Effects of chronic morphine treatment on tumor angiogenesis and growth.

Abstract

Morphine is one of the most effective analgesics commonly prescribed for the treatment of severe to moderate cancer pain. To date very little is known regarding the effect of long-term morphine treatment on tumor angiogenesis. At this time, the effect of morphine on tumor growth is contradictory and still inconclusive. As solid tumors grow, the formation of a blood supply or angiogenesis is essential. In previous studies, morphine inhibited vascular endothelial growth factor (VEGF) secretion from mice cardiomyocytes and human umbilical vein endothelial cells. VEGF is a highly potent pro-angiogeneic molecule and we therefore hypothesized morphine would also inhibit angiogenesis associated with tumor growth. In the first part of these studies we show that morphine inhibited the hypoxia-induced tumor cell expression of VEGF to significantly reduce tumor cell angiogenesis, and suppress tumor growth in vivo. Additional investigations supported the view that the effect of morphine was not due to a direct effect on tumor cell apoptosis, but instead indirectly through angiogenesis. Tumor, stromal and inflammatory cells within the tumor microenvironment all contribute to a large pool of chemoattractants that increase the recruitment of myeloid cells from peripheral blood circulation into the tumor tissues. These cells mature and differentiate into neutrophils, and macrophages that eventually result in a pro-inflammatory-like environment to support and maintain tumor growth. Considering that morphine is highly immuno-suppressive, we also hypothesized that morphine will inhibit immune cell recruitment and thus angiogenesis. In an in vivo model of cell migration and recruitment we found that morphine inhibited not only CD11b+ progenitors of inflammatory cells but also the recruitment of Tie2+/CD14+ endothelial cell precursors known to actively participate in vessel formation to tumor sites. These studies have allowed us to further understand the effects of a potent analgesic such as morphine in cancer growth. Our data support the use of morphine for pain associated with cancer. Our results support the view that morphine may not cause any further detriment in the cancer patients' quality of life but further suppress angiogenesis associated with tumor growth and progression.