Regulation of Cancer Cell Migration and Bone Metastasis by RANKL
D. Holstead Jones, et al. Regulation of Cancer Cell Migration and Bone Metastasis by RANKL. Nature 440 (2006) 692-696.
Summary:
Since the late nineteenth century, scientists has proposed that bone is a common site for cancer cells to metastasize to because it provides a fertile "soil." The paper shows that this "soil" for bone-specific metastases of epithelial tumors is the cytokine RANKL ((receptor activator of NF-kB ligand). RANKL, when bound to its receptor, RANK, controls differentiation and activation of osteoclast. It also induces strong actin polymerization in human breast cancer cells that express RANK. Its correlation with actin polymerization led the authors into thinking that RANK and RANKL might play a part in epithelial cell migration.
Concentration-dependent cell migration was observed in three human breast cancer cell lines (MDA-MB-231, MCF-7, Hs578T) that were stimulated with RANKL. Treating them with osteoprotegerin (OPG), the decoy receptor for RANKL that has no effect on chemokine-induced migration, blocked cell migration. Similarly, RANKL-induced migration was observed in two prostate cancer cell lines that expressed RANK, but RANKL had no noticeable effect on colon cancer cell line Colo205 that did not express RANK.
Experiments done on a mouse B16F10 melanoma subclone that expresses high levels of RANK mRNA and proteins yielded similar results. To study tumor metastasis in vivo, B16F10 melanoma cells were injected into syngeneic C57BL/6 mice. Melanin-producing cancer cells metastasized rapidly and almost all bones showed black color after 12, 14, and 17 days. Mice that were treated with OPG had significantly reduced B16F10 cancer cell foci and morbidity, as no animals died within the experimental time frame compared to some in control. The results showed that RANK triggers actin polymerization and cell migration in several human epithelial tumor cells, and inhibition by OPG can reduce bone metastasis.
Significance:
Bone metastases are frequent cancer complications that are diffidcult to avoid. It has been shown that the most common sources of cancer deaths are not primary tumors but metastases. Knowing the role RANKL play in cell migration and in bone metastasis of epithelial tumors, efforts may be made toward preventing interaction between RANK and RANKL to inhibit spreading of tumors.
4 comments:
If RANKL is contained within the cancerous cell that has metastasized into bone, how is the bone acting as the "fertile soil"? It seems like RANKL affects the general migration of the cell, not necessarily it's attraction to bone.
The authors of the paper showed that RANK was expressed in 3 breast cancer cell lines, 2 prostate cancer cell lines and tests on the mouse. However, colon cancer cell line, which was tested, showed no results because no RANK was expressed. If the authors suggest that cancer cell migration can be regulated by RANKL, it is necessary to know what is the factor that determines RANK expression in cancer cells?
Why did the authors use breast cancer cells to study RANKL stimulation? Are they more likely to metastasize to the bone than other cell lines?
Since OPG treatment resulted in reduced morbidity and foci, has it been considered for use in cancer therapy?
The idea of the bone acting as the "fertile soil" was proposed by scientists earlier in the century. This paper showed that the actual "soil" is RANKL.
Colon, prostate, melanoma cancer cells, in addition to the breast cancer cells, were used in the study. The study is relatively recent (2006), and it said the OPG treatment "may offer promising therapeutic target for interfering with tumour metastasis and progression in bone." However, I don't know whether it's actually been used or not.
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