Dr. Weeks’ Comment: Mine, for years, was a radical minority opinion: chemo and radiation make your cancer worse. Only Prof. Max Wicha, M.D. agreed, stating that the reason was because injuring the cancer TUMOR cells with radiation (or chemotherapy) made the really dangerous cancer STEM cells – the only cancer which can spread – “more numerous and more virulent“. Now more and more research confirms that he and I were correct.
Recently published in the journal Cancer, UCLA researchers showed that radiation makes breast cancer cells MORE malignant. They found that radiation kills about half of the cancer TUMOR cells but, as I have taught for over a decade, radiation also transforms benign stem cells into “induced breast cancer STEM cells.” Though cancer stem cells make up less than 1 percent of a tumor, they are the ones which persists – become more numerous and more virulent when exposed to chemo or radiation therapy and will regenerate the original tumor. In fact, these new stem cells are up to 30 times more likely to form tumors compared to cancer cells that didn’t get radiation. Unlike cancer TUMOR cells, cancer STEM cells (CSCs) can also migrate through blood vessels spreading cancer to secondary locations.
Radiation treatment generates therapy‐resistant cancer stem cells from less aggressive breast cancer cells
Researchers from the Department of Radiation Oncology at the UCLA Jonsson Comprehensive Cancer Center report that radiation treatment transforms cancer cells into treatment‐resistant breast cancer stem cells, even as it kills half of all tumor cells.1
“When we look at early‐stage cancer patients, we compare patients receiving exactly the same treatment, and some fail and some are cured, and we can’t predict who those patients will be,” says Frank Pajonk, MD, PhD, the study’s senior author and an associate professor of radiation oncology and Jonsson Cancer Center researcher.
In some cases, cancer stem cells are generated by the therapy, but scientists do not yet understand all the mechanisms that cause this to occur. If they can determine the pathway and remove the reprogramming of cancer cells, they ultimately may be able to reduce the amount of radiation given to patients along with its accompanying side effects, says Dr. Pajonk.
The investigators found that induced breast cancer stem cells (iBCSCs) were generated by radiation‐induced activation of the same cellular pathways used to reprogram normal cells into induced pluripotent stem cells in regenerative medicine.
In the study, Dr. Pajonk and colleagues eliminated the smaller pool of BCSCs and then irradiated the remaining breast cancer cells and put them in mice. They were able to observe the initial generation into iBCSCs in response to the radiation treatment through a unique imaging system. These new cells were highly similar to the BCSCs that had been found in tumors that had not been irradiated. They also found that these iBCSCs had a more than 30‐fold increased ability to form tumors than the nonirradiated breast cancer cells.
Their findings show that if tumors are challenged by certain stressors that threaten them (such as radiation), they generate iBCSCs that may, along with surviving cancer stem cells, produce more tumors.
The researchers’ work continues as they begin to identify the pathways and several classes of drugs to prevent this process from occurring. To date, they have identified 2 different targets and drugs that could prevent it. The group has published their results of the study in breast cancer but also has made similar observations in both glioblastoma and head and neck cancer.
Dr. Pajonk says the study does not discredit radiation therapy. “Patients come to me scared by the idea that radiation generates these cells, but it truly is the safest and most effective therapy there is.”
Dr. Weeks’ Comment: Dr. Pajonk is incorrect. As a scientist he should have stated what is accurate
“Patients come to me scared by the idea that radiation generates these cells, but it truly is the safest and most effective therapy THAT I KNOW OF.”
In fact, taking safe and effective anti-inflammatory foods make radiation therapy safer. For example: when you take SOUL it not only enhances the killing effect of radiation therapy to the cancer tumor cells but it also protects the patient from side-effects.
“It has been shown that Nigella sativa L. (NS) and reduced glutathione (GSH) have both an anti-peroxidative effect on different tissues and a scavenger effect on ROS.” “These results clearly show that NS and GSH treatment significantly antagonize the effects of radiation. Therefore, NS and GSH may be a beneficial agent in protection against ionizing radiation-related tissue injury.” In vivo radioprotective effects of Nigella sativa L oil and reduced glutathione against irradiation-induced oxidative injury and number of peripheral blood lymphocytes in rats.
Cemek, M; Photochem Photobiol. 2006 Nov-Dec 82(6):1691-6.
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Cancer Stem Cells
Radiation‐Induced Reprogramming of Breast Cancer Cells***
Author contributions: C.L.: conception and design, collection and assembly of data, data analysis and interpretation, and manuscript writing; E.V.: conception and design and data analysis and interpretation; L.D.D.: conception and design; C.D.: collection and assembly of data; F.P.: conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript, and financial support.
*Disclosure of potential conflicts of interest is found at the end of this article.
*First published online in STEM CELLSEXPRESS February 10, 2012.
