As part of the Program for Development of Innovative Research on Cancer Therapeutics (P-DIRECT), a research team including Distinguished Professor Keiichi Nakayama of the Kyushu University Medical Institute of Bioregulation discovered FBXW7, a key protein that inhibits the formation of metastatic niches , and succeeded in powerfully inhibiting cancer metastasis using the known drug propagermanium (a CCL2 receptor antagonist ).
Cancer cells are surrounded by a cluster of cells called a metastatic niche, which actively assists in the proliferation and metastasis of cancer cells. In particular, fibroblasts and monocytes originating in the blood are key elements in the composition of metastatic niches. Cancer treatment must simultaneously eliminate both the cancer cells and the metastatic niches. However, there was hitherto little understanding of the mechanism of the formation of metastatic niches. FBXW7 is a molecule that is frequently mutated in cancers, but there is constitutional variability in FBXW7 expression in humans, with some individuals having a high level of expression and others having a low level.
The research team examined the blood cells of breast cancer patients and discovered that those with a low level of FBXW7 expression were more prone to the recurrence of cancer. The team discovered that, as in humans, lowering the FBXW7 level in mice (by artificially destroying the gene) made the mice more prone to cancer metastasis. When the level of FBXW7 expression was low, the fibroblasts surrounding the cancer cells secreted a protein called CCL2 to excess, which recruited monocytes (Note 6) to the area around the cancer cells and created metastatic niches. When propagermanium, a CCL2 receptor antagonist, was administered to block the CCL2, monocytes ceased to accumulate, thereby inhibiting the proliferation of cancer cells at the metastatic site. Propagermanium is a drug that is already used in humans to treat hepatitis (a known drug), so there are plans to proceed with clinical trials of propagermanium as soon as possible.
The outcome of this study was published in the U.S. scientific journal The Journal of Clinical Investigation on January 2, 2015 (Eastern Standard Time).