Modes of resistance to anti-angiogenic therapy

Abstract

Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signalling pathways are affording demonstrable therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers. However, in both preclinical and clinical settings, the benefits are at best transitory and are followed by a restoration of tumour growth and progression. Emerging data support a proposition that two modes of unconventional resistance underlie such results: evasive resistance, an adaptation to circumvent the specific angiogenic blockade; and intrinsic or pre-existing indifference. Multiple mechanisms can be invoked in different tumour contexts to manifest both evasive and intrinsic resistance, motivating assessment of their prevalence and importance and in turn the design of pharmacological strategies that confer enduring anti-angiogenic therapies.

Figure 1. Two modes of resistance in response to anti-angiogenic therapy imply adaptive evasion and intrinsic non-responsiveness of tumours

Adaptive or evasive resistance refers to the ability of a tumour, after an initial response phase, to adapt so as to evade the therapeutic blockade by inducing or accentuating mechanisms that enable neovascularization despite the therapeutic blockade, or reduce dependence on such growth of new blood vessels by other means, leading to renewed tumour growth and progression. By contrast, intrinsic non-responsiveness is a pre-existing condition defined by the absence of any (even transitory) beneficial effect of an anti-angiogenic therapy, ranging from the inability to shrink or stabilize tumours to the lack of improvement in quality of life. Consequently tumours grow and progress unabated during the course of anti-angiogenic therapy. VEGF, vascular endothelial growth factor.

Figure 2. Induced pro-angiogenic factor substitution re-establishes tumour neovascularization

Activation and/or upregulation of other pro-angiogenic signalling pathways, including those involving members of the fibroblast growth factor (FGF), ephrin and angiopoietin families, can circumvent the anti-angiogenic therapy and, in due course, provoke neovascularization and subsequent tumour relapse.

Figure 3. Recruitment of bone marrow-derived cells can endorse restored neovascularization

Low oxygen conditions in tumours (hypoxia), acting in part through induced increases in hypoxia-inducible factor 1α and its targets stromal cell-derived factor 1α and vascular endothelial growth factor, can attract a heterogeneous population of bone marrow-derived cells consisting of vascular progenitors and pro-angiogenic monocytic cells. Endothelial and pericyte progenitors are incorporated as components of new vessels to directly build new blood vessels, and pro-angiogenic monocytes fuel the tumours with pro-angiogenic cytokines, growth factors and proteases, all of which facilitate neovascularization.

Figure 4. Increased pericyte coverage protects tumour blood vessels

Although inhibition of vascular endothelial growth factor signalling pathways can lead to vessel regression, a few ‘normal-appearing’ slim and functional vessels remain; these vessels are densely and tightly covered with pericytes, and are markedly distinct from the vessels that are seen in tumours of untreated animals, which are typically dilated, tortuous and irregularly shaped, and variably covered with less closely associated pericytes. Such coating by pericytes arguably helps the tumour endothelium to survive and function, and thereby enables tumours to grow (perhaps more slowly) during the course of an anti-angiogenic therapeutic regimen.

Figure 5. Increased tumour cell invasiveness to escape oxygen and nutrient deprivation

When tumours are not able to satisfactorily reinitiate angiogenesis, tumour cells may invade adjacent normal tissue to achieve vascular sufficiency in a dispersed fashion. Tumour cells can migrate along the outside of blood vessels (perivascu lar invasion), using them as conduits into normal tissue, or infiltrate through the extracellular matrix. In either case they depend on normal vasculature for sustenance.