METASTATIC DISEASE IN PEDIATRIC CANCER SHOWS HIGH LEVELS OF PROGENITOR ENDOTHELIAL CELLS

July 21, 2009 — Endothelial progenitor cells might play a pivotal role in metastatic disease progression among pediatric patients with solid tumors. The research, published in the July 15 issue of Clinical Cancer Research, is the first to evaluate circulating endothelial cells, bone-marrow-derived (BMD) endothelial progenitor cells, and angiogenic plasma proteins in the peripheral blood of pediatric cancer patients.

The findings of the study showed that there were increased levels of circulating vascular endothelial growth-factor receptor (VEGFR) BMD progenitor cells in pediatric patients with metastatic solid malignancies. "Not only were these cells found in higher levels in patients [than in] healthy volunteers, but endothelial progenitor cells were found in strikingly higher amounts in patients with metastatic disease," said author Françoise Farace, PhD, from the Institut Gustave Roussy in Villejuif, France, in a statement.

"Understanding these vascular precursor cells and seeing the changes over time may represent a real strategy for helping to identify drugs that might work in the pediatric population," noted James L. Abbruzzese, MD, FACP, chair of the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston.

"Insights as to which patients are likely to develop metastases may help us to identify a subset of patients that require more extensive therapy," he added.

Dr. Abbruzzese, who was not involved with the study, is also deputy editor of Clinical Cancer Research. In a statement, he pointed out that one challenge with this study was defining the characteristics of these cells, which can be more difficult to accomplish in a pediatric population because drawing a large volume of blood is not an easy task.

Cells Play Pivotal Role in Metastatic Disease Progression

Pediatric patients with solid tumors generally have better outcomes than adults, but the prognosis for those with metastatic or relapsed disease is poor. Therefore, the authors note, novel therapeutic approaches are urgently needed to improve prognosis for these patients. One possible strategy is antiangiogenic therapy, which has emerged as "one of the most significant advances in clinical oncology." Although most of the studies to date have focused on adult oncology patients, antiangiogenesis represents a potential therapeutic strategy for pediatric patients as well.

Solid tumors in pediatric patients display a strong angiogenic profile because they are nearly exclusively undifferentiated tumors characterized by high proliferation rates and increased vascularity, the researchers explain. In addition, preliminary data support the potential role of antiangiogenic agents in treating this population, and have shown the pivotal role of BMD progenitor cells in metastatic disease progression.

As a prerequisite to clinical trials with antiangiogenic therapy, Dr. Farace and colleagues evaluated the role of endothelial cells and progenitors in pediatric cancer patients. They drew blood samples from 23 children with localized cancer, 22 with metastatic disease, and 20 healthy children.

Subsets of circulating VEGFR2⁺ BMD progenitor cells, defined as CD45^–CD34⁺VEGFR2(KDR)⁺7AAD^– and CD45^dimCD34⁺VEGFR2⁺7AAD^– events, were measured in progenitor-enriched fractions by flow cytometry. They also measured mature circulating endothelial cells in whole blood as CD31⁺CD146⁺CD45^–7AAD^– viable events, and then correlated the data with plasma levels of vascular endothelial growth factor and the soluble form of VEGFR2 (sVEGFR2).

The researchers observed that "strikingly high levels of BMD endothelial progenitors" correlated with metastatic disease. The CD45^–CD34⁺VEGFR2(KDR)⁺7AAD^– subset represented less than 0.003% of circulating BMD progenitor cells, but the median level was higher in cancer patients than in healthy controls (1.5% [0%–10.3%] vs 0.3% [0%–1.6%] of circulating BMD progenitors; P < .0001). There was also a significant difference in levels of CD45^–CD34⁺VEGFR2(KDR)⁺7AAD^– when patients with localized disease were compared with those who had metastatic disease (0.7% [0%–8.6%] vs 2.9% [0.6%–10.3%] of circulating BMD progenitor cells; P < .001).

The median value of mature circulating endothelial cells value (7 [0–152] cells/mL) was similar in all 3 groups, and circulating endothelial cells, VEGF, or sVEGFR2 plasma levels did not correlate with disease status.

"These results support and extend recent preclinical findings indicating that these cells may play a pivotal role in metastatic disease progression," write the authors. These data suggest that "monitoring and targeting of BMD endothelial progenitor cells could be of interest to guide the optimal use of antiangiogenic treatments in patients with pediatric solid malignancies," they add.

The study was supported by grants from the Association pour la Recherche sur le Cancer and the Société Française des Leucémies et Cancers de l'Enfant. The authors have disclosed no relevant financial relationships.

Clin Cancer Res. 2009;15:4561-4571. Abstract