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Metastasis of Breast Cancer

Cancer Metastasis Biology and Treatment

Series Editors Richard J. Ablin, Ph.D., University of Arizona, College of Medicine and The Arizona Cancer Center, AZ, U.S.A. Wen G. Jiang, M.D., Wales College of Medicine, Cardiff University, Cardiff, U.K.

The relation between cancer cell motility and the development of metastases was historically first suggested by Rudolf Virchow, who situated the onset of cancer at the primary tumour. Here, normal cells have transformed into cancer cells, and from this site the cancer cells can disseminate towards locoregional and distant organs to found metastases. Bridging the distance between a primary tumour and its metastases is become highly motile when isolated and brought in culture, but do not metastasize when reinoculated into the host organism. Normal cells sometimes do metastasize, like leukocytes which can migrate from the bone marrow towards their homing or inflammation sites, or like trophoblast cells towards the lungs of certain rodents during pregnancy (1). The common denominator in the motility by these normal cells is the restricttion in time and space: sensitivity to contact inhibition and the switching off by an internal clock appear to be mechanisms that are deficient in cancer cells. Again, this should not be taken too strictly, since cancer cell motility is a transient phenomenon, which can be switched off spontaneously and often temporarily in cells once they have established a metastasis. Aware of this complexity, we should consider motility as a necessary, but not as a sufficient condition for metastasis, and thus not conceive it as a functional marker of metastatic capability. The content of this chapter is strictly related to the contribution of breast cancer motility to metastasis. Cell motility covers a number of aspects we will deal with separately for didactic reasons (Figure 1). First, breast cancer cells dispose of highly dynamic structures like actin filaments and a cytoplasmic microtubular complex, for which the traditional term cytoskeleton probably is a misnomer because it is too static (2). This intrinsic motility machinery can be considered as both the engine and the steering wheel of the cell, since it allows directional migration. This implicates that motility is not random, but that moving breast cancer cells are always on their way to form metastases. Second, motility is only one prerequisite for invasion, and is influenced by transient adhesive interactions with the cells microenvironment. So, homotypic (between cells of the same type) cellcell adhesions usually keep the cells in contact with each other, and serve an invasion suppressive aim. Heterotypic (between cells of different types) cellcell adhesions, however, can help the invading cancer cell to use neighbouring stromal cells as a grip. For cellmatrix adhesions the role in invasion is dual: some extracellular matrix structures, such as the basement membrane, can act as barriers or anchors for the cancer cells, while others rather offer tracks for the moving cell, such as interstitial type I collagen fibres. Third, extracellular proteases continuously help to remodel the cancer cells microenvironment by disrupting cellcell and cellmatrix adhesion proteins temporarily, and by dissolving extracellular matrix structures to facilitate cell displacement. For these reasons extracellular proteolysis is an important activity in invasion, not at least because it can generate chemotactic and angiogenic peptide fragments (3).