The interleukin-1 family of cytokines and receptors in human breast cancer: implications for tumor progression.
We have previously described the expression of interleukin cytokines (IL)-1alpha, IL-1beta, and IL-1 receptor antagonist (IL-1ra) in human breast cancer (HBC) tissue. Based on our previous studies, we hypothesize that the IL-1 family of cytokines, antagonists (IL-1ra) and receptors (IL-1RI and IL-1RII) are present within the human breast cancer (HBC) tumor microenvironment and that the IL-1 network of cytokines and receptors within the tumor microenvironment can control tumor cell subpopulation expression of other protumorigenic cytokines such as the angiogenic/growth factor, interleukin-8 (IL-8). To test this hypothesis we characterized the in vivo expression of the IL-1 network in HBC tissues and homogenates by immunohistochemistry (IHC) and ELISA. Additionally, we examined IL-1R expression in HBC cell lines in vitro and in a murine xenograft model by IHC. Finally, we determined the ability of IL-1 to induce IL-8 expression in in vitro using HBC cell lines. We observed that not only are the IL-1 cytokines present in HBC tissue and homogenates, but that IL-1Rs and IL-8 are also present in the HBC tumor microenvironment. Additionally, expression levels for some members of the IL-1/IL-8 network of cytokines correlated with the prognostic indicators, ER/PR. Using HBC cell lines, we observed that HBC cell lines express IL-1Rs in vitro and in the xenograft model. Furthermore, in vitro, HBC cell lines show a spectrum of responsiveness to IL-1 as measured by expression the proangiogenic/mitogenic cytokine IL-8. Our data clearly demonstrate the presence and distribution of IL-1 cytokines and receptors in HBC and suggests that the local expression of IL-1 results in the activation of a population of cells within the HBC tumor microenvironment. This activation of the IL-1/IL-1R cytokine family via autocrine and/or paracrine mechanisms leads to a cascade of secondary protumorigenic cytokines. These secondary signals induce the expression of numerous protumorigenic activities such as the expression of IL-8, and subsequently contribute to angiogenesis, tumor proliferation, and tumor invasion.
Pantschenko
Alexander G
AG
Department of Pathology, University of Connecticut, School of Medicine, Farmington, CT 06030, USA.
Pushkar
Irina
I
Anderson
Kathleen H
KH
Wang
Yanping
Y
Miller
Lauri J
LJ
Kurtzman
Scott H
SH
Barrows
George
G
Kreutzer
Donald L
DL
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D011960:Receptors, Estrogen / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I; D053574:Receptors, Interleukin-1 Type II; D011980:Receptors, Progesterone / Q000378:metabolism; D012795:Sialoglycoproteins / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D016209:Interleukin-8; D011960:Receptors, Estrogen; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D053574:Receptors, Interleukin-1 Type II; D011980:Receptors, Progesterone; D012795:Sialoglycoproteins