Introduction
Article Outline
This issue of Seminars in Radiation Oncology addresses the subject of stem cells and the radiation treatment of cancer, discussing both tumors and normal tissues. Stem cells are not a new topic for radiation oncology, but there has been renewed interest in stem cells in tumors since the publication of articles initially by John Dick's group showing that human leukemic stem cells could be isolated, based on the expression of specific cell surface proteins (markers), and that a single cell could regrow the leukemia in immune-deprived mice. This demonstration was followed by a series of articles in the last 4 to 5 years documenting the enrichment of stemlike cells from solid tumors by sorting using cell surface markers (such as CD24, CD44, and CD133) and based on the ability of these cells to regrow the tumors in immune-deprived animals. These studies in solid tumors are discussed in the articles by O'Brien and Dick and by Diehn et al. The essence of these studies is that small numbers (50-200) of marker-positive cells are capable of regenerating a tumor, whereas much larger numbers of marker-negative or unsorted cells are required to achieve the same end.
Based on evidence from normal bone marrow and from animal tumor studies performed primarily in the 1960s and 1970s and from in vitro clonogenic assays performed on cells derived from primary human tumors done mostly in the 1980s and 1990s, the proportion of stem cells in solid tumors has generally been thought to be quite low (<1%). However, recent studies have reported that the proportion of cancer cells in a tumor that actually express the putative stem cell markers may vary from 1% to upwards of 25% in different tumors. Because the elimination of all the stem cells is required for effective tumor control, the sensitivity of these cells to the currently available treatments is of paramount importance. A number of groups have been investigating whether the drug and radiation sensitivity of marker-positive (stem) cells are different to that of the bulk population of cells in the tumor, and there is evidence reported that this may be the case. These issues are discussed in the articles by O'Brien and Dick, Diehn et al and Woodward and Bristow for drugs and radiation. The article by Milas and Hittelman revisits some of the data from the earlier animal studies and weaves the ideas generated in these studies into an analysis of the effects of some recently introduced targeted drugs combined with radiation.
A critical aspect of cancer is its ability to spread and metastasize to other organs. By definition, the growth of a metastasis must involve a tumor cell that has stem cell properties. The issue of metastasis in the context of stem cells and the tumor microenvironment, particularly hypoxia, which is known to exist in most solid tumors, is discussed in the article Hill et al.
It has been known for many years that renewal tissues, such as the bone marrow and intestine, contain stem cells that can repopulate these tissues, but, recently, restricted (adult) stem cells have been shown to exist in many other normal tissues, including brain and neural tissue. The article by Coppes et al reviews this area of research and describes studies in rodents that have shown partial recovery of salivary gland function after radiation damage by mobilizing bone marrow stem cells or by direct injection of stem cells specific to the salivary gland. The article by Fike et al focuses specifically on the stem cells in the normal brain and provides a detailed discussion of their response to irradiation. Bone marrow–derived stem cells are discussed in the article by Greenberger and Epperley. They describe the “niche” environment in the bone marrow, the response of the bone marrow stem cells to irradiation, their ability to migrate to different tissues in the body, and their potential contribution both to restoration of tissue function and also to increased fibrosis. Finally, they discuss the possible role of these cells in radiation-induced carcinogenesis.
The field of stem cell research is evolving rapidly. An example is the recent demonstration that normal fibroblasts can be induced to express stem cell properties by transfecting them with a group of 4 genes (OCT-3/4, SOX-2, Myc, and KLF4, which are discussed in the article by Coppes et al) and even more recently by the report that the requirement for the oncogenes Myc and KLF4 can be replaced by treatment with a histone deacetylase inhibitor.1 The potential for these induced pluripotent stem cells in the area of regenerative medicine is obvious, and there are significant possibilities that, in the future, such cells could be used to rescue organs damaged by radiation in individuals. In the current situation in which there are increasing numbers of cancer patients who are at risk for the development of late radiation damage caused by their (successful) treatment, this possibility is an important translational research goal.
Meanwhile, a very recent article2 has suggested that, under the right conditions, up to 25% of tumor cells obtained from primary human melanomas can express a stem cell phenotype and regrow the tumor when transplanted into immune-deprived mice, regardless of whether they express specific surface markers. The applicability of these findings in a wider range of tumors remains to be established but, considering the different hierarchical arrangements of stem cells and maturing/differentiating cells in different normal tissues, it is entirely possible that similar (but deranged) arrangements exist in different tumor types. This leads to the idea that the depth of the hierarchy (and hence the proportion of tumor cells that are stem cells) may be very variable across the tumor spectrum. Such speculation suggests that developing drugs, which target cells expressing putative stem cell surface markers, may be more applicable to some tumor types than others. Nevertheless, the push to develop such drugs is certain to enhance the current emphasis on the development of molecularly targeted therapies. Understanding how such therapies can best be used in combination with modern radiation therapy needs to be an important component of this drug development enterprise.
References
PII: S1053-4296(08)00083-0
doi:10.1016/j.semradonc.2008.12.001
© 2009 Elsevier Inc. All rights reserved.
