Bericht der für den 9. Punkt des Programmes des Congresses deutscher Landwirthe niedergesetzten Commission

For the last several decades, cancer stem cells (CSCs) have been identified in many tumor types, including solid tumors such as colon, pancreatic and liver cancer. CSCs have been shown to be resistant to conventional chemotherapy and radiation therapy and are closely related to metastasis and recurrence. Radiation therapy is the most effective nonsurgical intervention for cancer treatment, but most cancers also invariably recur after radiation therapy. Therefore, development of powerful therapeutics could lead to advances in the treatment of cancer. The heavy ion medical accelerator in Chiba (HIMAC) is the world’s leading heavy ion cancer treatment facility, and we have treated more than 8000 of patients with various radioresistant cancers by HIMAC, and achieved promising results. Heavy-ion radiotherapy has several potential advantages over photon therapy such as the high relative biological effectiveness, the lack of the oxygen effect, and less cell cycle-related radiosensitivity. Here I try to report our recent new findings on the mechanisms of high radiocurability produced by carbon ion beam radiotherapy from the point of view of targeting cancer stem cells in vitro and in vivo.6th AnnualCongressof Regenerative Medicine & Stem Cell 201

Carbon-Ion Beam Irradiation Alone or in Combination with Zoledronic acid Effectively Kills Osteosarcoma Cells

Osteosarcoma(OSA)isthemostcommonmalignantbonetumorinchildrenandadolescents. The overall five-year survival rate for all bone cancers is below 70%; however, when the cancer has spread beyond the bone, it is about 15–30%. Herein, we evaluated the effects of carbon-ion beam irradiation alone or in combination with zoledronic acid (ZOL) on OSA cells. Carbon-ion beam irradiation in combination with ZOL significantly inhibited OSA cell proliferation by arresting cell cycle progression and initiating KHOS and U2OS cell apoptosis, compared to treatments with carbon-ion beam irradiation, X-ray irradiation, and ZOL alone. Moreover, we observed that this combination greatly inhibited OSA cell motility and invasion, accompanied by the suppression of the Pi3K/Akt and MAPK signaling pathways, which are related to cell proliferation and survival, compared to individual treatments with carbon-ion beam or X-ray irradiation, or ZOL. Furthermore, ZOL treatment upregulated microRNA (miR)-29b expression; the combination with a miR-29b mimic further decreased OSA cell viability via activation of the caspase 3 pathway. Thus, ZOL-mediated enhancement of carbon-ion beam radiosensitivity may occur via miR-29b upregulation; co-treatment with the miR-29b mimic further decreased OSA cell survival. These findings suggest that the carbon-ion beam irradiation in combination with ZOL has high potential to increase OSA cell death

A multimodal treatment of carbon ions irradiation, miRNA-34 and mTOR inhibitor specifically control high-grade chondrosarcoma cancer stem cells

Background and purposeHigh-grade chondrosarcomas are chemo- and radio-resistant cartilage-forming tumors of bone that often relapse and metastase. Thus, new therapeutic strategies are urgently needed.Material and methodsChondrosarcoma cells (CH-2879) were exposed to carbon-ion irradiation, combined with miR-34 mimic and/or rapamycin administration. The effects of treatment on cancer stem cells, stemness-associated phenotype, radioresistance and tumor-initiating properties were evaluated.ResultsWe show that high-grade chondrosarcoma cells contain a population of radioresistant cancer stem cells that can be targeted by a combination of carbon-ion therapy, miR-34 mimic administration and/or rapamycin treatment that triggers FOXO3 and miR-34 over-expression. mTOR inhibition by rapamycin triggered FOXO3 and miR-34, leading to KLF4 repression.ConclusionOur results show that particle therapy combined with molecular treatments effectively controls cancer stem cells and may overcome treatment resistance of high-grade chondrosarcoma

Synergistic Autophagy Effect of miR-212-3p in Zoledronic Acid-Treated In Vitro and Orthotopic In Vivo Models and in Patient-Derived Osteosarcoma Cells

Osteosarcoma (OS) originates from osteoid bone tissues and is prone to metastasis, resulting in a high mortality rate. Although several treatments are available for OS, an effective cure does not exist for most patients with advanced OS. Zoledronic acid (ZOL) is a third-generation bisphosphonate that inhibits osteoclast-mediated bone resorption and has shown efficacy in treating bone metastases in patients with various types of solid tumors. Here, we sought to clarify the mechanisms through which ZOL inhibits OS cell proliferation. ZOL treatment inhibited OS cell proliferation, viability, and colony formation. Autophagy inhibition by RNA interference against Beclin-1 or ATG5 inhibited ZOL-induced OS cell death. ZOL induced autophagy by repressing the protein kinase B/mammalian target of rapamycin/p70S6 kinase pathway and extracellular signal-regulated kinase signaling-dependent autophagy in OS cell lines and patient-derived OS cells. Microarrays of miRNA showed that ZOL increased the levels of miR-212-3p, which is known to play an important role in autophagy, in OS in vitro and in vivo systems. Collectively, our data provided mechanistic insight into how increased miR-212-3p through ZOL treatment induces autophagy synergistically in OS cells, providing a preclinical rationale for conducting a broad-scale clinical evaluation of ZOL + miR-212-3p in treating OS

