title: Involvement of cyclooxygenase-2 in the tumor site-dependent production of parathyroid hormone-related protein in colon 26 carcinoma.
abstract: It has been shown that in the mouse colon 26 tumor model, tumors grown in the subcutis (subcutis colon 26) caused early onset of cachectic syndromes, whereas those in the liver (liver colon 26) did not. Both interleukin (IL)-6 and parathyroid hormone-related protein (PTHrP) were involved in the development of cachectic syndromes in this tumor model. However, whether expression of PTHrP and IL-6 is differently regulated in the tumor microenvironment is unclear. In the present study, culturing the colon 26 cells under different conditions in vitro revealed that IL-6 production was increased by monolayer culture under a low-glucose condition but not by spheroid culture. In contrast, PTHrP production was increased by spheroid culture but not by monolayer culture, even under a low-glucose condition. Gene expression profiling revealed that the expression of cyclooxygenase (COX)-2 was up-regulated in both subcutis colon 26 and spheroid cultures, and that COX-2 inhibitor NS-398 suppressed PTHrP production in spheroid cultures. Furthermore, administration of NS-398 decreased the PTHrP level without affecting the tumor growth in mice bearing subcutis colon 26. These results demonstrate that production of PTHrP and IL-6 largely depends on the microenvironments in which tumors are developed or metastasized and that up-regulation of COX-2 in a necrobiotic environment leads to PTHrP production, thereby causing cachectic syndromes.
authors.affiliation: Pharmaceutical Research Department III, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Saito
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Inagaki
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tsunenari
authors.forename: Masako
authors.initials: M
authors.lastname: Ura
authors.forename: Hideaki
authors.initials: H
authors.lastname: Mizuno
authors.forename: Kaori
authors.initials: K
authors.lastname: Fujimoto-Ouchi
authors.forename: Etsuro
authors.initials: E
authors.lastname: Onuma
authors.forename: Koh
authors.initials: K
authors.lastname: Sato
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ogata
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Yamada-Okabe
mesh_terms: D000818:Animals; D000077214:Becaplermin; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002100:Cachexia / Q000209:etiology; D002118:Calcium / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D009336:Necrosis; D009578:Nitrobenzenes / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D016861:Cyclooxygenase Inhibitors; D015850:Interleukin-6; D009578:Nitrobenzenes; D044162:Parathyroid Hormone-Related Protein; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D000077214:Becaplermin; D051546:Cyclooxygenase 2; D005947:Glucose; D002118:Calcium