Given their unique functional properties, the CSC hypothesis has provided a potential explanation for several phenomena in clinical oncology. One such phenomenon is the noted discordance between early measures of clinical response and long-term outcomes for many cancers. For example, the efficacy of anti-tumor therapy is usually determined by serially evaluating tumor burden, and it is generally assumed that improvements in these parameters result in clinical benefit. Although disease control can alleviate symptoms in individual patients, the achievement of objective responses (i.e., tumor reduction) across a population may not be associated with improvements in long-term outcomes, such as the duration of overall survival (12
). In two large randomized clinical trials comparing initial therapies for newly diagnosed patients with AML, the administration of increased doses of chemotherapy significantly improved the proportion of patients achieving complete remissions (13
). However, despite improved disease control, no differences were observed in overall survival between treatment groups in either trial. In the plasma cell malignancy multiple myeloma, the relationship between the depth of response and overall survival has been examined in a variety of large randomized trials utilizing high-dose chemotherapy and autologous stem cell transplantation (15
). In many of these studies, the achievement of a complete response and total eradication of all macroscopic disease has not been associated with increased overall survival compared to patients achieving only partial remissions. These findings are also noted in solid tumors. For example, a number of large randomized studies utilizing combination chemotherapy in pancreatic adenocarcinoma have demonstrated improved rates of tumor response or progression free survival, but these demonstrated only negligible or no improvements in overall survival (16
). Overall, these studies demonstrate that response and survival rates may be independent entities in many diseases and suggest that each reflects treatment effects against distinct cancer cell types.
It is possible that the rarity of CSCs may explain the discrepancy between clinical response and survival in many malignancies since disease response primarily reflects short-term changes in bulk tumor cells, whereas long-term outcomes, such as disease relapse and progression, are dictated by rare CSCs. Initial studies using syngeneic transplants of murine cancer cells demonstrated that the frequency of tumor initiating cells are rare in multiple myeloma and lymphoma (1
), and similar findings have been observed through xenografting studies of primary human tumors in a wide variety of diseases (6
). However, a recent study in melanoma questioned the rarity of CSCs by demonstrating that modifications to the xenotransplantation protocol, including the use of more immunodeficient NOD/SCID/IL2γcnull
(NSG) mice, co-injection of tumor cells with matrigel, and waiting at least 20 weeks to assess tumor formation, dramatically increased the frequency of tumor initiating cells and eliminated their restriction to any specific phenotype (19
). These results may be specific to melanoma, since these experimental modifications have failed to significantly increase the frequency of clonogenic tumor cells in pancreatic, lung, and ovarian carcinomas (20
). Therefore, the relationship between disease response and survival may depend on the frequency of CSCs within a specific disease.
Tumor regrowth following treatment implies that CSCs persist and are relatively drug resistant compared to bulk tumor cells, and the mechanisms involved in this process have begun to be elucidated. CSC drug resistance can be broadly categorized as the ability to reduce intracellular levels of cytotoxic agents or the enhanced capacity to repair cytotoxic injury. In multiple myeloma, CSCs have been found to express several intrinsic properties that promote the resistance of normal stem cells to toxic injury (21
). These include increased expression of membrane-bound drug transporters and intracellular detoxification enzymes that mediate drug efflux and metabolism. CSCs in mantle cell non-Hodgkin's lymphoma (NHL) and CML have also been found to be relatively quiescent, and this property may promote drug resistance to cytotoxic agents that are dependent on cell cycle progression for their activity or by decreasing the expression of proteins or pathways inhibited by targeted therapies (22
In contrast, stem cells in glioblastoma and breast cancer have been found to be relatively radioresistant compared to the bulk tumor population based on enhanced repair mechanisms. Glioblastoma CSCs have increased activation of the DNA damage checkpoint response, while breast CSCs are able to minimize DNA damage via enhanced handling of reactive oxygen species (24
). Moreover, two studies using mouse xenograft models of colorectal and pancreatic cancer showed that tumors are enriched in CSCs following conventional chemotherapy, suggesting that they are also relatively drug resistant in vivo
). Finally, in a clinical study of patients with breast cancer, both the frequency of CSCs and the clonogenic growth potential of tumors were increased after treatment with conventional chemotherapy (28
). Therefore, CSCs have been found to be relatively resistant compared to bulk tumor cells in vitro
, in vivo
, and in the clinical setting.