFP leads to a significant elevation in intratumoral pressure [58].
This high IFP causes a stasis in flow throughout the tumor, which results in tumor hypoxia and acidosis [59]. Elevated hypoxia as a consequence of high IFP is associated with poor outcome in cancer patients and is considered an early response marker for cancer therapeutics such as chemotherapy and radiation [60][61]. As another consequence of reduced perfusion and flow within the tumor, there is impediment of drug uptake and delivery within the tumor tissue [62]. With the elevated IFP, there is an attenuated transvascular osmotic pressure difference, resulting in impaired delivery of drugs throughout the tumor [63]. Even in tumors in which there is vascular heterogeneity, drugs will become concentrated in regions that have sufficient blood supply but will have limited migration to areas in which IFP is higher and vessel density is decreased [64]. Although IFP is often discussed in relation to the primary tumor, it is important to note that larger metastatic tumors also demonstrate elevated IFP and decreased drug uptake, potentially contributing to the development of drug-resistant metastatic disease.
While intra-tumoral treatment delivery decreases off-target toxicities, it fails to account for metastatic disease and has not led to significant survival benefit compared to systemic administration [65]. Clinical use of intra-tumoral drugs is also impractical for some tumor subtypes such as ovarian and pancreatic cancers, which are inaccessible through transdermal injection. In order to prove effective, systemic agents must not only navigate from the injection site to the tumor vasculature but must also gain access and disperse throughout a tumor, which is often plagued with impediments to this process, posing a therapeutic challenge [66]. The properties of the tumor microenvironment that pose issues for treatment delivery are depicted in Figure 2.
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Figure 2. Tumor hypoxia activates several tumorigenic processes. Tumor vasculature has altered morphology, with reduced pericyte coverage. The immature tumor vessels are characterized by blind end shunts, torturous pathway, sacculations, decreased luminal size, and increased fenestrations. Excessively fenestrated vessels allow for fluid extravasation and increased interstitial fluid pressure (IFP) and facilitate intravasation and migration of metastatic tumor cells. Elevated IFP and disrupted tissue perfusion contribute to areas of acute and chronic hypoxia, which can activate numerous pro-tumorigenic processes.

2. Vascular Normalizing Agents as Adjuvants to Traditional Cancer Therapeutics

Normalized tumor vessels have also been shown to re-program many other aspects of the tumor microenvironment known to limit delivery of cancer therapies discussed earlier in this review, giving rise to the term ‘microenvironment normalization’ [67]. Anti-angiogenic drugs have opened new avenues for combination therapy. In a humanized murine model of colorectal adenocarcinoma, combination therapy with anti-PDGFR and anti-VEGFR tyrosine kinase inhibitors decreased IFP in tumors, allowing for enhanced delivery of taxol therapy [68]. Improved delivery of chemotherapy through vascular normalization in solid tumors has been extensively reviewed [69]. We and others have extended the utility of vascular normalization to enhancing the delivery and functionality of agents beyond traditional chemotherapy. The vascular shutdown typical of oncolytic viruses (OV) was prevented using thrombospondin type-1 repeats in a mouse model of advanced stage ovarian cancer [70]. This led to enhanced intratumoral trafficking of immune cell subsets, thereby improving immunotherapeutic success [67][70][71]. In addition to enhancing vascular perfusion and providing a conduit for immune cells, the enhanced oxygenation of tumors as a result of low-dose anti-angiogenic therapy has improved immune cell function and reprogramed immune cell subsets with greater anti-tumor capabilities [72]. Vascular normalizing therapies continue to be recognized for their oxygen-modulating function in sensitizing tumors to traditional therapies, which have often been met with resistance [73].

This entry is adapted from the peer-reviewed paper 10.3390/cancers13174444

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