IL-25 causes selective apoptosis of breast cancer cells
MedWire News: The cytokine interleukin-25 (IL-25) triggers apoptosis in breast cancer cells expressing the accompanying receptor without toxicity to nonmalignant cells, US researchers report.
"IL-25 thus holds promise as the basis for development of novel, effective breast cancer therapeutics with broad therapeutic windows," comment Mina Bissel (Lawrence Berkeley National Laboratory, Berkeley, California) and colleagues.
The researchers previously showed that conditioned medium (CM) from nonmalignant mammary epithelial cells (MECs) "reverts" the malignant phenotype of breast cancer cells, rendering them dormant.
In the present study, the team aimed to identify and characterize the signaling factors responsible for this phenotypic reversion.
Fractionation experiments using CM from MCF10A (nonmalignant) cells revealed that proteins could be divided into those with morphogenic (reversion) activity and those with cytotoxic activity.
There were six proteins specifically secreted by differentiating MECs that exerted cytotoxic activity on MCF7 breast cancer cells. These included antiangiogenic proteins, proinflammatory cytokines, and growth and differentiation proteins.
Among the proteins identified, IL-25 had the highest cytotoxic activity on MCF7 cells without affecting the nonmalignant MCF10A cells.
Moreover, IL-25 significantly slowed the growth of mammary tumors in mouse models. After 1 month, the size of IL-25-treated tumors in these animals was three times smaller than that of control tumors, while none of the treated animals showed evidence of systemic stress or toxicity compared with controls.
Further experiments showed that the IL-25-induced cytotoxicity was attributed to differential expression of the IL-25 receptor (IL-25R) on breast cancer cells.
Indeed, IL-25R was expressed in high amounts in tumors from patients with poor prognoses but was low in nonmalignant breast tissue.
The researchers explain that IL-25 exerts its cytotoxic effect by forming a complex with IL-25R, which in turn activates caspase-mediated apoptosis.
"Thus, the IL-25/IL-25R signaling pathway may serve as a new therapeutic target for advanced breast cancer," they write in the journal Science Translational Medicine.
"Unlike conventional immunotherapy in which a cytokine, such as IL-2, is administered by intravenous infusion to provoke global immunologic responses, a therapy that targets IL-25/IL-25R signaling would induce apoptosis specifically in cancer cells that express IL-25R," Bissel and co-authors conclude.
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By Laura Dean