Regular Article
Cancer Cells Responsible for Humoral Hypercalcemia Express mRNA Encoding a Secreted Form of ODF/TRANCE That Induces Osteoclast Formation

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Abstract

A novel cDNA encoding a secreted form of osteoclast differentiation factor/tumor necrosis factor-related activation-induced cytokine (sODF/TRANCE, GenBank Accession No. AB037599) was sequenced from 5′ RACE cDNA clones of squamous cell carcinoma cell lines, SCC-4 and T3M-1 Cl.2, of which parental malignant tissues had caused severe humoral hypercalcemia. The sODF/TRANCE cDNA was composed of unknown 5′ end sequence followed by the 100% identical sequence of the ODF/TRANCE extracellular domain-coding region. The longest open reading frame (ORF) of the novel cDNA completely matched the 3′ end of the ORF of the ODF/TRANCE cDNA encoding C-terminal amino acid residues (74–318) in the extracellular region. The corresponding protein that reacted with the antibody specific for the extracellular domain of ODF/TRANCE was detected in the culture media conditioned by the cancer cells. Furthermore, human promyeloblastic leukemia cells, HL60, differentiated into osteoclast-like cells (OCLs) when cultured in the media conditioned by SCC-4 and T3M-1 Cl.2 cells. The differentiation of HL60 cells into OCLs was inhibited by the anti-ODF/TRANCE antibody. These results strongly suggest that sODF/TRANCE plays an important role in enhanced bone-resorption in humoral hypercalcemia of malignancy.

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    Abbreviations used: ODF, osteoclast differentiation factor; TRANCE, tumor necrosis factor-related activation-induced cytokine; sODF/TRANCE, soluble fragment of ODF/TRANCE; ORF, open reading frame; OCL(s), osteoclast like cell(s); TNF, tumor necrosis factor; OPGL, osteoprotegerin ligand; RANKL, receptor activator of NF-kB ligand; HHM, humoral hypercalcemia of malignancy; PTHrP, parathyroid hormone-related protein; FBS, fetal bovine serum; RACE, rapid amplification of cDNA ends; Ab, antibody; CT-R, calcitonin receptor; RANK, receptor activator of NF-κB; nt, nucleotide

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