Open AccessInvolvement of cyclooxygenase‐2 in the tumor site‐dependent production of parathyroid hormone‐related protein in colon 26 carcinoma
Author(s) -
Saito Hidemi,
Inagaki Yukiko,
Tsunenari Toshiaki,
Ura Masako,
Mizuno Hideaki,
FujimotoOuchi Kaori,
Onuma Etsuro,
Sato Koh,
Ogata Etsuro,
YamadaOkabe Hisafumi
Publication year - 2007
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2007.00568.x
Subject(s) - spheroid , parathyroid hormone related protein , cyclooxygenase , colorectal cancer , medicine , endocrinology , cancer research , colon carcinoma , in vitro , parathyroid hormone , pathology , chemistry , calcium , cancer , enzyme , biochemistry
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. ( Cancer Sci 2007; 98: 1563–1569)