Angiopoietin expression in multiple myeloma

Multiple myeloma demonstrates a progressive, and usually fatal, course, with current treatments generally producing only temporary remissions. Antiangiogenic therapies represent a potential new approach to treating this cancer. While it is well established that growth in solid tumors is dependent on angiogenesis, the role of this process in hematopoietic tumors is not fully appreciated. There is a strong correlation between increased angiogenesis and poor survival in myeloma patients. Furthermore, both cellular and circulating levels of vascular endothelial growth factor (VEGF) are often elevated in hematologic malignancies, including myeloma, and have been shown to predict for a poor outcome, lending additional support to the concept that angiogenic cytokines are involved in the growth and progression of these malignancies.

In this issue, Giuliani and colleagues (page 638) extend our knowledge of marrow angiogenesis with their report on the expression of angiopoietin-1 in myeloma cell lines and patient samples. Angiopoietin-1 (Ang-1) was found to be expressed in 47% of the patient samples examined. Bone marrow angiogenesis was examined and found to be elevated in 12 of 15 patients examined (80%), and there was a significant correlation between Ang-1 expression and microvascular density (MVD), although no such correlation was present between Ang-1 and Tie2 expression. Giuliani and colleagues were also able to demonstrate that myeloma cells could up-regulate the angiopoietin receptor Tie2 in human bone marrow endothelial cells. Conditioned medium from myeloma cell lines was capable of stimulating angiogenesis, although such stimulation did not occur in the presence of an anti-Tie2 antibody. Angiopoietins, while not believed to be involved in the initial stages of angiogenesis, are known to play an essential role. Ang-1, acting through Tie2, contributes to the stabilization of newly formed vessels via recruitment of peri-endothelial supporting cells as well as endothelial cells, whereas Ang-2, also acting through Tie2, reduces these interactions, leading to vascular regression. It has also been reported that coexpression of Ang-2 and VEGF promotes new vessel sprouting and has been shown to predict a poor prognosis in myeloma and other malignancies.

The role, if any, of angiopoietins in myeloma is far from clear, however. Uneda et al have also recently reported their findings regarding angiopoietin expression in myeloma (Haematologica. 2003;88:113-115). In their study, 27 of 36 multiple myeloma patients studied showed expression of Ang-2 by reverse transcriptase–polymerase chain reaction (RT-PCR) and immunohistochemistry. Coexpression of VEGF and Ang-2 was detected in 18 of the myeloma samples. The survival rate was significantly lower in those patients expressing Ang-2. Interestingly, and in contrast to the findings by Giuliani et al, they found no evidence of Ang-1 expression.

The seemingly contradictory findings of Ang-1 and Ang-2 expression in these 2 studies should be carefully interpreted in the context of how the cells were isolated and examined. Both studies examined relatively few patients, and in neither study was the effect of the bone marrow microenvironment on expression of these molecules fully taken into account.

Several important outstanding questions remain to be addressed. First, the apparent contradiction in the results from these 2 studies must be resolved. Does expression of Ang-1 or Ang-2 have prognostic value in myeloma? The results from Uneda et al would suggest so. Does angiopoietin expression vary with the stage of the disease? Do the angiopoietins represent valid therapeutic targets? Even if the angiopoietins are not the major driving factors in marrow angiogenesis, the results of Giuliani et al suggest that they may represent a valid target. Although it is too early to answer these questions, the preliminary evidence is tantalizing.