Osteoblasts modulate Ca2+ signaling in bone-metastatic prostate and breast cancer cells.
Metastatic prostate and breast cancers display a predilection for the skeleton. The high incidence of skeletal metastasis may be a reflection of favorable reciprocal interactions between the bone microenvironment and disseminated cancer cells. Here we show that bone-metastatic PC3-ML prostate cancer cells and MDA-231 breast cancer cells-when co-cultured with human osteoblasts-down-regulate the increase in cytosolic free calcium (Ca(2+)) induced by agonist stimulation. This osteoblast promoted alteration of Ca(2+) signaling develops and reverts in a time-dependent manner. Most importantly, the Ca(2+) responses of cancer cells lacking bone metastatic potential are not affected by osteoblasts. The limited increase in cytosolic Ca(2+) observed in bone-metastatic cells does not result from depleted intracellular Ca(2+) stores but rather a decreased entry of Ca(2+) from the extracellular space. Interestingly, the inhibition of histone deacetylase in cancer cells replicates the changes in Ca(2+) signaling induced by osteoblasts, suggesting the participation of epigenetic mechanisms. Finally, cancer cells harvested from skeletal metastases induced in mice showed Ca(2+) responses identical to cells co-cultured with osteoblasts. However, Ca(2+) signaling in cancer cells recovered from metastases to soft-tissues was not affected, emphasizing the role of the bone microenvironment in regulating the functional behavior of bone-metastatic cells. We propose that osteoblasts protect selected malignant phenotypes from cell death caused by an excessive increase in cytosolic Ca(2+), thereby facilitating their progression into macroscopic skeletal metastases.
D'Ambrosio
Julia
J
Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N. 15th Street, New College Building, MS488, Philadelphia, PA, 19102, USA.
Fatatis
Alessandro
A
D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D002118:Calcium / Q000378:metabolism*; D002450:Cell Communication; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D018920:Coculture Techniques; D006801:Humans; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000473:pathology; D015398:Signal Transduction; D013997:Time Factors
D002118:Calcium