A number of recent reports have demonstrated that only CD133-positive cancer cells of glioblastoma multiforme (GBM) have tumor-initiating potential. These findings raise an attractive hypothesis that GBMs can be cured by eradicating CD133-positive cancer stem cells (CSCs), which are a small portion of GBM cells. However, as GBMs are known to possess various genetic alterations, GBMs might harbor heterogeneous CSCs with different genetic alterations. Here, we compared the clinical characteristics of two GBM patient groups divided according to CD133-positive cell ratios. The CD133-low GBMs showed more invasive growth and gene expression profiles characteristic of mesenchymal or proliferative subtypes, whereas the CD133-high GBMs showed features of cortical and well-demarcated tumors and gene expressions typical of proneuronal subtype. Both CD133-positive and CD133-negative cells purified from four out of six GBM patients produced typical GBM tumor masses in NOD-SCID brains, whereas brain mass from CD133-negative cells showed more proliferative and angiogenic features compared to that from CD133-positive cells. Our results suggest, in contrast to previous reports that only CD133-positive cells of GBMs can initiate tumor formation in vivo CD133-negative cells also possess tumor-initiating potential, which is indicative of complexity in the identification of cancer cells for therapeutic targeting. A recent concept in brain tumor biology is that brain tumors arise from cancer stem cells (CSCs) that are CD133 positive (CD133 ( þ ) ). It has been reported that a small number of CD133 ( þ ) glioblastoma multiforme (GBM) cells are able to recapitulate the original tumor in vivo, whereas millions of CD133-negative (CD133 (À) ) cells could not produce brain tumor masses. 1-6 However, accumulating evidence suggests that CD133 (À) GBM cells can also regenerate heterogenous tumors in vivo, 7,8 and generation of the huge and rapidly growing tumors by only CD133 ( þ ) CSCs would be difficult because more than 50% of GBM patients have few CD133 ( þ ) cells. 9 As a majority of neurogenic astrocytes in the adult brain are not recognized by a CD133 antibody, 8 it is likely that CD133 might be newly expressed in GBM CSCs that are derived from CD133 (À) adult neural stem cells (NSCs) or terminally differentiated brain cells, such as astrocytes, neurons, and oligodendrocytes. Given that the gene expression profile is changed when GBM recurs after treatments, 10 it is plausible that new CD133 expression may occur if the characteristics of CSCs are changed or if some CSCs are selected by treatment. Furthermore, the wide-range variation in CD133 ( þ ) cell ratio (0.1-50% in GBM patients) 1-6 also suggests the existence of other GBM CSCs that do not express CD133.Therefore, we hypothesize that there are several kinds of CSCs in the tumor mass of GMB, and these diverse CSCs

Missense somatic mutations in IDH1 gene affecting codon 132 have recently been reported in glioblastoma multiforme (GBM) and other gliomas. The recurrent nature of the IDH1 mutations in the same amino acid strongly suggests that the mutations may play important roles in the pathogenesis of glial tumors. The aim of this study was to see whether the IDH1 codon 132 mutations occur in other human cancers besides glial tumors. We also attempted to confirm the occurrence of the IDH1 mutations in GBM of Korean patients. We have analyzed 1,186 cancer tissues from various origins, including carcinomas from breast, colon, lung, stomach, esophagus, liver, prostate, urinary bladder, ovary, uterine cervix, skin and kidney, and malignant mesotheliomas, primary GBM, malignant meningiomas, multiple myelomas and acute leukemias by single-strand conformation polymorphism analysis. We found four IDH1 codon 132 mutations in the GBM (4/25; 16.0%), two in the prostate carcinomas (2/75; 2.7%) and one in the B-acute lymphoblastic leukemias (B-ALL) (1/60; 1.7%), but none in other cancers. The IDH1 mutations consisted of five p.R132H and two p.R132C mutations. The data indicate that IDH1 codon 132 mutations occur not only in GBM, but also in prostate cancers and B-ALL. This study suggests that despite the infrequent incidence of the IDH1 mutations in prostate cancers and B-ALL, mutated IDH1 could be therapeutically targeted in these cancers and in glial tumors with the IDH1 mutations. ' 2009 UICC

Mounting evidence indicates that alterations of autophagy processes are directly involved in the development of many human diseases, including cancers. Autophagy-related gene (ATG) products are main players in the autophagy process. In humans there are 16 known ATG genes, of which four (ATG2B, ATG5, ATG9B and ATG12) have mononucleotide repeats with seven or more nucleotides. Frameshift mutations of genes with mononucleotide repeats are features of cancers with microsatellite instability (MSI). It is not known whether ATG genes with mononucleotide repeats are altered by frameshift mutations in gastric and colorectal carcinomas with MSI. For this, we analysed the mononecleotide repeats in ATG2B, ATG5, ATG9B and ATG12 in 32 gastric carcinomas with high MSI (MSI-H), 13 gastric carcinomas with low MSI (MSI-L), 43 colorectal carcinomas with MSI-H and 15 colorectal carcinomas with MSI-L by a single-strand conformation polymorphism (SSCP) analysis. We found ATG2B, ATG5, ATG9B and ATG12 mutations in 10, 2, 13 and 0 cancers, respectively. The mutations were detected in MSI-H cancers but not in MSI-L cancers. Gastric and colorectal cancers with MSI-H harboured one or more ATG mutations in 28.1% and 27.9%, respectively. Our data indicate that frameshift mutations in ATG genes with mononucleotide repeats are common in gastric and colorectal carcinomas with MSI-H, and suggest that these mutations may contribute to cancer development by deregulating the autophagy process.