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Rich66 · 06-05-2009, 11:08 AM

Breast Cancer Stem Cells Seem to Survive Radiation Therapy

TUESDAY, Dec. 19 (HealthDay News) -- Breast cancer stem cells, a type of cell that scientists have recently discovered is difficult to kill, may be especially resistant to radiation therapy, a new study suggests.
In fact, the radiation can even increase the growth of these stubborn stem cells, report researchers from the University of California, Los Angeles, David Geffen School of Medicine.
"This population of stem cells is more radiation-resistant than are non-stem cells," said Dr. Frank Pajonk, an assistant adjunct professor of radiation oncology at UCLA and corresponding author on the study. "We are the first to report this."
Radiation treatment involves exposure to high-energy rays or particles that destroy cancerous cells. It is often recommended after surgery for breast cancer, according to the American Cancer Society.
Pajonk and his colleagues exposed breast cancer stem cells and "normal" breast cancer cells to either single or multiple doses of radiation. More of the stem cells, also called cancer-initiating cells, lived through the radiation than did the other breast cancer cells.
One good example, according to Pajonk: While 46 percent of the stem cells survived treatment with 2 Gray of radiation (a dose typically used for breast cancer treatment), only 20 percent of normal breast cancer cells did.
Then, the team simulated clinical treatment that is interrupted -- a challenge that Pajonk and other health-care providers face when patients don't make all their scheduled appointments due to fatigue, inconvenience or other factors. Pajonk and his colleagues suspect this reduces the effectiveness of radiation, and the study suggests they are correct.
When Pajonk's team exposed the cells to a higher dose of 3 Gray, every day for five days, then stopped the treatment before what would be considered a full round, the proportion of stem cells actually increased.
Pajonk's team speculated that this may happen because the radiation activates a signaling pathway that gives the stem cells the messages to self-renew.
How is it that these cells are resistant to radiation? "They may have something like a natural radiation protectant inside of them that prevents the radiation-induced DNA damage that normally kills the breast cancer cells," Pajonk said.
The findings are published in the Dec. 20 edition of the Journal of the National Cancer Institute.
The new study sends a clear message to cancer researchers, said Dr. Maximilian Diehn, a resident in radiation oncology and postdoctoral fellow at the Stanford University School of Medicine. He co-authored an editorial accompanying the study results. "The main take-home point is that this gives more evidence that we should be studying cancer stem cells more," he said. "Those cells have properties different than the rest of the tumor."
Eventually, he said, scientists may be able to develop new drugs that would overcome this resistance to radiation, he said.
The concept of cancer stem cells is fairly new, said Diehn and Pajonk. For five years or so, it has been increasingly the topic of discussion in breast cancer research, as well as prostate cancer, melanoma and other types of tumors.
A better understanding of cancer stem cells could go a long way toward treatment success, Diehn said. "Often, less than one percent of cancer cells in a tumor are actually cells critical for keeping the tumor alive and potentially spreading the cancer. This is the cancer stem cell," he said.
The new research should not discourage women from getting radiation therapy if it is recommended, Diehn and Pajonk agreed. "Radiation treatment is still one of the best treatments available for women with breast cancer," Diehn said. It's also important, he said, to follow the treatment schedule as recommended and not to have gaps in treatment because that could make the stem cells proliferate.
In another new study, Dutch researchers found that comparing current mammograms to previous ones is valuable and can reduce referrals for lesions that turn out not to be cancerous. The researchers asked 12 experienced radiologists to read 160 mammograms twice; in one case, they had previous mammograms to refer to and, in the other, they did not.
When they had access to the previous mammograms, their detection performance improved. Having the prior mammogram to look at reduced referrals by 44 percent for suspicious areas that turned out not to be cancerous.
The findings are published in the January issue of the journal Radiology.

SOURCES: Maximilian Diehn, M.D., Ph.D., resident in radiation oncology and postdoctoral fellow, Stanford University School of Medicine, Stanford, Calif.; Frank Pajonk, M.D., Ph.D., assistant adjunct professor of radiation oncology, University of California, Los Angeles, David Geffen School of Medicine; Dec. 20, 2006, Journal of the National Cancer Institute; January 2007, Radiology

1: J Natl Cancer Inst. 2006 Dec 20;98(24):1777-85. Links

Comment in:: J Natl Cancer Inst. 2006 Dec 20;98(24):1755-7.

