The Response of CD24−/low/CD44+ Breast Cancer–Initiating Cells to Radiation

Department of Radiation Oncology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095-1714, USA.
Journal of the National Cancer Institute (Impact Factor: 12.58). 01/2007; 98(24):1777-85. DOI: 10.1093/jnci/djj495
Source: PubMed


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.
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.
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).
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.

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Available from: William H Mcbride, Apr 08, 2015
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    • "ROS can also be produced by various oxidases, such as NADPH oxidases and peroxidases, in different cellular compartments or organelles, such as cell membranes, peroxisomes, and endoplasmic reticulum [3]. Furthermore, chemotherapy, radioactivity, and even smoking can increase ROS levels in the cell [4] [5] [6]. The low-to-moderate ROS level in the cell will generally promote cell proliferation and growth and increase cell survival [7]. "
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    ABSTRACT: Reactive oxygen species (ROS) and ROS-dependent (redox regulation) signaling pathways and transcriptional activities are thought to be critical in stem cell self-renewal and differentiation during growth and organogenesis. Aberrant ROS burst and dysregulation of those ROS-dependent cellular processes are strongly associated with human diseases including many cancers. ROS levels are elevated in cancer cells partially due to their higher metabolism rate. In the past 15 years, the concept of cancer stem cells (CSCs) has been gaining ground as the subpopulation of cancer cells with stem cell-like properties and characteristics have been identified in various cancers. CSCs possess low levels of ROS and are responsible for cancer recurrence after chemotherapy or radiotherapy. Unfortunately, how CSCs control ROS production and scavenging and how ROS-dependent signaling pathways contribute to CSCs function remain poorly understood. This review focuses on the role of redox balance, especially in ROS-dependent cellular processes in cancer stem cells (CSCs). We updated recent advances in our understanding of ROS generation and elimination in CSCs and their effects on CSC self-renewal and differentiation through modulating signaling pathways and transcriptional activities. The review concludes that targeting CSCs by manipulating ROS metabolism/dependent pathways may be an effective approach for improving cancer treatment.
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    • "In breast cancer, as few as 100 cells with the cell surface marker signature CD44 hi CD24 lo could generate a tumour, while tens of thousands of cells from the rest of the population were unable to do so [9]. Breast cancer stem-like cells (BCSCs) can be identified on the basis of this marker profile, as well as the ability to grow in serum-free anchorage independent cultures known as mammospheres [12] [22] [49]. In addition to their role in cancer Fig. 9. p38 MAPK mediates AJ-5 induced autophagy and apoptosis in breast cancer cells. "
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    • "Capability to develop into multiple lineages [4] [6] [7] [14] Potential to proliferate extensively [4] [6] [7] [14] Rare subpopulation of cells [4] Radioresistance [22] [23] Chemoresistance [19] [20] [21] Promote invasion and metastatic activity [26] [27] [28] "
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