Blocking inflammation receptor kills breast cancer stem cells, U-M study finds
Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center
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WATCH THESE VIDEOS to LEARN MORE ABOUT CANCER STEM CELLS than perhaps even your ONCOLOGIST knows…..
http://www.youtube.com/watch?v=Yax8MW0rloY (especially focus on info starting at the 2 minute mark)
http://www.scivee.tv/node/10121 (note: there is a 3 fold increase in lethal stem cells when tumors are shrunk after chemotherapy or radiation – and “only the stem cells metastasize”)
http://sciencestage.com/v/26206/treatment-options-with-stem-cells.html
“we need to fundamentally CHANGE THE WAY we treat cancer.”
http://www.youtube.com/watch?v=dSgTTV8eAi4
Breast cancer stem cells are regulated by cytokine loops which need to be interrupted inorder to kill cancer stem cell. When you give chemotherapy and measure the % stem cells,
Stems cells are not only resistant to chemotherapy and also chemotherapy STIMULATES the proliferation of the lethal stem cells. The stem cells are the only ones which metastasize.
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MORE INFO ON MAX WICHA
Scientists at the University of Michigan Comprehensive Cancer Center have uncovered an important link between inflammation and breast cancer stem cells that suggests a new way to target cells that are resistant to current treatments.
The researchers identified a receptor, CXCR1, on the cancer stem cells which triggers growth of stem cells in response to inflammation and tissue damage. A drug originally developed to prevent organ transplant rejection blocks this receptor, killing breast cancer stem cells and preventing their metastasis in mice, according to the study.
Cancer stem cells, the small number of cells that fuel a tumor’s growth, are believed to be resistant to current chemotherapies and radiation treatment, which researchers say may be the reason cancer so often returns after treatment.
“Developing treatments to effectively target the cancer stem cell population is essential for improving outcomes. This work suggests a new strategy to target cancer stem cells that can be readily translated into the clinic,” says senior study author Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center. Wicha was part of the team that first identified stem cells in breast cancer.
Results of the current study appear online Jan. 4 in the Journal of Clinical Investigation and will appear in the journal’s February print issue.
CXCR1 is a receptor for Interleukin-8, or IL-8, a protein produced during chronic inflammation and tissue injury. When tumors are exposed to chemotherapy, the dying cells produce IL-8, which stimulates cancer stem cells to replicate. Addition of the drug repertaxin to chemotherapy specifically targets and kills breast cancer stem cells by blocking CXCR1.
Mice treated with repertaxin or the combination of repertaxin and chemotherapy had dramatically fewer cancer stem cells than those treated with chemotherapy alone. In addition, repertaxin-treated mice developed significantly fewer metastases than mice treated with chemotherapy alone.
“These studies suggest that important links between inflammation, tissue damage and breast cancer may be mediated by cancer stem cells. Furthermore, anti-inflammatory drugs such as repertaxin may provide a means of blocking these interactions, thereby targeting breast cancer stem cells,” Wicha says.
Repertaxin has been tested in early phase clinical trials to prevent rejection after organ transplantation. In these studies, side effects seem to be minimal. There are no reports of using repertaxin to treat cancer.
For more information, go to www.cancer.med.umich.edu/news/breast_cancer_stem_cell_treatment10.shtml
Note to patients: This work was done in cell cultures and mice. Repertaxin is not available to patients at this time and no clinical trials are yet planned.
Breast cancer statisitics: 194,280 Americans will be diagnosed with breast cancer this year and 40,610 will die from the disease, according to the American Cancer Society.
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 doi:10.1016/j.bcp.2004.10.007 | How to Cite or Link Using DOICopyright © 2004 Elsevier Inc. All rights reserved. |
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Federica Casillia, 1, et al , Riccardo Bertinia, 
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Abstract
Repertaxin is a new non-competitive allosteric blocker of interleukin-8 (CXCL8/IL-8) receptors (CXCR1/R2), which by locking CXCR1/R2 in an inactive conformation prevents receptor signaling and human polymorphonuclear leukocyte (PMN) chemotaxis. Given the unique mode of action of repertaxin it was important to examine the ability of repertaxin to inhibit a wide range of biological activities induced by CXCL8 in human leukocytes. Our results show that repertaxin potently and selectively blocked PMN adhesion to fibrinogen and CD11b up-regulation induced by CXCL8. Reduction of CXCL8-mediated PMN adhesion by repertaxin was paralleled by inhibition of PMN activation including secondary and tertiary granule release and pro-inflammatory cytokine production, whereas PMN phagocytosis of Escherichia coli bacteria was unaffected. Repertaxin also selectively blocked CXCL8-induced T lymphocyte and natural killer (NK) cell migration. These data suggest that repertaxin is a potent and specific inhibitor of a wide range of CXCL8-mediated activities related to leukocyte recruitment and functional activation in inflammatory sites.
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INFO ON REPERTAXIN
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- Neutrophils are thought to play a major role in the mediation of reperfusion injury. CXC chemokines are known inducers of neutrophil recruitment. Here, we assessed the effects of Repertaxin, a novel low molecular weight inhibitor of human CXCL8 receptor activation, on the local, remote and systemic injuries following intestinal ischaemia and reperfusion (I/R) in the rat.
- Pre-incubation of rat neutrophils with Repertaxin (10−11-10−6 M) inhibited the chemotaxis of neutrophils induced by human CXCL8 or rat CINC-1, but not that induced by fMLP, PAF or LTB4, in a concentration-dependent manner. Repertaxin also prevented CXCL8-induced calcium influx but not CXCL8 binding to purified rat neutrophils.
- In a model of mild I/R injury (30 min of ischaemia and 30 min of reperfusion), Repertaxin dose-dependently (3-30 mg kg−1) inhibited the increase in vascular permeability and neutrophil influx. Maximal inhibition occurred at 30 mg kg−1.
- Following severe I/R injury (120 min of ischaemia and 120 min of reperfusion), Repertaxin (30 mg kg−1) markedly prevented neutrophil influx, the increase in vascular permeability both in the intestine and the lungs. Moreover, there was prevention of haemorrhage in the intestine of reperfused animals.
- Repertaxin effectively suppressed the increase in tissue (intestine and lungs) and serum concentrations of TNF-α and the reperfusion-associated lethality.
- For comparison, we also evaluated the effects of an anti-CINC-1 antibody in the model of severe I/R injury. Overall, the antibody effectively prevented tissue injury, systemic inflammation and lethality. However, the effects of the antibody were in general of lower magnitude than those of Repertaxin.
- In conclusion, CINC-1 and possibly other CXC chemokines, acting on CXCR2, have an important role during I/R injury. Thus, drugs, such as Repertaxin, developed to block the function of the CXCR2 receptor may be effective at preventing reperfusion injury in relevant clinical situations.
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