The importance of tissue environment surrounding the tumor on the development of cancer cachexia.

The relationship between host factors and cancer cachexia was investigated. A single cell clone (clone 5 tumor) established from colon 26 adenocarcinoma by limiting dilution cell cloning methods was employed to eliminate the inoculation site-dependent differences in the composition of cell clones. Clone 5 tumor did not provoke manifestations of cancer cachexia when inoculated in subcutaneous tissue. However, when inoculated in the gastrocnemius muscle, the peritoneal cavity or the thoracic cavity of CD2F1 male mice, typical manifestations of cancer cachexia were observed in all groups of mice with intergroup variations. The blood levels of various cytokines, chemokines and hormones were increased but with wide intergroup variations. Analyses by stepwise multiple regression models revealed that serum interleukin-10 was the most significant factor associated with manifestations of cancer cachexia, suggesting the possible involvement of mechanisms similar to cancer patients suffering cancer cachexia. White blood cells, especially neutrophils, seemed to have some roles on the induction of cancer cachexia, because massive infiltrations and an increase in peripheral blood were observed in cachectic mice bearing clone 5 tumors. The amount of malonyl-CoA in liver correlated with manifestations of cancer cachexia, however the mRNA levels of spermidine/spermine N-1 acetyl transferase (SSAT) (of which overexpression has been shown to provoke manifestations similar to cancer cachexia) were not necessarily associated with cancer cachexia. These data suggest that the induction of cancer cachexia depends on the environment in which the tumor grows and that the infiltration of host immune cells into the tumor and the resultant increase in inflammation result in the production of cachectic factors, such as cytokines, leading to SSAT activation. Further, multiple factors likely mediate the mechanisms of cancer cachexia. Finally, this animal model was suitable for the investigation of the mechanisms involved in cachexia of cancer patients.