Photonic hydrogel sensors

Analyte-sensitive hydrogels that incorporate optical structures have emerged as sensing platforms for point-of-care diagnostics. The optical properties of the hydrogel sensors can be rationally designed and fabricated through self-assembly, microfabrication or laser writing. The advantages of photonic hydrogel sensors over conventional assay formats include label-free, quantitative, reusable, and continuous measurement capability that can be integrated with equipment-free text or image display. This Review explains the operation principles of photonic hydrogel sensors, presents syntheses of stimuli-responsive polymers, and provides an overview of qualitative and quantitative readout technologies. Applications in clinical samples are discussed, and potential future directions are identified

New Insight into Molecular Mechanisms of Carbon-Ion Radiobiology: Targeting Cancer Stem Cells

Purpose Last few decades, more than 11000 cancer patients were treated by carbon-ion radiotherapy using HIMAC, and achieved promising outcomes. Here we attempt to elucidate underlying molecular mechanisms of high curability treated carbon-ion beams alone or in combination with DNA damaging drugs or with tyrosine kinase inhibitors or with microRNA modulators from the point of view of targeting cancer stem cells (CSCs). Methods Human pancreatic, liver, breast, and mesothelioma CSCs sorted from each cell line were treated with carbon-ion beam, X-ray irradiation alone or in combination with gemcitabine/cisplatin or sorafenib/lapatinib or miRNA200c mimic, and then cell viability assay, colony, spheroid formation ability assay, DNA damage assay (H2AX foci), and real time PCR analysis, and xenograft tumor control analysis were performed.Results The relative biological effectiveness (RBE) values for the carbon-ion beams relative to X-rays at the 10% survival levels for CSCs were estimated as 2.1 to 2.4. The colony and spheroid formation capability of CSCs was significantly inhibited by carbon-ion beam combined with gemcitabine/cisplatin or sorafenib/lapatinib or with micro RNA 200c mimic, accomplished with irreparable complex H2AX foci formation. RT Profiler PCR Array analysis showed that apoptosis- and autophagy-related gene expression was significantly induced after carbon ion beam combined with gemcitabine/cisplatin or with sorafenib/lapatinib compared to carbon ion alone in pancreatic, liver, breast cancer and mesothelioma cells. Xenograft tumors from pancreatic, liver, breast cancer and mesothelioma cells were effectively disrupted by 25 Gy of carbon-ion beam combined with 50 mg/kg gemcitabine for pancreatic xenograft tumors or 15 Gy of carbon-ion beam combined with 5 mg/kg cisplatin for breast and mesothelioma xenograft tumors. Conclusions Carbon-ion beam has high potential to kill various CSCs, and in combination with DNA damaging drugs or with tyrosine kinase inhibitors or with microRNA modulators can enhance its effects.16th International Congress of Radiation Researc

Overview of recent cutting-edge translational research in heavy-ion radiobiology

Research of heavy-ion radiobiology can be divided into two fields: for the heavy-ion radiotherapy and for the protection from the space radiation. Heavy-ion beams have definite advantages over the photon beams to treat many human cancers, especially effective in treating radioresistant tumors. Over the past 25 years, we have treated more than 11000 patients with many different cancer types using carbon-ion beams and achieved promising results. Here I try to present our cutting-edge research exploring mechanisms of how carbon-ion beams alone or in combination with DNA damaging drugs in targeting radioresistant cancer stem cells (CSCs). We found that carbon ion beam combined with DNA damaging drugs (gemcitabine or cisplatin) or with micro RNA 200c mimic significantly inhibited colony and spheroid formation capability of CSCs. Carbon ion beam combined with DNA damaging drugs significantly induced complex DNA damage, apoptosis- and autophagy-related gene expression compared to carbon ion alone in several cancer cells. Xenograft tumors from pancreatic, breast cancer and mesothelioma cells were effectively disrupted by 25 Gy of carbon ion beam combined with gemcitabine for pancreatic xenograft tumors or 15 Gy of carbon ion beam combined with cisplatin for breast and mesothelioma xenograft tumors. Taken together, carbon ion beam combined with DNA damaging drugs or with microRNA 200 mimic has high potential to kill pancreatic, breast and mesothelioma CSCs.7th international systems radiation biology worksho