Targeting the vasculature in hepatocellular carcinoma treatment: Starving versus normalizing blood supply

Abstract

Traditional treatments for intermediate or advanced stage hepatocellular carcinoma (HCC) such as transarterial chemoembolization (TACE) and anti-angiogenesis therapies were developed to starve tumor blood supply. A new approach of normalizing structurally and functionally abnormal tumor vasculature is emerging. While TACE improves survival in selected patients, the resulting tumor hypoxia stimulates proliferation, angiogenesis, treatment resistance and metastasis, which limits its overall efficacy. Vessel normalization decreases hypoxia and improves anti-tumor immune infiltrate and drug delivery. Several pre-clinical agents aimed at normalizing tumor vasculature in HCC appear promising. Although anti-angiogenic agents with vessel normalizing potential have been trialed in advanced HCC with modest results, to date their primary intention had been to starve the tumor. Judicious use of anti-angiogenic therapies is required to achieve vessel normalization yet avoid excessive pruning of vessels. This balance, termed the normalization window, is yet uncharacterized in HCC. However, the optimal class, dose and schedule of vascular normalization agents, alone or in combination with other therapies needs to be explored further.

Figure 1

Structure of normal vessels vs. tumor vessels in the liver sinusoid. (a) In healthy liver sinusoids, the endothelium is regular, fenestrated and lacks a basement membrane. Hepatic stellate cells remain in a quiescent state. (b) In hepatocellular carcinoma, the endothelium is thickened and loses its fenestrations while a discontinuous basement membrane is formed through a process called capillarization. Tumor cells form the vessel wall in some areas. Hepatic stellate cells become activated and release vascular endothelial growth factor as well as other angiogenic factors. These vessels are structurally and functionally abnormal.

Figure 2

Vicious cycle of hypoxia, non-productive angiogenesis and tumor growth. Angiogenesis is required for a tumor to grow beyond a few millimeters. However, this neovascularisation produces abnormal leaky vessels which give rise to interstitial hypertension, edema and tumor hypoxia. Although some treatments (e.g., TACE) aim to achieve hypoxia in order to kill the tumor by starvation, hypoxia has been demonstrated to stimulate further angiogenesis and tumor growth through a variety of mechanisms (see text: Limitations of TACE and the effect of tumor hypoxia). HIF-1α, hypoxia-inducible factor 1α IGF-2, insulin-like growth factor-2; MDSC, myeloid-derived suppressor cell; MMP, matrix metalloproteinases; TACE, transarterial chemoembolization; VEGF, vascular endothelial growth factor.