Vessel abnormalization: another hallmark of cancer?

As a result of excessive production of angiogenic molecules, tumor vessels become abnormal in structure and function. By impairing oxygen delivery, abnormal vessels fuel a vicious cycle of non-productive angiogenesis, which creates a hostile microenvironment from where tumor cells escape through leaky vessels and which renders tumors less responsive to chemoradiation. While anti-angiogenic strategies focused on inhibiting new vessel growth and destroying pre-existing vessels, clinical studies showed modest anti-tumor effects. For many solid tumors, anti-VEGF treatment offers greater clinical benefit when combined with chemotherapy. This is partly due to a normalization of the tumor vasculature, which improves cytotoxic drug delivery and efficacy and offers unprecedented opportunities for anti-cancer treatment. Here, we overview key novel molecular players that induce vessel normalization.

Introduction

Angiogenesis promotes tumor growth and malignancy. In contrast to the healthy vasculature, tumor vessels are, however, highly abnormal structurally and functionally [1, 2, 3]. This is the result of an uncontrolled, relentless production of angiogenic stimulators, in excess of inhibitors, which tips the balance in favor of hyperactive vessel growth (Figure 1). These abnormal tumor vessels are characterized by a mal-shaped, irregular, disorganized and tortuous architecture with a highly dysfunctional and leaky endothelial cell (EC) layer [1, 3]. The abnormal tumor vasculature exhibits remarkable spatiotemporal heterogeneity. In certain regions, ECs with irregular shape are stacked upon each other and obstruct blood flow by extending multiple protrusions, while in other sites, ECs move away or die and leave behind gaps. Also, they are often loosely connected, have wider junctions and are covered by fewer and abnormal mural pericytes (PCs) [1, 2, 4••]. These changes not only impair drug delivery and perfusion, but also convert the tumor into a hostile hypoxic and acidic milieu, from where cancer cells escape through leaky vessels [5, 6]. Such an unnatural milieu also promotes a vicious cycle of non-productive angiogenesis and stimulates pro-malignant reprogramming of tumor cell metabolism (Figure 1). In addition, it hampers the anti-tumor immune defense and highjacks inflammatory cells for angiogenesis, enhances tumor tissue swelling (potentially life-threatening in brain tumors) and makes chemoradiotherapy less efficient [1]. Paradoxically thus, even though tumors crave for oxygen, they stimulate a non-productive process of angiogenesis extremely, so that abnormal tumor vessels deliver less — rather than more — oxygen to the hypoxic cancer cells, which in turn continues to fuel the cycle. Thus, tumor vessel abnormalization promotes tumor invasiveness, dissemination and overall malignancy.

Current anti-angiogenic therapies are based on the concept of starving and depriving the tumor from its nutrient supply by destroying existing vessels and preventing new vessel growth (anti-angiogenic ‘vessel pruning’) [7, 8]. However, despite successes, clinical trials with VEGF-targeted monotherapy have shown a more modest prolongation of progression-free or overall survival of cancer patients than anticipated [8, 9]. Aside from the benefit of anti-VEGF monotherapy in glioblastoma and renal cell carcinoma, other solid cancers (breast, lung and colorectal) showed a greater therapeutic effect when anti-VEGF was combined with conventional chemotherapy. Recent findings have resolved the paradox of how an anti-angiogenic vessel pruning strategy (which would be expected to impede vascular supply of cytotoxic drugs) can, in fact, improve chemotherapy by partially normalizing the tumor vasculature and thereby enhancing drug delivery [1]. This has not only fostered the novel concept that judicious use of vessel pruning agents may induce vessel normalization by restoring the angiogenic balance, but also raised the question whether more selective anti-angiogenic ‘vessel normalization’ strategies could be developed. In this review, we will briefly illustrate some examples of both strategies.