Abstract
The role for the hypoxia-inducible angiogenic factor adrenomedullin (AM) in tumor growth and progression has been suggested. Calcitonin receptor-like receptor (CL) is a G protein-coupled receptor (GPCR) that mediates effects of AM, but little information is available on its expression and functional state in human tumors. The present study attempted to determine CL potential for antiangiogenic therapy of uterine leiomyoma. GPCR CL is transported to the cell surface and recognized by AM only when terminally/mature glycosylated. The presence and localization of this form of the receptor in tumor and surrounding myometrial tissues obtained from leiomyoma-bearing uteri were examined using deglycosylation, immunoblotting, and immunofluorescence analysis. The mature CL glycoprotein was expressed in both tissues and localized exclusively in normal and tumor endothelium within leiomyoma-bearing uteri. The functionality of the receptor expressed in myometrial microvascular endothelial cells (MMVEC) was examined in vitro using receptor internalization and angiogenic assays. The mature CL glycoprotein expressed by primary MMVECs was functional because AM interacted with this GPCR and induced its internalization as well as angiogenic effects (proliferation and migration) in MMVECs in vitro. Finally, the levels of tissue-expressed mature CL glycoprotein as a functional form of this GPCR were analyzed by immunoblotting. The expression of this functional form of the receptor in vivo was significantly decreased (P = 0.01) in leiomyoma tissue, and this was concurrent with the decrease in microvascular density (measured by Chalkley counting) in tumor compared with surrounding myometrium (P = 0.031). Our findings suggest that GPCR CL mediates angiogenic effects of AM in myometrium and that further evaluation of the properties of the CL expressed in both normal and tumor endothelium in vivo may be essential before targeting this endothelial GPCR for antiangiogenic therapies.
Highlights
The role for the hypoxia-inducible angiogenic factor adrenomedullin (AM) in tumor growth and progression has been suggested
It follows that the presence of the mature CL glycoprotein in these tissues suggests the functional state of the receptor expressed in vivo [20, 23]
Because expression of mature CL glycoprotein was down-regulated in fibroids and because RAMPs are essential for terminal glycosylation, cell surface targeting, and ligand-binding selectivity of this G protein ^ coupled receptor (GPCR) [18], we studied the expression of RAMPs
Summary
The role for the hypoxia-inducible angiogenic factor adrenomedullin (AM) in tumor growth and progression has been suggested. Conclusions: Our findings suggest that GPCR CL mediates angiogenic effects of AM in myometrium and that further evaluation of the properties of the CL expressed in both normal and tumor endothelium in vivo may be essential before targeting this endothelial GPCR for antiangiogenic therapies. Functional GPCR CL in Uterine Leiomyoma individual tumor types/stages by defining the role for the known and novel key as well as tissue-specific angiogenic factors. This would enable the selection of a specific antiangiogenic therapy from a range of those that are currently used in clinical trials or under development as well as to determine the likelihood of its effectiveness for an individual patient [5]. No studies have been done to evaluate the expression of AM receptors in vivo within leiomyoma or any other tumors, where AM expression is up-regulated (reviewed in ref. 17)
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