Abstract
Although carbon ion therapy facilities are expensive, the biological effects of carbon ion beam treatment may be better against cancer (and cancer stem cells) than the effects of a photon beam. To investigate whether a carbon ion beam may have a biological advantage over X-rays by targeting cancer stem-like cells, human colon cancer cells were used in vitro and in vivo. The in vitro relative biological effectiveness (RBE) values of a carbon ion beam relative to X-rays at the D10 values were from 1.63 to 1.74. Cancer stem-like CD133(+), CD44(+)/ESA(+) cells had a greater ability for colony and spheroid formation, as well as in vivo tumorigenicity compared with the CD133(-), CD44(-)/ESA(-) cells. FACS (fluorescence-activated cell sorting) data showed that cancer stem-like cells were more highly enriched after irradiation with X-rays than carbon ion at doses that produced the same level of biological efficacy. A colony assay for cancer stem-like cells showed that RBE values calculated by the D10 levels were from 2.05 to 2.28 for the carbon ion beam relative to X-rays. The in vivo xenotransplant assay showed an RBE of 3.05 to 3.25, calculated from the slope of the dose-response curve for tumor growth suppression. Carbon ion irradiation with 15 Gy induced more severe xenograft tumor cell cavitation and fibrosis without significant enhancement of cells with putative cancer stem cell markers, CD133, ESA, and CD44, compared with 30 Gy X-rays, and marker positive cells were significantly decreased following 30 Gy carbon ion irradiation. Taken together, carbon ion beam therapy may have an advantage over photon beam therapy by improved targeting of putative colon cancer stem-like cells.
Highlights
Colorectal cancer is currently the most common gastrointestinal malignancy and remains the third most common cancer and second leading cause of cancer-related deaths in developed countries [1]
When equal numbers of 500 cells were plated in a dish, CD133þ, CD44þ/ESAþ colorectal cancer cells from HCT116 formed 64 Æ 10 and 87 Æ 6 clones, whereas CD133À or CD44À/ESAÀ cancer cells formed only 20 Æ 6 and 22 Æ 3 clones (P < 0.01; Fig. 2A)
These data showed that CD133þ or CD44þ/ESAþ colorectal cancer cells had much greater clonal formation capacities than that of CD133À or CD44À/ESAÀ cancer cells
Summary
Colorectal cancer is currently the most common gastrointestinal malignancy and remains the third most common cancer and second leading cause of cancer-related deaths in developed countries [1]. Determination of the mechanisms of recurrence and radioresistance in these tumors and development of powerful therapeutics could lead to advances in the treatment of cancer. Authors' Affiliations: 1Heavy-Ion Radiobiology Research Group, 2Research Center Hospital for Charged Particle Therapy, and 3Department of Radiation Emergency Medicine, Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences (NIRS); 4Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan. HIMAC has been successful in treating more than 5,000 cases of various human cancers and achieved promising clinical outcomes for many radioresistant tumor types, including recurrent colorectal cancer, hepatocellular carcinoma, chondroma, and sarcoma [7,8,9,10]
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