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The phenotype and severity of cancer cachexia differ among tumor types and metastatic site in individual patients. In this study, we evaluated if differences in tumor microenvironment would affect the development of cancer cachexia in a murine model, and demonstrated that body weight, adipose tissue and gastrocnemius muscle decreased in tumor-bearing mice. Interestingly, a reduction in heart weight was observed in the intraperitoneal tumor group but not in the subcutaneous group. We evaluated 23 circulating cytokines and members of the TGF-β family, and found that levels of IL-6, TNF-α and activin A increased in both groups of tumor-bearing mice. Eotaxin and G-CSF levels in the intraperitoneal tumor group were higher than in the subcutaneous group. Atrogin 1 and MuRF1 mRNA expressions in the gastrocnemius muscle increased significantly in both groups of tumor-bearing mice, however, in the myocardium, expression of these mRNAs increased in the intraperitoneal group but not in subcutaneous group. Based on these results, we believe that differences in microenvironment where tumor cells develop can affect the progression and phenotype of cancer cachexia through alterations in various circulating factors derived from the tumor microenvironment.The progressive wasting syndrome that characterizes cancer cachexia affects most terminally ill patients, but it does not affect them equally. Incidence and severity are highly variable, even for the same tumor type. The authors of the present study explored the role of the tumor microenvironment in driving variability in cachexia. Mice inoculated with cancer cells via intraperitoneal injection exhibited a more severe cachexia phenotype than mice inoculated subcutaneously. Myocardium weight loss and changes in circulating cytokines were marked in the IP group. The results indicate that the site of tumor development influences the production of cachexia-promoting factors.