Vascular remodelling during the normal and malignant life cycle of the mammary gland

The mammary gland life cycle is exemplified by massive, physiologically dictated changes in cell number and composition, architecture, and functionality. These drastic upheavals, by necessity, also involve the mammary endothelium, which undergoes angiogenic expansion during pregnancy and lactation followed by ordered regression during involution. In this review, we summarise data obtained using the Mercox methyl methacrylate corrosion cast technique to analyse the mammary gland vasculature during normal development and carcinogenesis. Concomitant with epithelial cell expansion, the mammary vasculature grows during the first half of pregnancy by sprouting angiogenesis whereas the last half of pregnancy and lactation are characterised by the non-proliferative intussusceptive angiogenesis. The vasculature of the lactating gland is composed of a well-developed capillary meshwork enveloping the secretory alveoli with basket-like honeycomb structures. During involution, regression of the vasculature is achieved by regional collapse of the honeycomb structures, capillary retraction, and endothelial attenuation. This process appears partly to involve apoptosis. However, an additional mechanism involving remodelling without cell death, which we have termed angiomeiosis, must exist to explain the morphological observations. Interestingly, in mammary tumours of neuT transgenic mice, both sprouting and intussusceptive angiogenesis was observed simultaneously in the same nodules, a finding with potential implications for cancer therapy. The underlying molecular mechanisms controlling angiogenic modulation in the mammary gland, particularly angiogenic regression and the endothelial:parenchymal interplay, are poorly understood. However, the data summarised in this review indicate that precisely these molecular mechanisms offer novel alternatives for specific and effective treatment of breast cancer.