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It is well known that embryonic stem cells and induced pluripotent stem cells need feeder cells/ECM including laminins for their survival and growth in vitro [49]. We have also demonstrated that normal gastric epithelial cells can survive only in the presence of ECM [50]. Thus gastric TICs identified in the present study seem to retain some characteristics of normal stem cells, and TICs which can grow in the non-adherent condition may be derived from those which need ECM to grow. Our culture system may be useful to analyze how ECM-independent TICs emerge from ECM-dependent ones, and how it is related to the progression of cancer. It is interesting that HGC-1 cells were more tumorigenic than HGC-4 cells (Table 2), while the latter was more resistant to chemotherapeutic agents than the former (Figure 5), indicating that chemo-resistance and tumorigenicity are independent features of TICs.

Recently several drugs have been identified which specifically suppress the growth and induce the differentiation/apoptosis of TICs [51]�C[53]. Our culture system may also be useful to identify such new drugs that selectively target gastric TICs, especially at the first stage of tumorigenesis. Such compounds may work as prophylactic drugs to suppress gastric cancer especially for individuals and families at high risk for the disease. Supporting Information Figure S1 CD44-negative, CD133-negative cells form tumors with histological features of parental ones. HGC-2 and HGC-5 PDTXs were dissociated into single cells, and their tumorigenicity was analyzed by injecting sorted cells into immunodeficient mice.

CD44-negative, CD133-negative cell fractions (shown by red squares in FACS analyses) formed tumors with histological features of parental ones while CD44-positive cells (shown by black squares) were not tumorigenic. Tissue specimens are stained with Alcian blue-PAS-hematoxylin. Scale bars represent 50 ��m. (TIF) Click here for additional data file.(10M, tif) Figure S2 Cell surface antigen profiles are maintained in tumors formed by injection of CD49fhigh cells. Cell surface antigen profiles of HGC-3 and HGC-4 PDTX cells differed greatly, but these profiles of secondary tumors (right panels) formed by injection of CD49fhigh cells (shown by red squares in FACS analyses) into immunodeficient mice were similar to those of primary tumors (left panels).

(TIF) Click Cilengitide here for additional data file.(2.3M, tif) Figure S3 Gene expression profiles of human gastric tumor cell lines, PDTXs and sphere-forming TICs. MKN74 and MKN45 human gastric tumor cell lines, HGC-1 and HGC-4 PDTXs, and HGC-1 and HGC-4 sphere cells formed by culture of unsorted cells expressed stem cell-related genes including BMI1, NANOG, POU5F1, SOX2 and ITGA6 at similar levels though MKN74 cells did not express SOX2, and HGC-4 sphere cells expressed NANOG strongly. (TIF) Click here for additional data file.

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