Abstract
Chemotherapy, radiation, and growth inhibitory drugs preferentially eliminate actively growing cancer cells. Cancer recurrence is currently thought to be due to nondividing cancer stem/progenitor cells that are resistant to these therapies. Different therapeutic approaches need to be considered for the elimination of the cancer stem cell population. Immunotherapy is one such approach. In addition to specificity and lack of toxicity, immunotherapy targets cancer cells irrespective of their state of proliferation, as long as they express particular tumor antigens. For that reason, it is important to examine if the tumor antigens that are currently being tested as immunotherapeutic agents are also present on cancer stem cells. This study aimed to determine if one well-known tumor antigen, MUC1, which is being tested as an immunotherapy target on tumor cells, is also expressed on the quiescent cancer stem/progenitor cells. We used the so-called side population (SP) cells found in the MCF7 breast cancer cell line, which we first confirmed by cell surface markers and gene profiling to be highly enriched in cells that fulfill specific functional, phenotypic, and molecular criteria for being tumor stem/progenitor cells. We show that these cells express MUC1 and give rise to MUC1(+) tumors in vivo, which maintain the MUC1(+) SP population. MUC1 on SP cells is hypoglycosylated and heavily sialylated; the characteristics of the tumor-specific form were expressed on mature cancer cells and recognized by tumor-specific T cells and antibodies. This suggests that stem/progenitor cells, like mature tumor cells, would be targets of MUC1-directed immunotherapy.
Highlights
Most current therapies for cancer preferentially target rapidly cycling cells and are not expected to have a cytotoxic effect on nondividing cells
When Hoechst blue and red fluorescence signals are plotted against one another, cells that have effluxed the dye form a tail-like structure called side population (SP), which separates these cells from the majority of brightly staining mature tumor cells
Our study reports for the first time that MUC1 molecule is expressed on mature cancer cells, and on tumor cells that have multiple characteristics of stem and progenitor cells
Summary
Most current therapies for cancer preferentially target rapidly cycling cells and are not expected to have a cytotoxic effect on nondividing cells. If the hypothesis is correct that tumor recurrence is driven by a small population of resting, therapyresistant stem cells [1], this has enormous implications for designing new tumor therapies that would target these cells as well. Immunotherapy is one type of therapy that could be expected to target both the mature dividing tumor cells and the quiescent tumor stem cells, dependent primarily on their expression of the target antigens. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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