**Abstract**

Hepatocarcinoma is one of the most common lethal human malignant tumors, mainly because of active angiogenesis. This kind of high angiogenesis often accounts for early metastasis, rapid recurrence, and poor survival. Growing evidence has proved that hepatocarcinoma angiogenesis is closely associated with multiple risk factors, such as DNA damages resulting from hepatitis B and C virus infection, aflatoxin B1 exposure, ethanol intake, and obesity. Genetic alterations and genomic instability, probably resulting from low DNA damage repair response (DRR) and the following unrepaired DNA lesions, are also increasingly recognized as important risk factors of hepatocarcinoma angiogenesis. Dysregulation of DRRs and signaling to cell cycle checkpoints involving in DRR pathways may accelerate the accumulation of DNA damages and trigger the dysregulation of angiogenesisrelated genes and the progression of hepatocarcinoma. In this review, we discussed DNA damages/DRRs and angiogenesis during hepatocarcinogenesis and their interactive regulations. Hopefully, the review will also remind the medical researchers and clinic doctors of further understanding and validating the values of DNA damages/DRRs in hepatocarcinoma angiogenesis.

**Keywords:** hepatocarcinoma, angiogenesis, DNA damage, DNA damage repair response

## **1. Introduction**

 Hepatocellular carcinoma, also termed as hepatocarcinoma, is one of the most common malignant tumors, with more than 500,000 new cases per year [1]. Until recently, it has been frequent to consider hepatocarcinoma as a tumor with low incidence in the western world but with high incidence in the eastern countries [1]. However, increasing data exhibit that the incidence of this tumor has increased in both western and eastern countries. Etiologically, several risk factors, including hepatitis B virus (HBV), hepatitis C virus (HCV), aflatoxin B1 (AFB1), and alcohol, have been identified for increasing disease incidence worldwide [2]. Although molecular mechanisms of hepatocarcinoma caused by these risk factors have not still been clear, chronic and permanent liver damage and damage response may play a vital role. Macrocosmically, liver damage consists of a series of pathological changes, such as chronic hepatitis, liver cirrhosis, nodular hyperplasia, and

dysplasia [3]. Microcosmically, chronic DNA damage, including the formation of DNA adducts, DNA strand break and bulk, gene mutations, and genomic instability, is the most important type [4].

 Because of early blood metastasis and high death rate of this malignancy, it has become the third most common cause of cancer-associated deaths worldwide. This death risk could be explained by high angiogenesis capacities of hepatocarcinoma [1, 2]. Increasing evidence has exhibited that hepatocarcinoma patients with high microvessel density (MVD) in tumor tissues would feature a poor prognosis, and angiogenesis has been regarded as an important marker predicting the risk of invasiveness and metastasis [5]. This chapter summarizes the latest findings in hepatocarcinoma angiogenesis, DNA damage, and damage repair response (DRR). We also try to shed light on the effects of DNA damage and dysregulation of DRR on tumor angiogenesis.
