Breast cancer frequently metastasizes to the skeleton, interrupting the normal bone remodeling process and causing bone degradation. Osteolytic lesions are the end result of osteoclast activity; however, osteoclast differentiation and activation are mediated by osteoblast production of RANKL (receptor activator for NFκB ligand) and several osteoclastogenic cytokines. Osteoblasts themselves are negatively affected by cancer cells as evidenced by an increase in apoptosis and a decrease in proteins required for new bone formation. Thus, bone loss is due to both increased activation of osteoclasts and suppression of osteoblasts. This review summarizes the current understanding of the osteolytic mechanisms of bone metastases, including a discussion of current therapies.

Electron spin resonance was used to measure the diffusion of a small (Mr 170) spin label in the aqueous cytoplasm of mammalian cells. Translational and rotational motion were determined from the same spectra. Based on measurements made in model systems, it was hypothesized that calculations of the apparent viscosity from either rotational or translational motion would distinguish between the effects of cytoplasmic viscosity or cytoplasmic structure on diffusion. The diffusion coefficient calculated from spin label collision frequency, averaged 3.3 X 10(-6) cm2/sec in several cell lines. It was greater in growing cells and in cells treated with cytochalasin B than in quiescent cells. The viscosity of the cytoplasm calculated from the translational diffusion coefficient or the rotational correlation time was 2.0-3.0 centipoise (1 P = 0.1 Pa X sec), about 2-3 times that of the spin label in water. Therefore, over the dimensions measured by the technique, 50-100 A, solvent viscosity appears to be the major determinant of particle movement in cells under physiological conditions. However, when cells were subjected to hypertonic conditions, the translational motion decreased by 67%, while the rotational motion changed less than 20%. These data suggested that the decrease in cell volume under hypertonic conditions was accompanied by an increase in cytoplasmic barriers and a decrease in the spacing between existing components. In addition, a comparison of reported values for diffusion of a variety of molecules in water and in cells indicates that cytoplasmic structure plays an important role in the diffusion of proteins such as bovine serum albumin.

A case for the involvement of PRL in the regulation of the immune system is strong. However, no mechanism by which PRL exerts this regulation has yet been identified. We studied the in vitro effects of PRL on splenocytes from ovariectomized (OVX) rats and discovered that PRL induced the formation of interleukin-2 (IL-2) cell surface receptors. However, PRL did not induce IL-2 secretion. This response, which was dependent on the concentration of PRL, also depended upon the estrogen status of the splenocyte donor; thus, splenocytes from OVX rats or rats in diestrus responded to PRL, whereas those from estrogen-treated OVX rats or rats in estrus did not. We propose that in vivo exposure of PRL, under certain physiological conditions, may prime a pool of splenocytes to express IL-2 cell surface receptors, allowing these cells to be responsive to variations in local concentrations of IL-2.