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. C ancer cachexia is a complex disease, and the development of cachectic syndromes does not correlate with tumor mass or metastases.(1) Several factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, leukemia inhibitory factor (LIF), interferon (IFN)-γ, and parathyroid hormone-related protein (PTHrP) are thought to cause cachectic symptoms in animal models.(2) Among these, PTHrP plays a key role in the development of cachexia. Nude rats and nude mice bearing the human lung cancer xenograft that expresses PTHrP and several inflammatory cytokines, including IL-6, develop cachectic syndromes such as body-weight loss, hypercalcemia, hypoglycemia, and hypolipidemia.(3) Administration of an anti-PTHrP antibody nearly completely cured cachectic symptoms as revealed by the restoration of body-weight gain and blood calcium, but neither affected the serum levels of IL-6 nor abolished acute-phase reactions.(3) Human cachectic cancer patients with elevated blood levels of PTHrP also showed increasing levels of multiple inflammatory cytokines, including IL-1β, IL-6, IL-8, IL-11, TNF-α, and IFN-γ.(4) Furthermore, gastroesophageal cancer patients with elevated blood PTHrP levels have been shown to have shorter survival than those with low blood PTHrP levels. (5) However, whether the expression of PTHrP and other inflammatory cytokines such as IL-6 is differently regulated in the microenvironments of tumors remains unexplored.It was demonstrated that mice with subcutaneously transplanted colon 26 (subcutis colon 26) developed cachectic symptoms, whereas those with intrahepatically transplanted colon 26 (liver colon 26) did not.(6) In addition, blood levels of PTHrP and IL-6 were elevated in mice with subcutis colon 26 (7) and both PTHrP and IL-6 have been shown to play important roles in the development of cachexia in the subcutis colon 26 model. (7,8) In the present study, the authors show that in mice bearing subcutis colon 26, PTHrP and IL-6 are differently expressed under different condition...
