title: Parathyroid hormone-related protein: potential therapeutic target for melanoma invasion and metastasis.
abstract: The role of PTHrP in the highly metastatic human melanoma disease is not known. This study investigates the mechanisms of action of this secreted factor through homozygous inactivation of the Pthrp gene in A375 human melanoma cells. In vitro, Pthrp-ablated cells (knockout [KO]-A375, -/-) showed decreased motility and anchorage-independent growth, rounder morphology, and a significant reduction in invasion capacity compared with nonablated A375 cells (wild-type [WT]-A375, +/+). PTHrP peptide 1-34 and conditioned medium from WT-A375 cells partially restored the invasive phenotype in KO-A375. Pthrp ablation substantially decreased actin polymerization, matrix metallopeptidase 9 expression and focal adhesion kinase phosphorylation. In vivo, green fluorescent protein-transduced ablated and nonablated A375 cells were injected intracardially or sc into nude mice to study proliferation and multiorgan metastasis. Dissemination of injected Pthrp-ablated cells to lung and liver was reduced by 85% and 50%, respectively, compared with nonablated controls (120 hours after injection). The number of metastatic lesions and the percentage of animals with metastasis were markedly lower in mice injected with Pthrp-ablated A375, and 45% of these animals survived a 7-week period compared with 15% of mice injected with nonablated WT-A375. When mice injected with WT-A375 were treated with our blocking anti-PTHrP monoclonal antibody raised against the first 33 amino acids of human PTHrP, tumor size was decreased by more than 80% over 4 weeks and survival was significantly improved over 8 months. This study provides direct evidence of the major role for PTHrP in melanoma invasion and metastasis and suggests that agents that suppress PTHrP may be beneficial against melanoma progression.
authors: Department of Medicine, Calcium Research Laboratory, Royal Victoria Hospital, Montréal, Québec, Canada, H3A 1A1.
authors: Dao Chao
authors: DC
authors: Huang
authors: Xian Fang
authors: XF
authors: Yang
authors: Benoît
authors: B
authors: Ochietti
authors: Ibtihal
authors: I
authors: Fadhil
authors: Anne
authors: A
authors: Camirand
authors: Richard
authors: R
authors: Kremer
mesh_terms: D000818:Animals; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D044162:Parathyroid Hormone-Related Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D044162:Parathyroid Hormone-Related Protein; D034741:RNA, Small Interfering