Interleukin-1 alpha promotes tumor growth and cachexia in MCF-7 xenograft model of breast cancer

Am J Pathol. 2003 Dec;163(6):2531-41. doi: 10.1016/s0002-9440(10)63608-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cachexia / complications
  • Cachexia / etiology
  • Cachexia / pathology*
  • Cachexia / physiopathology
  • Cell Division
  • Cell Line, Tumor
  • Female
  • Fibroblasts
  • Humans
  • Interleukin-1 / metabolism*
  • Leptin / blood
  • Leptin / genetics
  • Mammary Neoplasms, Experimental / blood
  • Mammary Neoplasms, Experimental / complications
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology*
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Peptides / genetics
  • RNA, Messenger / metabolism
  • Severity of Illness Index
  • Skin Diseases / etiology
  • Transplantation, Heterologous
  • Weight Loss


  • Interleukin-1
  • Leptin
  • Peptides
  • RNA, Messenger
  • lipid mobilizing substance