Effects of carbon ion and X-ray irradiation on pancreatic cancer stem cells

Purpose:To investigate whether a carbon ion beam has beneficial effects compared to X-rays by targeting putative human pancreatic cancer stem cells. Materials:Human pancreatic cancer stem-like cells sorted from PANC1 and PK45 cells were treated with or without carbon ion or X-ray irradiation and then colony formation assay, spheroid formation assay, FACS analysis, as well as xenograft tumor growth control analyses were performed. Results:The in vitro relative biological effectiveness (RBE) values of carbon ion beams relative to X-rays calculated by the D10 levels were 1.71 to 2.18. FACS analysis showed that the proportion of cancer stem-like marker CD44+ and ESA+ cells were 4.8% and 0.9%, but CD133+ was undetectable. The proportion of CD44+, ESA+ cells was more significantly enriched by X-rays or gemcitabine treatment compared to carbon-ion irradiation. The proportion of CD44+ cells did not change after treatment with PI3K inhibitor LY29402 or MAPK inhibitor PD98059 only, but remarkably enriched in combination with X-rays or C-ion irradiation, suggesting that PI3K-AKt survival pathway as well as MAPK kinase pathway are involved in IR induced enrichment of CSC. CD44+/CD24+ and CD44+/ESA+ cells significantly have higher number of colony and spheroid compared to CD44-/CD24- and CD44-/ESA- cells. CD44+/CD24+ and CD44+/ESA+ cells showed radioresistance to both X-ray and carbon ion irradiation, but carbon ion irradiation was more effective at killing those of cancer stem-like cells. CD44+/CD24+ and CD44+/ESA+ cells have shown more potential to form tumors in SCID mice than CD44-/CD24- and CD44-/ESA- cells, and carbon ion beam more effectively eradicates xenograft tumors compared to X-rays at doses of same biological efficacy. Conclusion:Carbon ion irradiation has potential advantages over X-rays in targeting radioresistant pancreatic cancer stem-like cells.The 4th Asian-Oceanic Pancreatic Association (AOPA

Effects of Carbon Ion Beam on Pancreatic Cancer Stem-Like Cells In Vitro and In Vivo

PurposeTo investigate whether a carbon ion beam has beneficial effects compared to X-rays by targeting putative human pancreatic cancer stem cells. MaterialsHuman pancreatic cancer stem-like cells sorted from MiaPaca2, BxPc3, PANC1 and PK45 cells were treated with or without carbon ion or X-ray irradiation and then colony formation assay, spheroid formation assay, FACS analysis, as well as tumor formation analysis were performed. ResultsThe relative biological effectiveness (RBE) values of a carbon ion beam relative to X-ray for above pancreatic cancer cells at the D10 values were 1.71-2.18. The ability for colony, spheroid formation, and tumorigenicity from cancer stem-like CD44+/CD24+ cells is significantly higher than that from non-cancer stem-like cells CD44-/CD24-cells. FACS data showed that CD44+/CD24+ cells were more highly enriched after X-rays compared to carbon ion irradiation at isoeffective doses. The RBE values for the carbon ion beam relative to X-ray at the D10 levels for CD44+/CD24+ cells were 2.0-2.19. The number of gammaH2AX foci in CD44-/CD24- cells was higher than that of CD44+/CD24+ cells after irradiation with either X-ray or carbon ion beam. The number of gammaH2AX foci in CD44+/CD24+ cells was almost the same in the early time, but it persists for significantly longer in carbon ion beam irradiated cells compared to X-rays. ConclusionCarbon ion beam has superior potential to kill pancreatic cancer stem cell-like cells, and prolonged induction of DNA damage might be one of the pivotal mechanisms of its high radiobiological effects compared to X-rays.51st Annual Meeting of Particle Therapy Co-Operative Group (PTCOG51

Effects of Carbon Ion Beams on Liver Cancer Stem-Like Cells and Its Comparison with X-rays

