Breast cancer: another line of defense
Normal breast cells cause cancer cell apoptosis
by means of the IL-25/IL-25R signaling path
LifeSciencesToday by Lawrence Berkeley National Laboratory:
Berkeley Lab Scientists Find that Normal Breast Cells Help Kill Cancer Cells
Everyone knows that the human body has a highly developed immune system that detects and destroys pathogens and tumor cells. Scientists from the Lawrence Berkeley National Laboratory of the US Department of Energy have convincingly demonstrated that the body has a second line of defense against cancer – healthy cells. A new study shows that during their development, normal breast epithelial cells secrete interleukin-25 (IL-25), a protein known for its role in the immune system's response to inflammation, causing apoptosis of nearby tumor cells.
"We found that by producing interleukin-25 for the active and specific destruction of breast cancer cells, normal breast cells function as an innate defense mechanism," says breast cancer specialist Mina Bissell, who led this study. "This suggests that the IL-25 signaling receptor may become a new therapeutic target for the treatment of breast cancer."
The results are published in the journal Science Translational Medicine (IL-25 Causes Apoptosis of IL-25R-Expressing Breast Cancer Cells Without Toxicity to Nonmalignant Cells).
Although cancer remains the leading cause of premature death worldwide today, most people have not contracted it for decades. Given the fact that our body is exposed to radiation, chemical and a number of other factors that cause harmful DNA mutations and malignant tumors every day throughout our life, the prevalence of cancer in the human population cannot but be recognized as surprisingly low.
"Even in healthy people, up to 1,000 cells with genetic disorders are formed daily. However, as part of homeostatic regulation, these cancer–prone cells are effectively destroyed by the so-called antitumor surveillance system of our body," explains Saori Furuta, lead author of the article. "There are a number of mechanisms of antitumor protection already described in the past, including classical molecular suppressors, immune surveillance and suppression by extracellular matrix and other microenvironment factors. We have added to this list a new tumor suppression factor – interleukin-25 and other proteins secreted by normal breast cells that kill or suppress their mutated neighbors."
Bissell, Furuta and their colleagues found that while IL-25 is highly toxic to breast cancer cells, it does not damage its normal cells. This selectivity is explained by the abundance of interleukin-25 receptors on cancer cells and, accordingly, their absence on normal breast cells.
"Since IL-25 is produced by healthy breast tissue as a natural anti-cancer protective factor in the process of cell differentiation, we need to find ways to use the IL–25 signaling pathway and its receptors as an organic approach to breast cancer therapy," Furuta believes.
Interleukin-25 has a cytotoxic effect on breast cancer cells,
expressing interleukin-25 (IL-25R) receptors.
Unmalignized epithelial cells (MECs) do not express IL-25R
and resistant to IL-25 induced apoptosis,
while expressing IL-25 receptors, cancer cells are sensitive to it.
Credit: Saori Furuta
Normal epithelial cells together with their surrounding microenvironment actively help to maintain the health and integrity of the tissue. They do this by partially regulating the secretion of both autocrine and paracrine cellular signaling factors, which ensures the development of healthy organs and prevents abnormal growth of nearby cells. In previous studies, Furuta and her colleagues have shown that an environment conditioned by normal breast epithelial cells that are in the process of forming acinuses in a three-dimensional lamin-rich culture of extracellular matrix can "reverse" the malignized phenotype of breast cancer cells, and these cells begin to behave as if they were normal.
Acinus is a structural and functional unit of the alveolar (vesicular) glands, including the mammary gland, a vesicular formation of one or different types of glandular cells located on the basement membrane and surrounded by connective tissue, capillaries and nerve fibers – VM.
Similar results have been achieved with the help of certain inhibitors of the cellular signaling pathway.
"These observations suggest that non-malignated breast epithelial cells forming acinuses secrete factors capable of suppressing the phenotype of breast cancer cells growing in three-dimensional cultures. We have suggested that such a complex phenotypic return is probably the result of the action of several signaling factors that, in combination, allow cancer cells to form resting structures similar to acinuses. We tried to identify and characterize these factors using solubility and size fractionation of the medium conditioned by normal breast epithelial cells along with functional tests to identify active molecules," says Bissell about the work.
Fractionation of the conditioned medium first on the basis of solubility showed that its tumor-suppressing activity is determined by morphogenic insoluble and cytotoxic soluble fractions. Fractionation of the cytotoxic soluble part by the size of the molecules showed that the most powerful antitumor activity is observed in the range from 10 to 50 kDa, which approximately corresponds to the size of the protein. Then, using mass spectrometry, interleukin-25 was determined as the protein with the highest cytotoxic activity. Subsequent functional tests showed that IL-25 interacts with IL-25 receptors and acts as a trigger for apoptosis (programmed cell death).
Stained sections of control (a) and exposed to interleukin-25 (b) tumors.
The control sample shows actively growing tumor cells (arrows),
while in the second sample (b), the tumor completely regressed.
Photo: Saori Furuta
"We analyzed randomized cohorts of breast biopsy samples and found that 20 percent of breast cancer samples were IL-25 receptor-positive," Furuta says. "It is important to note that IL-25 receptor-positive tumors were highly invasive and correlated with poor clinical results. We believe that in the future, the IL-25 receptor will become a new therapeutic marker for the diagnosis and treatment of cancer."
Furuta, Bissell and their colleagues are now investigating five other proteins they discovered secreted by normal differentiating breast cells. Although these proteins exhibit cytostatic rather than cytotoxic properties, stopping the growth of cancer cells rather than killing them, scientists are studying whether a combination of these proteins with interleukin-25 may be effective in the treatment of some particularly aggressive forms of breast cancer and other cancers.
Portal "Eternal youth" http://vechnayamolodost.ru18.04.2011