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(American Journal of Pathology. 2003;163:2531-2541.)
© 2003 American Society for Investigative Pathology

Interleukin-1 Promotes Tumor Growth and Cachexia in MCF-7 Xenograft Model of Breast Cancer

Suresh Kumar^*, Hiromitsu Kishimoto^*, Hui Lin Chua^*, Sunil Badve, Kathy D. Miller, Robert M. Bigsby and Harikrishna Nakshatri^*¶||**

From the Departments of Surgery,^* Pathology, Medicine, Gynecology and Obstetrics, Biochemistry and Molecular Biology,^¶ and the Walther Oncology Center,|| Indiana University School of Medicine, Indianapolis; and the Walther Cancer Institute,^** Indianapolis, Indiana

Progression of breast cancer involves cross-talk between epithelial and stromal cells. This cross-talk is mediated by growth factors and cytokines secreted by both cancer and stromal cells. We previously reported expression of interleukin (IL)-1 in a subset of breast cancers and demonstrated that IL-1 is an autocrine and paracrine inducer of prometastatic genes in in vitro systems. To understand the role of IL-1 in breast cancer progression in vivo, we studied the growth of MCF-7 breast cancer cells overexpressing a secreted form of IL-1 (MCF-7IL-1) in nude mice. MCF-7IL-1 cells formed rapidly growing estrogen-dependent tumors compared to parental cells. Interestingly, IL-1 expression alone was not sufficient for metastasis in vivo although in vitro studies showed induction of several prometastatic genes and matrix metalloproteinase activity in response to cross-talk between IL-1-expressing cancer cells and fibroblasts. Animals implanted with MCF-7IL-1 cells were cachetic, which correlated with increased leptin serum levels but not other known cachexia-inducing cytokines such as IL-6, tumor necrosis factor, or interferon gamma. Serum triglycerides, but not blood glucose were lower in animals with MCF-7IL-1 cell-derived tumors compared to animals with control cell-derived tumors. Cachexia was associated with atrophy of epidermal and adnexal structures of skin; a similar phenotype is reported in triglyceride-deficient mice and in ob/ob mice injected with leptin. Mouse leptin-specific transcripts could be detected only in MCF-7IL-1 cell-derived tumors, which suggests that IL-1 increases leptin expression in stromal cells recruited into the tumor microenvironment. Despite increased serum leptin levels, animals with MCF-7IL-1 cell-derived tumors were not anorexic suggesting only peripheral action of tumor-derived leptin, which principally targets lipid metabolism. Taken together, these results suggest that cancer cell-derived cytokines, such as IL-1, induce cachexia by affecting leptin-dependent metabolic pathways.

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