To investigate whether a carbon ion beam has beneficial effects compared to X-rays by targeting putative cancer stem cells, human liver cancer stem-like cells sorted from HepG2 and Huh7 cells were treated with or without carbon ion or X-ray irradiation and then colony formation assay, spheroid formation assay, in vivo tumorigenesis analyses, FACS analysis, as well as gammaH2AX foci formation assay were performed. FACS analysis showed that the proportion of CD133+/CD90+, CD44+/ESA+ was more significantly enriched by X-rays compared to carbon-ion beam. CD133+/CD90+ and CD44+/ESA+ cells significantly have higher number of colony and spheroid compared to CD133-/CD90- and CD44-/ESA- cells. In addition, CD133+/CD90+ and CD44+/ESA+ cells have shown more potential to form tumors in SCID mice than CD133-/CD90- and CD44-/ESA- cells. Colony assay showed that CD133+/CD90+ and CD44+/ESA+ cells appeared to be radioresistant to both X-ray and carbon ion beam, but carbon beam was more effective at killing those of cancer stem-like cells. The number of gammaH2AX foci in CD44-/CD24- cells was higher than that of CD44+/CD24+ cells after irradiation with either X-ray or carbon ion beam. The number of gammaH2AX foci in CD44+/CD24+ cells was almost the same in the early time, but it persists for significantly longer in carbon ion beam irradiated cells compared to X-rays. In conclusion, CD133+/CD90+ and CD44+/ESA+ cells are putative liver cancer stem cells, and carbon ion beams induce prolonged DNA damage, therefore potentially have advantage by targeting liver cancer stem-like cells compared to X-rays.International Society for Stem Cell Research (ISSCR) 10 th Annual Meetin

Effects of Carbon Ion Beam on Pancreatic Cancer Stem-Like Cells In Vitro and In Vivo

PurposeTo investigate whether a carbon ion beam has beneficial effects compared to X-rays by targeting putative human pancreatic cancer stem cells. MaterialsHuman pancreatic cancer stem-like cells sorted from MiaPaca2, BxPc3, PANC1 and PK45 cells were treated with or without carbon ion or X-ray irradiation and then colony formation assay, spheroid formation assay, FACS analysis, as well as tumor formation analysis were performed. ResultsThe relative biological effectiveness (RBE) values of a carbon ion beam relative to X-ray for above pancreatic cancer cells at the D10 values were 1.71-2.18. The ability for colony, spheroid formation, and tumorigenicity from cancer stem-like CD44+/CD24+ cells is significantly higher than that from non-cancer stem-like cells CD44-/CD24-cells. FACS data showed that CD44+/CD24+ cells were more highly enriched after X-rays compared to carbon ion irradiation at isoeffective doses. The RBE values for the carbon ion beam relative to X-ray at the D10 levels for CD44+/CD24+ cells were 2.0-2.19. The number of gammaH2AX foci in CD44-/CD24- cells was higher than that of CD44+/CD24+ cells after irradiation with either X-ray or carbon ion beam. The number of gammaH2AX foci in CD44+/CD24+ cells was almost the same in the early time, but it persists for significantly longer in carbon ion beam irradiated cells compared to X-rays. ConclusionCarbon ion beam has superior potential to kill pancreatic cancer stem cell-like cells, and prolonged induction of DNA damage might be one of the pivotal mechanisms of its high radiobiological effects compared to X-rays.51st Annual Meeting of Particle Therapy Co-Operative Group (PTCOG51

The Role of XRCC4 in Sensitizing Human Colon Cancer Stem-Like Cells to X-ray or Carbon Ion Beam

