Resident Macrophages Influence Stem Cell Activity in the Mammary Gland.

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 (CSF^op/op). MaSCs from CSF^op/op mice exhibit significantly reduced clonogenicity in vitro with a reduction in colony size and number in CSF^op/op mice. Transplantation assays confirmed a reduced regenerative capacity of the MaSCs derived from CSF^op/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 CSF^op/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.