IL25 and other proteins = that?

IL25 and other proteins = that?

yes

rewritten.
We are now adding a new type of tumor suppression to this list, IL25 and other proteins. These proteins, secreted by normal breast cells, kill or subdue their mutated neighbors."

Cool.

Thank you.

Interesting. Ori, what comes next after the above sentence?

We are now adding a new type of tumor suppression to this list, IL25 and other proteins secreted by normal breast cells that kill or subdue their mutated neighbors."



In their study, Furuta, Bissell, Lee and their colleagues found that whereas IL25 was highly toxic to breast cancer cells, it did not harm normal breast cells. The selectivity, they discovered, is due to the presence of an abundance of exposed IL25 receptors on breast cancer cells. These IL25 receptors were absent on normal breast cells.

"Since IL25 is produced by healthy breast tissue as a natural defense mechanism against cancer during the cell differentiation process, we should be able to utilize IL25/IL25 receptor signaling as an organic approach to breast cancer therapy," Furuta says.

Normal epithelial cells, in cooperation with the microenvironment that surrounds them, actively help maintain the health and integrity of tissue. They do this in part by regulating the secretion of cell signaling factors -- both autocrine and paracrine -- that promote the development of healthy organs and prevent the aberrant growth of neighboring cells. In previous studies, Furuta and collaborators have shown that conditioned-medium, taken from normal mammary epithelial cells while in the process of forming acini in a 3D lamin-rich extracellular matrix culture, can "revert" the malignant phenotype of breast cancer cells so that they behave as if they were normal breast cells. Similar results were also achieved with certain cell signaling inhibitors.

Says Bissell, "These observation suggested that acinus-forming nonmalignant mammary epithelial cells secrete factors that can suppress the phenotype of breast cancer cells growing in 3D cultures. We hypothesized that such a complex phenotypical reversion is likely the result of multiple signaling factors that in combination allow cancer cells to form quiescent acinar-like structures. We sought to identify and characterize these factors using solubility and size-fractionation of the conditioned medium from normal mammary epithelial cells, along with functional assays to identify the active molecules."

Fractionating the conditioned medium first by solubility revealed that its tumor suppressive activity could be divided into a morphogenic insoluble fraction and a cytotoxic soluble fraction. Fractionating this cytotoxic soluble portion according to molecule size revealed that the most potent tumor cell-killing activity took place in the 10-to 50-kiloDalton range, which would be something the size of a protein. Mass spectrometry was then used to identify the cytokine IL25 as the protein with the most potent cytotoxic activity. Subsequent functional assays revealed that IL25 interacts with the IL25 receptor to activate apoptosis (cell death).

"We analyzed randomized cohorts of breast biopsy samples and found that 20-percent of the breast cancer samples tested were IL25 receptor-positive," Furuta says. "Importantly, these IL25 receptor-positive tumors were highly invasive and correlated to poor clinical outcome patients. We believe that in the future the IL25 receptor will serve as a novel therapeutic marker for breast cancer diagnosis and treatment."

Furuta says she and Bissell and their colleagues are now looking at five other proteins they discovered being secreted by normal developing breast cells. While these other proteins are cytostatic rather than cytotoxic, meaning they stop the growth of cancer cells rather than kill the cells, Furuta says she and her colleagues are investigating whether combinations of these other proteins with IL25 could prove to be an effective therapy against some forms of especially aggressive breast and other cancers.

This work was primarily supported by a grant from theNational Institutes of Health's National Cancer Institute.

Journal Reference:

1.S. Furuta, Y.-M. Jeng, L. Zhou, L. Huang, I. Kuhn, M. J. Bissell, W.-H. Lee. IL-25 Causes Apoptosis of IL-25R-Expressing Breast Cancer Cells Without Toxicity to Nonmalignant Cells. Science Translational Medicine, 2011; 3 (78): 78ra31 DOI: 10.1126/scitranslmed.3001374