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See article in J. Gastroenterol. Hepatol. 2011; 26: 866–874.

Hepatocellular carcinoma (HCC), the most common primary liver malignancy, with over 660 000 new cases and 630 000 resultant deaths estimated in 2009, is the sixth most prevalent cancer and the third leading cause of cancer-related deaths worldwide.1 The lethality of HCC is apparent in its equal annual incidence and mortality, and the dismal 6–8-month median survival without treatment.2 Sorafenib, a small molecule tyrosine kinase inhibitor of Raf and intracellular vascular endothelial growth factor (VEGF) receptor,3 as the only current “standard therapy” for non-surgical, non-ablatable cases, has a 2% objective response, and improves overall survival by a mere 2–3 months.4 When detected early, surgical resection, liver transplantation, and ablative therapies can be employed, achieving 5-year survival rates up to 75%.5 However, only 10–15% of patients present with localized disease, limiting broad application. Catheter-based chemoembolization and radioembolization therapies prolong survival in selected cases, but their role is largely palliative.6 Thus, novel effective therapies are needed for this global health crisis.

HCC is one of the most vascular solid tumors, characterized by its propensity for vascular invasion and high metastatic potential. It is responsible for the high rate of early postoperative recurrence in the liver remnant or distant sites following resection. Angiogenesis plays a crucial role in all stages of tumor development: growth, invasion, and metastasis. For this reason, assessment of tumor neovascularity might provide additional prognostic information regarding the tumor biology, risk of metastasis or recurrence, and resultant patient survival.7 Thus, it might be useful in guiding the selection of HCC patients at high risk of treatment failure for neo/adjuvant therapies.

In this issue of the Journal of Gastroenterology and Hepatology, Chen et al. report that the morphological patterns of microvessel formation in HCC correlate with patient outcome following surgical resection.8 They observed that the sinusoidal type of neovasculature, rather than the capillary type, was predominantly encountered in patients with larger tumors, and predicted significantly worse disease-free and overall survivals in these patients, to whom adjuvant therapy would be most applicable., The most established reported indices of angiogenic activity in HCC are: (i) measurement of microvessel density; (ii) quantification of tumor and circulating levels of angiogenic factors; and (iii) evaluation of tumor vascularity demonstrated on angiographic imaging.

Microvessel density (MVD) is determined by counting neovasculature in tumor tissue sections after immunohistochemical staining with one or more endothelial cell markers, such as CD34, CD31, von Willebrand factor, and CD105. Controversy remains regarding which marker is most effective and comprehensive, exact methods of assessment, and at what size or stage of the tumor MVD is predictive of outcome. However, there appears to be general consensus that a correlation between high MVD and poor outcomes exists, and that MVD is an independent prognostic factor of overall and disease-free survival after the resection of HCC.9,10 As there is considerable variation in outcomes in patients of the same stage based on the current American Joint Committee on Cancer staging system for HCC, this information might be used to guide the addition of adjuvant therapy in patients with high MVD tumors. An inherent issue in MVD measurements is subjective variability and bias, even if the panel of immunohistochemical markers to apply, and the tumor region to analyze, and techniques used for measurement are standardized. MVD is most accurately employed on the whole-tumor surgical specimen after resection, limiting its predictive value to the adjuvant setting.

Circulating levels of various angiogenic factors, for example, VEGF,11 basic fibroblast growth factor (FGF),12 and angiopoietin-213 have been found to be significantly elevated in HCC patients compared with normal control or patients with benign chronic liver disease. Further, correlation has been found with higher levels of such factors and advanced tumor stage, as well as poor prognostic features, such as vascular invasion, with resultant early recurrence following resection. These serum or plasma measurements have been demonstrated to be reasonable surrogate markers of tumor overexpression of these factors. Among them, most attention has been focused on VEGF, with suggestions of ELISA-based detection of plasma VEGF levels as a biomarker to complement current screening protocols.14 Compared to MVD measurements, circulating angiogenic factor levels are less subject to observer interpretation and can be assessed prior to planned surgical resection, affording an opportunity for consideration of neoadjuvant therapy.

Another non-invasive method of assessing tumor angiogenesis is angiographic imaging of tumor vascularity. Enhancement patterns on dynamic contrast-enhanced magnetic resonance imaging have been demonstrated to be influenced by tumor angiogenesis, as corroborated by elevated VEGF expression.15 As advances in molecular imaging techniques evolve, it might be possible to identify neovascularity that signals transformation of a dysplastic nodule into an established HCC, or distinguish between HCC with high versus low metastatic potential. Angiogenic imaging will not only be useful in diagnosis and prognosis, but might also provide dynamic monitoring of tumor response to anti-angiogenic therapy.

Assessment of angiogenic activity in HCC using a combination of these angiogenic measurements might provide useful information to guide therapy. In addition to identifying patients with tumors with high-risk features for neo/adjuvant therapy, tumor angiogenic activity might predict tumor response to cytotoxic chemotherapy, radiotherapy, or catheter-based liver-directed therapy. High pretreatment serum VEGF levels in HCC patients undergoing transarterial chemoembolization (TACE) predicted poor treatment response. Post-treatment VEGF levels can also be used to monitor response to therapy.16

Anti-angiogenic therapy targeting the proliferating endothelial cells in the neovasculature of HCC provides theoretical advantages over cytotoxic agents; these advantages include low toxicity, lower rates of drug resistance, and ease of drug delivery. The VEGF pathway is the most studied. Reports abound of VEGF inhibition using neutralizing antibodies against VEGF, VEGF receptor (VEGFR), soluble VEGFR mutants or fusion proteins, and intracellular interference with silencing RNA or tyrosine kinase inhibitors. However, results from clinical trials of single-agent anti-angiogenic therapy in HCC demonstrate poor efficacy, reflecting the complexity of tumor angiogenesis.16 This has lead to trials combining anti-angiogenic therapy with cytotoxic chemotherapy and multikinase inhibitors targeting several different components along this complex pathway. An example is brivanib alaninate,17 a dual inhibitor of VEGFR and FGF receptor currently in clinical trials. FGF blockade might circumvent resistance to VEGF/VEGFR modulating agents. Combination VEGF/EGFR inhibition using bevacizumab/erlotinib regimen also shows promise, with significantly higher response rates compared to multikinase inhibitors sorafenib or sunitinib alone.18

TACE, a catheter-based regional therapy that is proven effective for HCC localized to the liver, takes advantage of the angiogenic hypervascular nature of HCC and the liver's dual blood supply. It is used in well-compensated cirrhotics with advanced or multifocal unresectable disease, or as bridging therapy to orthotopic liver transplantation. However, following embolization of the tumor supplying vessels, the surviving tumor cells express hypoxia induced factor- Iα and VEGF in response to ischemia, and this stimulates tumor revascularization with resultant treatment failure.19 The addition of anti-angiogenic therapy might enhance the therapeutic efficacy of TACE, and this is currently under investigation using sorafenib and sunitinib.

As our understanding of factors governing the behavior of tumor-associated endothelial cells improves, novel therapeutic angiogenic targets will become available for therapeutic application. One example is the observation that the overexpression of transforming growth factor-β1 in the most malignant HCC promotes migration of CD105+ tumor endothelial cells.20 Blockade of either TGF-β1 or CD105 abolished this migration, and proposed as treatment strategies. Many novel diagnostic and therapeutic applications of the angiogenic properties of HCC are anticipated.


  1. Top of page
  2. Abstract
  3. References