Abstract
Epithelial/mesenchymal cell interactions are necessary for proper ductal morphogenesis throughout all stages of mammary gland development. Besides the well-established stromal components, such as adipocytes and fibroblasts, the mammary stroma is also infiltrated with migrating blood cells, mostly macrophages and eosinophils. The focus of this review is on the role of macrophages and their growth factor colony-stimulating factor 1 (CSF-1) in promoting branching morphogenesis during postnatal mammary gland development through to lactation. The more restricted role of eosinophils and their chemoattractant eotaxin during pubertal ductal morphogenesis is also discussed. A possible interaction between macrophages and eosinophils in ductal morphogenesis is considered, along with the roles of other chemokines. This role of macrophages in normal development also appears to be subverted by tumors of the mammary gland to promote the escape of the tumor cells from the local environment and enhance their rate of metastasis. These data emphasize the dual role of macrophages in the promotion of epithelial growth in normal and cancer states.
Highlights
It is well established that epithelial/mesenchymal interactions are important for postnatal development of the mammary ductal tree and its differentiation during pregnancy into a milk-producing structure [1]
This review focuses on the role of two types of migrant hematopoietic cells, macrophages and eosinophils, that have been recently found to accumulate extensively around terminal end buds (TEBs) during the pubertal burst of ductal growth [7]
It is clear that the stroma of the developing mammary gland and mammary tumor is constantly changing, through movement and differentiation of resident cells, and by recruitment of migrating hematopoietic cells, macrophages and eosinophils
Summary
It is well established that epithelial/mesenchymal interactions are important for postnatal development of the mammary ductal tree and its differentiation during pregnancy into a milk-producing structure [1]. The expression of CSF-1 in the mammary epithelium corrected the ductal outgrowth significantly as well as restoring macrophage recruitment in Csf1op/Csf1op mice This indicated that the defects observed in the mammary glands of CSF-1-null mutant mice are not due to secondary effects induced by a systemic CSF-1 deficiency [40]. The eosinophil population is strongly depleted in the blood of IL-5-deficient mice, mammary ductal outgrowth is normal and eosinophils are still found around TEBs in these mice (V Gouon-Evans and JW Pollard, unpublished data) These observations agree with the notion that IL-5 provides the signal for the release of a pool of eosinophils from the bone marrow, while eotaxin remains the critical local chemoattractant for eosinophils into the mammary gland. A putative cytokine, HIN-1 (high in normal-1), has been newly identified and shown to be highly expressed in normal human luminal mammary epithelial cells but hypermethylated and not expressed in the majority of breast cancers [106]
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