Cloning of the molecules associated with bone metastases of cancers and its characterization

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(1) Role of TGF-beta and IGF-1 in bone metastases of breast cancersIn bone tissues/there are large amount of Transforming growth factor-beta (TGF-beta) and Insulin-like growth factor-1 (IGF-1), it is, therefore, likely that these two major growth factors play some roles in bone remodeling in physiological or pathological conditions. It is well know that breast cancers resorb the bone after metastasizing into bone. To examine the role of IGF-1 in bone metastases, we established the breast cancer cell line MDA231 overexpressing dominant-negative IGF-1 receptor, and assessed its bone-metastatic effects using animal model. We found that the cell line showed much less bone metastatic activity compared with parental MDA231 cells. We next evaluated the effects of TGF-beta on MDA231 cells. TGF-beta had little effects on the growth of MDA231 cells but markedly enhanced the production of PTHrP which is one of the important factor in bone metastases by cancers. In addtion, TGF-beta activates the Smad signaling through Smad2, Smad3 and Smad4. Finally, we found the breast cancer cell line that is deficient in Smad4 showed no ability to metastasize into bone. These finding suggest that important roles of TGF-beta and IGF-1 in bone metastases by breast cancers.(2) The effects of bisphosphonate on soft-tissue metastases of breast cancersIt is well know that bisphosphonate is a powerful inhibitor for osteoclasts and useful to treat the bone metastasized cancers. However, little is know the effects on soft tissue metastases of breast cancers. To address this, we established the system in which we can evaluate the bone metastases as well as soft tissues metastases. Using this system, we found that bisphosphonate blocked the bone metastases but stimulated the metastases into soft tissues such as lung and liver. It is likely that bisphosphonate has distinct effects on bone and soft tissues.