A bone marrow protein that normally works to reduce inflammation after infection was found to also send signals to prostate cancer cells to promote their spread and growth outside of the prostate, a new study shows. The findings could provide the missing link as to why prostate cancer cells migrate to bones and may lead to new therapies that stop the process.
The study, “The immunosuppressive cytokine interleukin-4 increases the clonogenic potential of prostate stem-like cells by activation of STAT6 signaling,” was published in the journal Oncogenesis.
Inflammation is linked to poor prognosis in cancer. Cytokines, which are proteins secreted by cells as part of the normal immune response, are associated with the inflammatory process. For example, the pro-inflammatory cytokine interleukin-6 (IL-6) influences the growth and survival of prostate cancer cells.
Patients with progressive prostate cancer have elevated levels of the anti-inflammatory cytokine interleukin-4 (IL-4), and previous studies have shown that IL-4 can promote the growth and proliferation of certain cancer cells in vitro. This prompted the researchers to investigate the effect of IL-4 on prostate cancer cells isolated from patients.
After six days of growth in the presence of IL-4, the team found that the ability of malignant prostate cancer cells to form colonies, which is a measure of cell survival and proliferation, was enhanced in a concentration-dependent manner. But the cytokine did not influence the migration or invasive potential of prostate cancer cells.
The researchers then set out to identify the mechanism mediating IL-4’s effect on prostate cancer cells. They found that the signaling pathway is mediated by the STAT6 protein, which is known to be involved in metastasis.
The findings suggest that prostate cancer cells that have spread from the prostate into circulation, dock in the bones through the IL-4/STAT6 signaling and multiply to form a new tumor.
Norman Maitland, a professor at the University of York’s Department of Biology in the U.K., and one of the study’s authors, compares the process to that of a space rocket.
“We have always known that the two places where prostate cancer spreads are the bones and lymph nodes, but we have not fully understood why these two locations are preferred,” he explained in a press release. “If we imagine the prostate cancer cell as a floating ‘space rocket’ and the only way for it to perform its mission is to ‘dock’ with another ‘space vehicle’, we start to get a picture of what happens when a cancer cell moves around the body in search of a new home.
“Without this docking station, the ‘ship’, or cell, will just float around, not causing any further harm. The receptors on the ‘docking station’, or the protein in bone, act like a magnet for the receptors on the stem cells of the cancer and once it is ‘docked’, getting rid of the cancer becomes much harder,” he added.
The identification of this pathway offers a potential therapeutic opportunity by blocking STAT6 signaling. By using a STAT6 inhibitor that already has been tested in asthma, the team was able to disrupt the metastatic process.
“Clinical trials are some way off, but this is a positive and exciting step forward in tackling this disease and reducing the number of deaths,” Maitland said.
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