Abstract
Abstract Background: Increasing evidence suggests that macrophages play a role in the normal development of certain organs, including the breast1. Intriguingly, macrophages are often found in the stroma of breast tumours, where they may promote tumour growth and metastasis. The mechanism underpinning the requirement for macrophages during normal development may involve their interactions with mammary stem cells (MaSCs). Recently, a population enriched for MaSCs has been prospectively identified in mice2. We have used 2 approaches to determine whether macrophages are required for normal MaSC function.Methods and Results: The role of macrophages in mammary development was studied in mice with an inactivating recessive mutation in the CSF-1 gene (CSFop/op). MaSCs from CSFop/op mice exhibit significantly reduced clonogenicity in vitro with a reduction in colony size and number in CSFop/op mice. Transplantation assays confirmed a reduced regenerative capacity of the MaSCs derived from CSFop/op mice when transplanted into wild-type recipients. Furthermore, in reciprocal experiments, we found that a macrophage-deficient micro-environment does not support stem cell growth with an inability for wild-type stem cells to repopulate the fat pad of CSFop/op mice.To support these findings, an alternative strategy was used to eliminate the macrophages from the stem cell microenvironment by co-transplanting stem cells with liposomes containing clodronate or saline. Clodronate-containing liposomes are toxic to macrophages after ingestion. There was a greater than 80% impairment in stem cell repopulating frequency as well as a marked decrease in outgrowth potential when cotransplanted with clodronate-containing liposomes.Discussion: These studies indicate a major role for macrophages in supporting stem cell growth during mammary development. This may relate to a role in the stem cell niche. Understanding the mechanisms by which mammary stem cells interact with macrophages during mammary development will shed light on why macrophage infiltration in tumours portends a poor prognosis in breast cancer.1. Gouon-Evans V, Lin EY, Pollard JW. Requirement of macrophages and eosinophils and their cytokines/chemokines for mammary gland development. Breast Cancer Res. 2002; 4:155-64.2. Shackleton M, Vaillant F, Simpson KJ, et al. Generation of a functional mammary gland from a single stem cell. Nature. 2006; 439:84-8. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 49.
Highlights
Macrophages in the mammary gland are essential for morphogenesis of the ductal epithelial tree and have been implicated in promoting breast tumor metastasis
Utilizing an alternative strategy for selective depletion of macrophages from the mammary gland, we demonstrate that co-implantation of the mammary stem cell (MaSC)-enriched subpopulation with clodronate-liposomes leads to a marked decrease in repopulating frequency and outgrowth potential
Our data reveal a key role for mammary gland macrophages in supporting stem/progenitor cell function and suggest that MaSCs require macrophage-derived factors to be fully functional
Summary
Macrophages in the mammary gland are essential for morphogenesis of the ductal epithelial tree and have been implicated in promoting breast tumor metastasis. In the pubertal mammary gland, macrophages are recruited to the highly mitotic terminal end buds (TEBs) from which ducts elongate and branch to give rise to a mature ductal tree. Macrophages are presumed to play a role in tissue remodeling by engulfing apoptotic epithelial cells during ductal morphogenesis [1,2]. Csf1op/op mice, homozygous for a null mutation in Csf, exhibit multiple defects and have reduced macrophage numbers in most tissues including the mammary gland. These mice are severely runted, toothless and osteopetrotic, owing to an osteoclast deficiency that impairs bone resorption. The mammary glands of Csf1op/op mice display lower numbers of terminal end buds as well as reduced ductal branching and elongation [4]. Mammary-specific rescue has shown that the mammary gland phenotype is not due to secondary
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