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)-1α in a subset of breast cancers and demonstrated that IL-1α is an autocrine and paracrine inducer of prometastatic genes in in vitro systems. To understand the role of IL-1α in breast cancer progression in vivo, we studied the growth of MCF-7 breast cancer cells overexpressing a secreted form of IL-1α (MCF-7IL-1α) in nude mice. MCF-7IL-1α cells formed rapidly growing estrogen-dependent tumors compared to parental cells. Interestingly, IL-1α 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-1α-expressing cancer cells and fibroblasts. Animals implanted with MCF-7IL-1α 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-1α 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-1α cell-derived tumors, which suggests that IL-1α increases leptin expression in stromal cells recruited into the tumor microenvironment. Despite increased serum leptin levels, animals with MCF-7IL-1α 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-1α, induce cachexia by affecting leptin-dependent metabolic pathways.
ASJC Scopus subject areas
- Pathology and Forensic Medicine