title: Interleukin-1 alpha promotes tumor growth and cachexia in MCF-7 xenograft model of breast cancer.
abstract: 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 alpha in a subset of breast cancers and demonstrated that IL-1 alpha is an autocrine and paracrine inducer of prometastatic genes in in vitro systems. To understand the role of IL-1 alpha in breast cancer progression in vivo, we studied the growth of MCF-7 breast cancer cells overexpressing a secreted form of IL-1 alpha (MCF-7IL-1 alpha) in nude mice. MCF-7IL-1 alpha cells formed rapidly growing estrogen-dependent tumors compared to parental cells. Interestingly, IL-1 alpha 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 alpha-expressing cancer cells and fibroblasts. Animals implanted with MCF-7IL-1 alpha 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 alpha 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 alpha cell-derived tumors, which suggests that IL-1 alpha increases leptin expression in stromal cells recruited into the tumor microenvironment. Despite increased serum leptin levels, animals with MCF-7IL-1 alpha 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 alpha, induce cachexia by affecting leptin-dependent metabolic pathways.
authors: Departments of Surgery, Indiana University School of Medicine, Indianapolis 46202, USA.
authors: Suresh
authors: S
authors: Kumar
authors: Hiromitsu
authors: H
authors: Kishimoto
authors: Hui Lin
authors: HL
authors: Chua
authors: Sunil
authors: S
authors: Badve
authors: Kathy D
authors: KD
authors: Miller
authors: Robert M
authors: RM
authors: Bigsby
authors: Harikrishna
authors: H
authors: Nakshatri
mesh_terms: D000818:Animals; D002100:Cachexia / Q000150:complications / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D002455:Cell Division; D045744:Cell Line, Tumor; D005260:Female; D005347:Fibroblasts; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D020738:Leptin / Q000097:blood / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010455:Peptides / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D012871:Skin Diseases / Q000209:etiology; D014183:Transplantation, Heterologous; D015431:Weight Loss
chemical_list: D007375:Interleukin-1; D020738:Leptin; D010455:Peptides; D012333:RNA, Messenger; C008287:lipid mobilizing substance