Impact of phosvitin on cancer-bone interactions evaluated using co-cultures of live mouse calvarial bone organs and tumor cells
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A novel three-dimensional cancer-bone metastasis model, using ex-vivo co-cultures of live mouse calvarial bones and cancer cells was developed recently (82). These model systems were found to be very conductive to testing new drugs/agents such as phosvitin, either in its native and/or dephosphorylated form, as well as studies targeted to the mechanism of bone cancer-interactions. The discovery that phosvitin facilitates new bone formation (7).The hypothesis that cancer cells utilize specific bone remodeling stages for homing and colonizing bone microenvironment. This led to postulate that this phosphoprotein may interfere with the cancer-bone interactions. For these reasons, to determine the effects of egg yolk phosvitin on the mechanism of cancer-bone metastasis the co-culture model systems under conditions whereby the two naturally occurring bone remodeling stages are dissociated, viz., bone resorption and formation, was used. Co-cultured live mouse calvarial bones, were carried out using a prostate cancer cells(PC3), and breast cancer cells(MDA-MB-231) in the absence and presence of added phosvitin (native or ndephosphorylated) in a roller-tube model system. These studies were carried out under: (a) bone resorption and (b) bone formation conditions. For the resorption model, the co-cultures of calvarial bones, PC3 cells, and MDA-MB-23 1cells were carried out in the absence of vitamin C/Ascorbic acid, with (native or dephosphorylated) phosvitin. For the formation model, the same cultures as above were carried out in the presence of ascorbic acid. The experiments were carried out for 10 days with change of media every 2-3 days. The used media and calvarial bones were evaluated by chemical, biochemical, histological and quantitative histomorphometric analyses. These studies revealed that under resorption conditions PC3 cells and MDA-MB-231 cells induces osteoclatsic differentiation, and stimulate bone resorption, whereas, the bone resorption associated with MDA-MB-231 is significantly higher than that associated with PC3 cells. Moreover, with the presence of native phosvitin, still under bone resorption condition, led to osteoblast differentiation, complete inhibition of bone resorption, and new osteoid formation with PC3 cells. On the other hand, a reduced bone resorption with no evidence of new bone formation, and moderate osteoblastic differentiation were observed with MDA-MB-231 when co-cultured with native phosvitin. However, dephosphorylated phosvitin effectts on both PC3 cells and MDA-MB-231 were reduce bone resorption only. In the formation model, the presence of native phosvitin and ascorbic acid individually or in combination led to higher osteoblast differentiation and bone formation, whereas, with dephosphorylated phosvitin in combination with vitamin C, led to the lowest osteoblastic differentiation for both cell lines, PC3 and MDA-MB-231.These results demonstrated that the phenotypic expressions of bone cells are dependent on the specific bone remodeling stage and can be modulated by agents such as phosvitin/vitamin C.
PLEASE NOTE: This work is protected by copyright. Downloading is restricted to the BU community: please click Download and log in with a valid BU account to access. If you are the author of this work and would like to make it publicly available, please contact email@example.com.Thesis (MSD) --Boston University, Henry M. Goldman School of Dental Medicine, 2015 (Department of Periodontology and Oral Biology).Includes bibliography: leaves 136-150.
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