Inactivation of XRCC4 is associated with various human carcinogenesis. Here we report expression changes of cancer stem-like cell markers in XRCC4 deficient human colon cancer cells after X-ray or carbon ion beam. FACS analysis showed that the percentage of CD133+, CD44+ and ESA+ cells in HCT116-WT cells were 3.2%, 6.8%, and 7.2%, whereas 1.6%, 19.2% and 20% in HCT116-XRCC4 KO cells. The proportion of CD133+ and CD44+ cells was increased 3 to 4-fold after 2 Gy X-ray irradiation in HCT116-WT cells, in comparison, 4 to 6- fold increment of CD133+ and CD44+ cells was induced in HCT116-XRCC4 KO cells. There was no change in proportion of ESA+ cells in HCT116-WT cells, but 10-fold enhancement of ESA+ cells was induced in HCT116-XRCC4 KO cells after 2 Gy X-ray irradiation. Colony and spheroid formation from CD133+, CD44+/ESA+ cells were higher compared to CD133-, CD44-/ESA- cells in HCT116-XRCC4 KO cells, but extremely decreased compared to HCT116-WT cells. In conclusion, expression of cancer stem-like cell markers significantly increased after X-ray irradiation in XRCC4 deficient cells, suggesting that XRCC4 may be involved in cancer cell stemness.54th Annual Meeting of ASTR

Carbon-Ion Therapy for Patients with Locally Recurrent Rectal Cancer

Purpose: To evaluate the tolerance for and effectiveness of carbon ion radiotherapy in patients with locally recurrent rectal cancer.Patients and Methods: We conducted a phase I/II dose escalation study of carbon ion radiotherapy. One hundred twenty-nine patients with 134 sites of locally recurrent cancer receiving carbon ion radiotherapy were analyzed.Fifty-eight relapses originated in the presacral region, 45 in the pelvic sidewalls, 20 in the perineal region and 9 in the colorectal anastomosis.The total dose ranged from 67.2 to 73.6 gray equivalent (GyE) and was administered in 16 fixed fractions over 4 weeks (4.2 to 4.6 GyE/fraction).Results: None of the 104 lesions treated with the highest total dose of 73.6 GyE experienced National Cancer Institute - Common Toxicity Criteria grade 3 to 5 acute reactions. The local control rate in patients treated with 73.6 GyE in the present study was 98% at one year and 95% at 5 years. The dose escalation was then halted at this level. The median survival in the patients treated with 73.6 GyE was 54 months (range, 7 to 82 months), and the overall survival rates were 74% at 3 years and 45% at 5 years, respectively.Conclusion: Carbon ion radiotherapy seems to be a safe and effective modality in the management of locally recurrent rectal cancer, providing good local control and offering a survival advantage without unacceptableThe 4th Japanese-European Joint Symposium on Ion Cancer Therap

Carbon Ion Radiotherapy for Pancreatic Cancer

The Heavy Ion Medical Accelerator in Chiba (HIMAC) is the world first heavy ion accelerator complex dedicated to medical use in a hospital environment. Carbon ion therapy offers the potential advantages of improved dose localization and enhanced biological effects. It has been suggested that carbon ion therapy is effective against radioresistant pancreatic cancer. In April 2000, clinical studies examining the treatment of pancreatic cancer with carbon ions were begun at the HIMAC. As of February 2010, 48 patients treated with preoperative carbon ion radiotherapy and 89 patients treated for locally advanced pancreatic cancer were enrolled into the clinical trials. Both protocols are still ongoing. The interim results of these clinical trials suggest that carbon ion radiotherapy provides good local control and offers a survival advantage for patients with otherwise hard to cure pancreatic cancer, without unacceptable morbidity.The KI-NIRS Joint Symposium on Ion-Radiation Science

Carbon Ion Radiotherapy for Pancreatic Cancer

The Heavy Ion Medical Accelerator in Chiba (HIMAC) is the world first heavy ion accelerator complex dedicated to medical use in a hospital environment. Carbon ion therapy offers the potential advantages of improved dose localization and enhanced biological effects. It has been suggested that carbon ion therapy is effective against radioresistant pancreatic cancer. In April 2000, clinical studies examining the treatment of pancreatic cancer with carbon ions were begun at the HIMAC. As of February 2010, 48 patients treated with preoperative carbon ion radiotherapy and 89 patients treated for locally advanced pancreatic cancer were enrolled into the clinical trials. Both protocols are still ongoing. The interim results of these clinical trials suggest that carbon ion radiotherapy provides good local control and offers a survival advantage for patients with otherwise hard to cure pancreatic cancer, without unacceptable morbidity