DIFFERENTIAL REGULATION OF FOLATE RECEPTOR ISOFORMS IN NORMAL AND MALIGNANT-TISSUES IN-VIVO AND IN ESTABLISHED CELL-LINES - PHYSIOLOGICAL AND CLINICAL IMPLICATIONS

Background. Despite significant differences in ligand binding between the two known isoforms of the human membrane folate receptor (FR), des ignated herein as FR-beta (placenta) and FR-alpha (placenta, KB cells) , little is known about their tissue specificities, and there is no re port on the relative expression of FR-beta in any tissue other than in placenta. Methods. The mRNA for each FR isoform in a wide variety of normal fetal and adult tissue explants, primary normal cell cultures, malignant tumor explants, and established tumor cell lines was estimat ed by a polymerase chain reaction assay. Total receptor levels were es timated by a [H-3] folic acid binding assay. Results. Both the FR isof orms were expressed in fetal as well as adult tissues. Normal tissues generally expressed low to moderate amounts of FR-beta FR-alpha alone was expressed in normal epithelial cells and was frequently strikingly elevated in a variety of carcinomas, with the exception of squamous c ell carcinomas of the head and neck. In contrast, a variety of maligna nt tissues of nonepithelial origin generally expressed elevated levels of FR-beta alone. Established tumor cell lines expressed FR-alpha vir tually alone and did not reflect FR expression patterns in vivo. KB ce lls and JEG-3 cells grown at low folate concentrations further up-regu lated FR-alpha but not FR-beta. Conclusions. Although FR-beta is the m ore common isoform, FR-alpha and FR-beta are differentially regulated in normal tissues, carcinomas, nonepithelial malignancies, and immorta lized cells or in response to changes in extracellular folate concentr ations. The tissue specificity of FR isoforms and their elevation in m alignant tissues may be a significant factor in FR-mediated folate upt ake, in tissue responsiveness to promising novel antifolates, and in F R-related immunodiagnosis/immunotherapy.