The cancer stem cell (CSC) concept has been proposed as an attractive theory to explain cancer development, and CSCs themselves have been considered as targets for the development of diagnostics and therapeutics. However, many unanswered questions concerning the existence of slow cycling/quiescent, drug-resistant CSCs remain. Here we report the establishment of colon cancer CSC lines, interconversion of the CSCs between a proliferating and a drug-resistant state, and reconstitution of tumor hierarchy from the CSCs. Stable cell lines having CSC properties were established from human colon cancer after serial passages in NOD/Shi-scid, IL-2Rc null (NOG) mice and subsequent adherent cell culture of these tumors. By generating specific antibodies against LGR5, we demonstrated that these cells expressed LGR5 and underwent self-renewal using symmetrical divisions. Upon exposure to irinotecan, the LGR5 1 cells transitioned into an LGR5 2 drug-resistant state. The LGR5 2 cells converted to an LGR5 1 state in the absence of the drug. DNA microarray analysis and immunohistochemistry demonstrated that HLA-DMA was specifically expressed in drug-resistant LGR5 2 cells, and epiregulin was expressed in both LGR5 1 and drug-resistant LGR5 2 cells. Both cells sustained tumor initiating activity in NOG mice, giving rise to a tumor tissue hierarchy. In addition, anti-epiregulin antibody was found to be efficacious in a metastatic model. Both LGR5 1 and LGR5 2 cells were detected in the tumor tissues of colon cancer patients. The results provide new biological insights into drug resistance of CSCs and new therapeutic options for cancer treatment.
Antibodies can swiftly provide therapeutics to target disease-related molecules discovered in genomic research. Antibody engineering techniques have been actively developed and these technological innovations have intensified the development of therapeutic antibodies. From the mid-1990’s, a series of therapeutic antibodies were launched that are now being used in clinic. The disease areas that therapeutic antibodies can target have subsequently expanded, and antibodies are currently utilized as pharmaceuticals for cancer, inflammatory disease, organ transplantation, cardiovascular disease, infection, respiratory disease, ophthalmologic disease, and so on. This paper briefly describes the modes of action of therapeutic antibodies. Several non-clinical study results of the pathological changes induced by therapeutic antibodies are also presented to aid the future assessment of the toxic potential of an antibody developed as a therapeutic.
We examined the compression behavior of hexagonal‐close‐packed (hcp) (Fe0.88Si0.12)1H0.61 and (Fe0.88Si0.12)1H0.79 (in atomic ratio) alloys up to 138 GPa in a diamond anvil cell (DAC). While contradicting experimental results were previously reported on the compression curve of double‐hcp (dhcp) FeHx (x ≈ 1), our data show that the compressibility of hcp Fe0.88Si0.12Hx alloys is very similar to those of hcp Fe and Fe0.88Si0.12, indicating that the incorporation of hydrogen into iron does not change its compression behavior remarkably. The present experiments suggest that the inner core may contain up to 0.47 wt % hydrogen (FeH0.26) if temperature is 5000 K. The calculated density profile of Fe0.88Si0.12H0.17 alloy containing 0.32 wt % hydrogen in addition to geochemically required 6.5 wt % silicon matches the seismological observations of the outer core, supporting that hydrogen is an important core light element.
We examined the crystal structure of FeHX (X~1) (FeH hereafter) at high pressure and temperature by X-ray diffraction up to 137 GPa. Results show that FeH adopts a face-centered cubic (fcc) structure at pressures of 43 to 137 GPa and temperatures of ~1000 to 2000 K. Our study revises a phase diagram of stoichiometric FeH in which fcc has a wider-than-expected stability field at high pressure and temperature. Based on our findings, the FeH end-member of the Fe-FeH system is expected to be stable in the fcc structure at the P-T conditions of the Earth's core, rather than in the double-hexagonal close packed (dhcp) structure as previously reported. We compared the experimentally determined unit-cell volumes of FeH with those from ab initio calculations. Additionally, we observed a change in compressibility at ~60 GPa, which could be attributed to a magnetic transition—an interpretation supported by our ab initio computations.
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