Endothelial Progenitor Cell Counts Predict Liver Cancer Prognosis

HONG KONG, Oct. 5 -- Higher levels of bone marrow-derived endothelial progenitor cells in patients with hepatocellular carcinoma signal the likelihood of unresectable disease, according to researchers here.

"Our evidence supports the potential use of circulating level of endothelial progenitor cells as a prognostic marker in patients with hepatocellular carcinoma," wrote Ronnie T.P. Poon, M.D., at the University of Hong Kong, and colleagues, in the October issue of Hepatology.

In a comparison study, the authors found that patients with liver cancer had significantly higher levels of the progenitor cells in circulation than either patients with cirrhosis or healthy people.

"Our data suggest that further studies are worthwhile to validate the prognostic value of circulating endothelial progenitor cell levels in patients with hepatocellular carcinoma, and to explore possible therapeutic strategies against hepatocellular carcinoma by targeting bone marrow mobilization of endothelial progenitor cells," Dr. Poon and colleagues concluded.

The elevated levels of endothelial progenitor cells may be a marker for the aggressive angiogenesis that is a hallmark of hepatocellular carcinoma pathology, the authors suggested.

"Tumor neovascularization requires recruitment and proliferation of endothelial cells," they wrote. "Traditionally, it was thought that the original source of the recruitment of endothelial cells came from neighboring endothelial cells in adjacent normal tissues. However, recent studies have overturned such paradigm by demonstrating that endothelial progenitor cells are mobilized from bone marrow by cytokines such as vascular endothelial growth factor, migrate via peripheral blood, and home to the site of tumor neovascularization."

To determine whether circulating bone marrow-derived endothelial progenitor cell levels correlated with the aggressiveness of the tumor, the authors enrolled 80 patients (44 men, 36 women, mean aged 57.6 years, range 31-82 years). They also recruited 16 patients with liver cirrhosis for comparison purposes, and 14 healthy volunteers as controls.

All blood samples were taken before treatment. In all, 27 of the 80 patients with liver cancer had resectable disease and underwent curative surgery shortly after collection of blood samples for the study; 17 of these patients were followed for at least one year for disease-free survival.

The patients were followed with serum alpha-fetoprotein levels, chest x-ray, and contrast CT scan every three months for signs of tumor recurrence. The other 53 patients had unresectable disease and were treated palliatively.

The investigators isolated total mononuclear cells from peripheral blood and pre-plated them to eliminate mature circulating endothelial cells. They them determined endothelial progenitor cell levels by count colony-forming units formed by circulating progenitor cells.

They also used flow cytometry with CD133, vascular endothelial growth factor receptor-2 (VEGFR2) and CD34 as cellular markers to verify their manual counts of colony-forming units in 30 cases.

They found that blood from patients with hepatocellular carcinoma contained significantly higher mean colony-forming units than blood from cirrhosis patients (P=0.001) or controls (P=0.009). In addition, the colony-forming unit scores correlated positively in patients with cancer with levels of serum AFP (r=0.303, P=0.017), plasma VEGF (r=0.242, P=0.035), and plasma interleukin-8 (r = 0.258, P= 0.025).

Patients with unresectable hepatocellular carcinoma had higher colony-forming unit scores than patients with resectable tumors (P= 0.027).

And among patients who underwent presumably curative surgery, those who had recurrence within one year had significantly higher levels of endothelial progenitor cells at baseline compared with similar patients who remained disease-free over the same period (P=0.013).

Furthermore, for those who underwent curative surgery, higher preoperative colony-forming unit scores were observed in patients with recurrence within one year compared with those who were disease-free after one year (P = .013).

The authors suggested that a study with a much larger cohort in the surgical group with serial collection of blood samples over a longer follow-up period should be carried out to further confirm the prognostic significance of hepatocellular carcinoma.