Angiogenesis soluble factors as hepatocellular carcinoma noninvasive markers for monitoring hepatitis C virus cirrhotic patients awaiting liver transplantation.

BACKGROUND: Physiological angiogenesis occurs during liver regeneration, leading to the formation of new functional sinusoids. Pathological angiogenesis occurs in hepatocellular carcinoma (HCC). We aimed to evaluate the expression of angiogenic factors in hepatitis C virus (HCV)-HCC tissues and the utility of angiogenesis soluble factors as noninvasive markers of HCC and tumor growth. METHODS: Thirty-eight HCV-HCC tumors with 10 corresponding nontumor cirrhotic tissues, as well as 42 independent HCV cirrhotic and 6 normal liver tissues were studied using high-density oligonucleotide arrays. Human angiogenesis microarray was used for the protein detection of EGF, TIMP-1, TIMP-2, HGF, angiopn-1, angiopn-2, VEGF-A, IP-10, PDGF, KGF, angiogenin, VEGF-D, ICAM-1, and FGF in plasma samples from 40 patients (30 HCCs and 10 HCV cirrhosis). RESULTS: From the gene expression analysis of the HCV-HCC tumors compared to normal livers, we found an important number of genes related to angiogenesis differentially expressed (alpha=0.01), including VEGF, PDGF, AGPTL2, ANG, EGFL6, EGFR, angiopn-1, angiopn-2, ICAM2, TIMP-2, among others. Moreover, angiogenic genes were also differentially expressed when HCV-HCC samples were compared to HCV cirrhotic tissues (alpha=0.01; VEGF, EGFL3, EGFR, VEGFB, among others). Ten out of 14 angiogenic proteins analyzed were statistically differentially expressed between HCV cirrhosis and HCV-HCC groups (TIMP-1, TIMP-2, HGF, angiopn-1, angiopn-2, VEGF-A, IP-10, PDGF, KGF, and FGF; P<0.05). In addition, we observed that angiopn-2 was the most significant predictor (area under the curve: 0.83). CONCLUSION: Differentially expressed angiogenesis genes were observed between HCV patients with and without HCC. Soluble angiogenic factors might be useful for monitoring high-risk HCV patients.

Genes associated with progression and recurrence of hepatocellular carcinoma in hepatitis C patients waiting and undergoing liver transplantation: preliminary results.

BACKGROUND: Liver transplantation (LT) represents a curative treatment for small hepatocellular carcinoma (HCC). Potentially curable higher-stage HCC patients are denied LT due to the lack of cancer markers that predict progression and recurrence. METHODS: Thirty-eight candidates for LT with hepatitis C virus (HCV) cirrhosis and HCC were studied. Gene expression (Gexp) analysis of tumor samples was performed using microarrays. RESULTS: Twenty patients underwent transplantation, 13 progressed while waiting for transplantation, 4 are alive awaiting transplantation, and 1 died without progression while waiting for LT. Differences in GExp among patients who underwent LT or did not progress (n=25) versus those whose disease progressed while waiting for LT (n=13) were assessed. Thus, 54 probe sets (Pset) were significantly differentially expressed. Among LT patients, 10 Psets were differentially expressed between LT patients with the same explanted stage that recurred (n=5) versus LT patients who did not recur (n=5). Ninety-eight Psets were significantly associated with survival at the alpha=0.005 level. CONCLUSIONS: Here, we have identified genes associated with HCC progression in HCV-HCC patients awaiting LT transplantation. A limited number of genes were related to overall survival and cancer-free survival after LT. Incorporation of these molecular markers could help to improve organ allocation for HCV-HCC patients.