The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation.

Phillips TM, McBride WH, Pajonk F.
Department of Radiation Oncology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095-1714, USA.
BACKGROUND: If cancer arises and is maintained by a small population of cancer-initiating cells within every tumor, understanding how these cells react to cancer treatment will facilitate improvement of cancer treatment in the future. Cancer-initiating cells can now be prospectively isolated from breast cancer cell lines and tumor samples and propagated as mammospheres in vitro under serum-free conditions. METHODS: CD24(-/low)/CD44+ cancer-initiating cells were isolated from MCF-7 and MDA-MB-231 breast cancer monolayer cultures and propagated as mammospheres. Their response to radiation was investigated by assaying clonogenic survival and by measuring reactive oxygen species (ROS) levels, phosphorylation of the replacement histone H2AX, CD44 levels, CD24 levels, and Notch-1 activation using flow cytometry. All statistical tests were two-sided. RESULTS: Cancer-initiating cells were more resistant to radiation than cells grown as monolayer cultures (MCF-7: monolayer cultures, mean surviving fraction at 2 Gy [SF(2Gy)] = 0.2, versus mammospheres, mean SF(2Gy) = 0.46, difference = 0.26, 95% confidence interval [CI] = 0.05 to 0.47; P = .026; MDA-MB-231: monolayer cultures, mean SF(2Gy) = 0.5, versus mammospheres, mean SF(2Gy) = 0.69, difference = 0.19, 95% CI = -0.07 to 0.45; P = .09). Levels of ROS increased in both mammospheres and monolayer cultures after irradiation with a single dose of 10 Gy but were lower in mammospheres than in monolayer cultures (MCF-7 monolayer cultures: 0 Gy, mean = 1.0, versus 10 Gy, mean = 3.32, difference = 2.32, 95% CI = 0.67 to 3.98; P = .026; mammospheres: 0 Gy, mean = 0.58, versus 10 Gy, mean = 1.46, difference = 0.88, 95% CI = 0.20 to 1.56; P = .031); phosphorylation of H2AX increased in irradiated monolayer cultures, but no change was observed in mammospheres. Fractionated doses of irradiation increased activation of Notch-1 (untreated, mean = 10.7, versus treated, mean = 15.1, difference = 4.4, 95% CI = 2.7 to 6.1, P = .002) and the percentage of the cancer stem/initiating cells in the nonadherent cell population of MCF-7 monolayer cultures (untreated, mean = 3.52%, versus treated, mean = 7.5%, difference = 3.98%, 95% CI = 1.67% to 6.25%, P = .009). CONCLUSIONS: Breast cancer-initiating cells are a relatively radioresistant subpopulation of breast cancer cells and increase in numbers after short courses of fractionated irradiation. These findings offer a possible mechanism for the accelerated repopulation of tumor cells observed during gaps in radiotherapy.
PMID: 17179479 [PubMed - indexed for MEDLINE]

1: J Cell Biochem. 2009 Jul 21. [Epub ahead of print]

Radiation responses of cancer stem cells.

Vlashi E, McBride WH, Pajonk F.
Division of Molecular and Cellular Oncology, Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California.
Recent experimental evidence indicates that many solid cancers have a hierarchical organization structure with a subpopulation of cancer stem cells (CSCs). The ability to identify CSCs prospectively now allows for testing the responses of CSCs to treatment modalities like radiation therapy. Initial studies have found CSCs in glioma and breast cancer relatively resistant to ionizing radiation and possible mechanisms behind this resistance have been explored. This review summarizes the landmark publications in this young field with an emphasis on the radiation responses of CSCs. The existence of CSCs in solid cancers place restrictions on the interpretation of many radiobiological observations, while explaining others. The fact that these cells may be a relatively quiescent subpopulation that are metabolically distinct from the other cells in the tumor has implications for both imaging and therapy of cancer. This is particularly true for biological targeting of cancer for enhanced radiotherapeutic benefit, which must consider whether the unique properties of this subpopulation allow it to avoid such therapies. J. Cell. Biochem. (c) 2009 Wiley-Liss, Inc.
PMID: 19623582 [PubMed - as supplied by publisher]

