Angiogenesis: from chronic liver inflammation to hepatocellular carcinoma

Abstract

Recently, new information relating to the potential relevance of chronic hepatic inflammation to the development and progression of hepatocellular carcinoma (HCC) has been generated. Persistent hepatocellular injury alters the homeostatic balance within the liver; deregulation of the expression of factors involved in wound healing may lead to the evolution of dysplastic lesions into transformed nodules. Progression of such nodules depends directly on the development and organization of a vascular network, which provides the nutritional and oxygen requirements to an expanding nodular mass. Angiogenic stimulation promotes intense structural and functional changes in liver architecture and physiology, in particular, it facilitates transformation of dysplasia to nodular lesions with carcinogenic potential. HCC depends on the growth and spreading of vessels throughout the tumor. Because these vascular phenomena correlate with disease progression and prognosis, therapeutic strategies are being developed that focus on precluding vascular expansion in these tumors. Accordingly, an in-depth study of factors that promote and support pathological angiogenesis in chronic hepatic diseases may provide insights into methods of preventing the development of HCC and/or stimulating the regression of established HCC.

Figure 1

Angiogenic switch: transformed cells proliferate as an avascular nodule until they reach a certain size. Angiogenic switch enables exponential tumor growth and facilitates dissemination of tumor cells to secondary locations, where pathological angiogenesis may again be initiated.

Figure 2

Oxygen-dependent regulation of HIF-1α: in normal oxidative conditions, HIF-1α is hydroxylated and it becomes ubiquitinated by VHL. Subsequently, HIF-1α  is degraded by the proteasome. In contrast, low oxygen tension leads to stabilization of HIF-1 and its interaction with beta subunit, which triggers translocation to the nucleus and modulation of the transcription of diverse genes that are involved in the response to hypoxia.

Figure 3

Innate immunity-driven angiogenesis: immune cells, mostly neutrophils and monocyte-macrophages, mediate initial tunnel formation in certain models of angiogenesis. Other myeloid cell types, such as dendritic cells (DCs) and natural killer cells (NK), produce angiogenic factors that attract endothelial cells that become essential components of developing blood vessels. Adapted from Noonan et al., 2008.

Figure 4

Stages of angiogenesis: angiogenic stimuli, by promoting production of NO and VEGF, lead to dilatation and increased permeability of blood vessels. Subsequently, other factors, particularly Ang-1, TGF-β, and MMPs, facilitate degradation of basement membrane and extracellular matrix and detachment of pericytes. Consequently, angiogenic stimuli facilitate proliferation and migration of endothelial cells. In addition, mesenchymal cells proliferate and differentiate into pericytes and smooth muscle cells that contribute to the stabilization of the new blood vessels.

Figure 5

Hepatic angiogenesis: during liver regeneration, newly formed sinusoids have normal architecture consistent with their physiological roles. In contrast, pathological hepatic angiogenesis leads to the capillarization of hepatic sinusoids with the result that the structure of sinusoids becomes distorted and characteristic endothelial fenestrations are lost.