Abstract
Breast cancers are thought to be organized hierarchically with a small number of breast cancer stem cells (BCSCs) able to regrow a tumor while their progeny lack this ability. Recently, several groups reported enrichment for BCSCs when breast cancers were subjected to classic anticancer treatment. However, the underlying mechanisms leading to this enrichment are incompletely understood. Using non‐BCSCs sorted from patient samples, we found that ionizing radiation reprogrammed differentiated breast cancer cells into induced BCSCs (iBCSCs). iBCSCs showed increased mammosphere formation, increased tumorigenicity, and expressed the same stemness‐related genes as BCSCs from nonirradiated samples. Reprogramming occurred in a polyploid subpopulation of cells, coincided with re‐expression of the transcription factors Oct4, sex determining region Y‐box 2, Nanog, and Klf4, and could be partially prevented by Notch inhibition. We conclude that radiation may induce a BCSC phenotype in differentiated breast cancer cells and that this mechanism contributes to increased BCSC numbers seen after classic anticancer treatment. STEM CELLS 2012;30:833–844
INTRODUCTION
Recent clinical and preclinical data support the view that many solid cancers, including breast cancers, are organized hierarchically with a small number of cancer stem cells (CSCs) able to regrow a tumor while their progeny lack this feature [1, 2]. Clinically, CSCs have been associated with higher rates of recurrence and metastasis [3, 4]. Importantly, CSCs in breast cancer and glioma have been found to be relatively resistant to radiation and chemotherapy compared with their nontumorigenic progeny [5–7]. Consistent with these reports, several groups reported enrichment for CSCs when solid cancers were subjected to classic anticancer treatments [5, 6, 8].
Using an in vitro system, we quantified the number of breast CSCs (BCSCs) surviving after radiation treatment in patient samples as well as in several breast cancer lines. When we compared the absolute number of BCSCs that survived radiation treatment to the number of BCSCs expected to survive, we found a profound enrichment in BCSCs after exposure to ionizing radiation, and such a drastic increase in numbers could not easily be explained by differences in radiation sensitivity and/or by active repopulation. Here, we report that ionizing radiation induced a BCSC phenotype in previously nontumorigenic cells. This transition was Notch dependent and coincided with upregulation of transcription factors used to generate induced pluripotent cells from differentiated normal cells.
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DISCUSSION
Treatment gaps in radiation therapy have long been known to worsen the outcome for patients suffering from epithelial cancers including cancers of the head and neck region and the breast [22, 23]. The underlying mechanisms are incompletely understood but in general are attributed to accelerated repopulation, a phenomenon that refers to the increased growth rates of cancers during treatment gaps that far exceed their initial growth rates. It is thought that during accelerated repopulation, CSCs switch from an asymmetric type of cell division, which leads to one daughter CSC and one differentiating cell, to a symmetric type of cell division, which yields two identical daughter CSCs. Our data suggest that in addition to the classic view of accelerated repopulation in which CSCs switch from an asymmetric type of cell division that leads to one daughter CSC and one differentiating cells to a symmetric type of cell division that yields in two daughter CSCs, differentiated cancer cells may also be able to acquire stem cell traits under certain conditions of tumor microenvironmental stress, including stress induced by ionizing radiation. Acquisition of stem cell traits by CD133‐negative, nontumorigenic glioma cells was previously reported under hypoxic conditions [24] and in response to nitric oxide‐induced notch signaling [25], suggesting that CSC plasticity may be a common response to multiple stimuli including cancer therapies.
Our observation that ionizing radiation reactivated the same transcription factors in differentiated breast cancer cells that reprogram differentiated somatic cells into iPS cells is provoking. However, it is in line with recent reports that baseline levels of Sox2, Oct4, and Nanog expression can be detected in breast cancers [26, 27] and that ectopic overexpression of Oct4 in normal mammary epithelial cells induces a BCSCs phenotype [28]. Our data further indicate that an increase number of gene copies of Oct4 and Sox2 in polyploid cells could be one possible mechanism behind radiation‐induced reprogramming. This was supported by our data showing that downregulation of Sox2 prevented mammosphere formation. Downregulation of the Sox2 downstream target Nanog was less efficient, indicating that multiple genes downstream of Sox2 contribute to the acquisition of a CSCs phenotype. Similar observations have been reported for lymphoma cells [29]. Furthermore, this is in accordance with previous reports on Notch‐dependent induction of polyploidy [21] and our data showing that inhibition of Notch signaling partially prevented the occurrence of iBCSCs (Supporting Information Fig. S5B), suggesting that targeting Notch signaling might enhance local control after radiation therapy.
The CSC hypothesis was formulated more than a century ago [30]. However, until recently prospective identification of CSCs was impossible. The discovery of marker combinations that identify CSCs has resulted in novel insights into the biology of cancer. Still, the CSC hypothesis has been challenged and some experimental data support a model of clonal evolution as an alternative organizational structure of tumors [31] in which every cancer cell may acquire stem cell traits at some point.
Our study unites the competing models of clonal evolution and hierarchical organization of cancers [32], as it suggests that undisturbed growing tumors indeed maintain a low number of CSCs. However, if challenged by various stressors including ionizing radiation, iCSCs are generated, which may together with the surviving CSCs repopulate a tumor. These findings have implications for the design of novel treatment protocols that target CSCs, including radiation therapy. The curability of a cancer may not only be dependent on the intrinsic radiosensitivity of CSCs but also on the radiosensitivity of induced CSCs and the rate at which they are generated. Controlling the radio resistance of BCSCs and the generation of new iBCSCs during radiation treatment may ultimately improve curability and may allow for de‐escalation of the total radiation doses currently given to breast cancer patients thereby reducing acute and long‐term adverse effects.
CONCLUSIONS AND SUMMARY
In summary, our study shows that ionizing radiation reactivated the expression of Oct4 and Sox2 and induced a CSC phenotype in previously nontumorigenic breast cancer cells. The phenomenon was dependent on the induction of polyploidy and Notch signaling. We conclude that a detailed understanding of the underlying pathways could lead to novel combination therapies that will potentially enhance the efficacy of radiation treatment.
F.P. was supported by grants from the California Breast Cancer Research Program (15NB‐0153), the Department of Defense (W81XWH‐07‐1‐0065), and the National Cancer Institute (5RO1CA137110). C.L. was supported by an award from the Ward Family Foundation.