06-05-2009, 11:08 AM	#8
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Breast Cancer Stem Cells Seem to Survive Radiation Therapy TUESDAY, Dec. 19 (HealthDay News) -- Breast cancer stem cells, a type of cell that scientists have recently discovered is difficult to kill, may be especially resistant to radiation therapy, a new study suggests. In fact, the radiation can even increase the growth of these stubborn stem cells, report researchers from the University of California, Los Angeles, David Geffen School of Medicine. "This population of stem cells is more radiation-resistant than are non-stem cells," said Dr. Frank Pajonk, an assistant adjunct professor of radiation oncology at UCLA and corresponding author on the study. "We are the first to report this." Radiation treatment involves exposure to high-energy rays or particles that destroy cancerous cells. It is often recommended after surgery for breast cancer, according to the American Cancer Society. Pajonk and his colleagues exposed breast cancer stem cells and "normal" breast cancer cells to either single or multiple doses of radiation. More of the stem cells, also called cancer-initiating cells, lived through the radiation than did the other breast cancer cells. One good example, according to Pajonk: While 46 percent of the stem cells survived treatment with 2 Gray of radiation (a dose typically used for breast cancer treatment), only 20 percent of normal breast cancer cells did. Then, the team simulated clinical treatment that is interrupted -- a challenge that Pajonk and other health-care providers face when patients don't make all their scheduled appointments due to fatigue, inconvenience or other factors. Pajonk and his colleagues suspect this reduces the effectiveness of radiation, and the study suggests they are correct. When Pajonk's team exposed the cells to a higher dose of 3 Gray, every day for five days, then stopped the treatment before what would be considered a full round, the proportion of stem cells actually increased. Pajonk's team speculated that this may happen because the radiation activates a signaling pathway that gives the stem cells the messages to self-renew. How is it that these cells are resistant to radiation? "They may have something like a natural radiation protectant inside of them that prevents the radiation-induced DNA damage that normally kills the breast cancer cells," Pajonk said. The findings are published in the Dec. 20 edition of the Journal of the National Cancer Institute. The new study sends a clear message to cancer researchers, said Dr. Maximilian Diehn, a resident in radiation oncology and postdoctoral fellow at the Stanford University School of Medicine. He co-authored an editorial accompanying the study results. "The main take-home point is that this gives more evidence that we should be studying cancer stem cells more," he said. "Those cells have properties different than the rest of the tumor." Eventually, he said, scientists may be able to develop new drugs that would overcome this resistance to radiation, he said. The concept of cancer stem cells is fairly new, said Diehn and Pajonk. For five years or so, it has been increasingly the topic of discussion in breast cancer research, as well as prostate cancer, melanoma and other types of tumors. A better understanding of cancer stem cells could go a long way toward treatment success, Diehn said. "Often, less than one percent of cancer cells in a tumor are actually cells critical for keeping the tumor alive and potentially spreading the cancer. This is the cancer stem cell," he said. The new research should not discourage women from getting radiation therapy if it is recommended, Diehn and Pajonk agreed. "Radiation treatment is still one of the best treatments available for women with breast cancer," Diehn said. It's also important, he said, to follow the treatment schedule as recommended and not to have gaps in treatment because that could make the stem cells proliferate. In another new study, Dutch researchers found that comparing current mammograms to previous ones is valuable and can reduce referrals for lesions that turn out not to be cancerous. The researchers asked 12 experienced radiologists to read 160 mammograms twice; in one case, they had previous mammograms to refer to and, in the other, they did not. When they had access to the previous mammograms, their detection performance improved. Having the prior mammogram to look at reduced referrals by 44 percent for suspicious areas that turned out not to be cancerous. The findings are published in the January issue of the journal Radiology. SOURCES: Maximilian Diehn, M.D., Ph.D., resident