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The Folate Receptor Is Frequently Overexpressed in Osteosarcoma Samples and Plays a Role in the Uptake of the Physiologic Substrate 5-Methyltetrahydrofolate

Authors' Affiliations: ¹ Department of Pediatrics and Molecular Pharmacology, The Albert Einstein College of Medicine, The Children's Hospital at Montefiore, Bronx, New York and Departments of ² Epidemiology and Biostatistics, ³ Pediatrics, and ⁴ Pathology, and ⁵ Orthopedic Surgery Service, Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Richard Gorlick, Department of Pediatrics, The Children's Hospital at Montefiore, 3415 Bainbridge Avenue, Rosenthal 3rd Floor, Bronx, NY 10467. Phone: 718-741-2333, Fax: 718-920-6506; E-mail: rgorlick{at}montefiore.org.

Purpose: Two major systems exist for folate cell entry: the reduced folate carrier (RFC) and the folate receptor (FR). Although defective RFC-mediated transport was frequently identified as a mechanism of methotrexate (MTX) resistance in osteosarcoma, the status of FR and its role in this disease are unknown.

Experimental Design: mRNA for FR was measured in 107 osteosarcoma specimens using quantitative reverse transcription-PCR and was related to RFC expression. The effect of FR overexpression on MTX resistance and natural folate uptake was studied using FR non-expressing osteosarcoma 143B cells transfected with FR cDNA in comparison with those transfected with sense or antisense RFC in the same genetic background.

Results: Eighty-four samples (78.5%) had detectable FR mRNA, and 29.9% had higher levels than the ovarian cancer cell line SKOV-3. No correlation was found between mRNA levels of FR and RFC (r² = 0.002). FR overexpression had minor effects on the transport of MTX and sensitivity to this drug. Among the transfected 143B sublines, only the 143B-FR was able to uptake 5-methyltetrahydrofolate when the extracellular concentration was reduced to 2 nmol/L, which conferred a growth advantage in physiologic folate concentrations compared with vector-only–transfected cells. Importantly, this was not similarly achieved by RFC overexpression.

Conclusions: This study suggests that FR plays a role in the uptake of 5-methyltetrahydrofolate when the concentration gradient is insufficient for RFC-mediated transport. FR overexpression is unlikely secondary to the decreased RFC expression in osteosarcoma.

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