An odyssey from breast to bone: multi-step control of mammary metastases and osteolysis by matrix metalloproteinases

Abstract

Development of metastases distant to the primary site of solid tumors marks late stages of tumor progression. Almost all malignant mammary tumors are carcinomas arising from the breast epithelium, but the morphological and molecular alterations in the mammary stroma surrounding the premalignant and the growing tumor contribute to its conversion into neoplastic tissue. Two parameters are critical for initiation of the metastatic process and access of tumor cells to the circulation. These are the ability of tumor cells to invade the basement membrane and the stroma, and the neovascularization of breast tumor tissue. A major site for development of distant metastases is the skeleton. After colonizing the bone, tumor cells promote a cascade of events leading to recruitment of osteoclasts and subsequent osteolytic bone destruction. A ubiquitous theme of neoplastic progression of breast tumors is the overproduction of matrix metalloproteinases. In this review, we summarize the recent insights into the functional consequences of matrix metalloproteinase expression and activation during malignant conversion in the breast, and after bone colonization. The current literature supports the hypothesis that matrix metalloproteinases play a key role in the metastatic expansion of most, if not all, mammary tumors and in the ensuing bone loss.

Fig. 1

Schematic representation of major events associated with neoplastic progression in mammary tissue. Epithelial cells are depicted in red, stromal cells in blue. See text for details.

Fig. 2

Schematic representation of major events associated with mammary carcinoma cell-induced osteolysis. Carcinoma cells are depicted in red, cells of the osteoclast lineage in blue and cells of the osteoblast lineage in green. See text for details.

Fig. 3

Transdifferentiation of mammary epithelial cells in response to stromelysin-1. Functionally normal mouse mammary epithelial cells (SCp2 cell line) were cultured for 6 days without (w/o) or with 1 μg/ ml of activated recombinant stromelysin-1 (rh SL-1). Cells were then immunostained for epithelial cytokeratins (green) and mesenchymal vimentin (red). Note the scattered morphology of cells exposed to stromelysin-1 and the concomitant induction of vimentin intermediate filaments.