in radiation oncology and postdoctoral fellow, Stanford University School of Medicine, Stanford, Calif.; Frank Pajonk, M.D., Ph.D., assistant adjunct professor of radiation oncology, University of California, Los Angeles, David Geffen School of Medicine; Dec. 20, 2006, Journal of the National Cancer Institute; January 2007, Radiology 1: J Natl Cancer Inst. 2006 Dec 20;98(24):1777-85. Links Comment in: J Natl Cancer Inst. 2006 Dec 20;98(24):1755-7. The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. Phillips TM, McBride WH, Pajonk F. Department of Radiation Oncology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095-1714, USA. BACKGROUND: If cancer arises and is maintained by a small population of cancer-initiating cells within every tumor, understanding how these cells react to cancer treatment will facilitate improvement of cancer treatment in the future. Cancer-initiating cells can now be prospectively isolated from breast cancer cell lines and tumor samples and propagated as mammospheres in vitro under serum-free conditions. METHODS: CD24(-/low)/CD44+ cancer-initiating cells were isolated from MCF-7 and MDA-MB-231 breast cancer monolayer cultures and propagated as mammospheres. Their response to radiation was investigated by assaying clonogenic survival and by measuring reactive oxygen species (ROS) levels, phosphorylation of the replacement histone H2AX, CD44 levels, CD24 levels, and Notch-1 activation using flow cytometry. All statistical tests were two-sided. RESULTS: Cancer-initiating cells were more resistant to radiation than cells grown as monolayer cultures (MCF-7: monolayer cultures, mean surviving fraction at 2 Gy [SF(2Gy)] = 0.2, versus mammospheres, mean SF(2Gy) = 0.46, difference = 0.26, 95% confidence interval [CI] = 0.05 to 0.47; P = .026; MDA-MB-231: monolayer cultures, mean SF(2Gy) = 0.5, versus mammospheres, mean SF(2Gy) = 0.69, difference = 0.19, 95% CI = -0.07 to 0.45; P = .09). Levels of ROS increased in both mammospheres and monolayer cultures after irradiation with a single dose of 10 Gy but were lower in mammospheres than in monolayer cultures (MCF-7 monolayer cultures: 0 Gy, mean = 1.0, versus 10 Gy, mean = 3.32, difference = 2.32, 95% CI = 0.67 to 3.98; P = .026; mammospheres: 0 Gy, mean = 0.58, versus 10 Gy, mean = 1.46, difference = 0.88, 95% CI = 0.20 to 1.56; P = .031); phosphorylation of H2AX increased in irradiated monolayer cultures, but no change was observed in mammospheres. Fractionated doses of irradiation increased activation of Notch-1 (untreated, mean = 10.7, versus treated, mean = 15.1, difference = 4.4, 95% CI = 2.7 to 6.1, P = .002) and the percentage of the cancer stem/initiating cells in the nonadherent cell population of MCF-7 monolayer cultures (untreated, mean = 3.52%, versus treated, mean = 7.5%, difference = 3.98%, 95% CI = 1.67% to 6.25%, P = .009). CONCLUSIONS: Breast cancer-initiating cells are a relatively radioresistant subpopulation of breast cancer cells and increase in numbers after short courses of fractionated irradiation. These findings offer a possible mechanism for the accelerated repopulation of tumor cells observed during gaps in radiotherapy. PMID: 17179479 [PubMed - indexed for MEDLINE] 1: J Cell Biochem. 2009 Jul 21. [Epub ahead of print] Radiation responses of cancer stem cells. Vlashi E, McBride WH, Pajonk F. Division of Molecular and Cellular Oncology, Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California. Recent experimental evidence indicates that many solid cancers have a hierarchical organization structure with a subpopulation of cancer stem cells (CSCs). The ability to identify CSCs prospectively now allows for testing the responses of CSCs to treatment modalities like radiation therapy. Initial studies have found CSCs in glioma and breast cancer relatively resistant to ionizing radiation and possible mechanisms behind this resistance have been explored. This review summarizes the landmark publications in this young field with an emphasis on the radiation responses of CSCs. The existence of CSCs in solid cancers place restrictions on the interpretation of many radiobiological observations, while explaining others. The fact that these cells may be a relatively quiescent subpopulation that are metabolically distinct from the other cells in the tumor has implications for both imaging and therapy of cancer. This is particularly true for biological targeting of cancer for enhanced radiotherapeutic benefit, which must consider whether the unique properties of this subpopulation allow it to avoid such therapies. J. Cell. Biochem. (c) 2009 Wiley-Liss, Inc. PMID: 19623582 [PubMed - as supplied by publisher]