Notch Signaling in Prostate Cancer Cells Promotes Osteoblastic Metastasis
Technical Report,01 Jun 2016,31 May 2017
Van Andel Research Institute Grand Rapids United States
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Better understanding of the hosttumor interactions that trigger and drive metastatic processes could provide avenues for improved therapeutic intervention. Overexpression of the activated form of Notch3 NICD3 in PC3 cells decreased osteolytic lesions and decreased the number of osteoclasts in the tumor-bone microenvironment. Conversely, inhibition of Notch3 in PC3, 22rv1 and C42B cells with shRNA, promoted prostate cancerinduced osteolytic lesions when injected in the tibiae. Conditioned medium from PC3-NICD3 cells generated ALP-positive osteoblasts, and increased osteoblast proliferation in vitro, and this was associated with increase expression of Cyclins A, D and E. Conditioned medium from PC3-NICD3 cells also decreased osteoclasts and inhibited osteoclastgenesis, but had no effect on osteoclast apoptosis. PC3-NICD3 cells injected into tibiae expressed more human-specific MMP3 than tibiae injected with control cells. Conversely, PCa cells expressing Notch 3sh RNA expressed less of human-specific MMP-3. Notch signaling in PCa tumors probably favors osteoblastic metastasis by stimulating the production of MMP3 in the tumor microenvironment to inhibit osteoclast function and number while inducing osteoblast proliferation. Our results suggest that Notch signaling from cancer cells promotes osteoblastic metastasis and thus may be a therapeutic target for such metastatic lesions.
- Medicine and Medical Research