The cancer stem cell (CSC) hypothesis suggests that neoplastic clones are maintained exclusively by a rare fraction of cells with stem cell properties. Although the existence of CSCs in human leukaemia is established, little evidence exists for CSCs in solid tumours, except for breast cancer. Recently, we prospectively isolated a CD133+ cell subpopulation from human brain tumours that exhibited stem cell properties in vitro. However, the true measures of CSCs are their capacity for self renewal and exact recapitulation of the original tumour. Here we report the development of a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo. Only the CD133+ brain tumour fraction contains cells that are capable of tumour initiation in NOD-SCID (non-obese diabetic, severe combined immunodeficient) mouse brains. Injection of as few as 100 CD133+ cells produced a tumour that could be serially transplanted and was a phenocopy of the patient's original tumour, whereas injection of 10(5) CD133- cells engrafted but did not cause a tumour. Thus, the identification of brain tumour initiating cells provides insights into human brain tumour pathogenesis, giving strong support for the CSC hypothesis as the basis for many solid tumours, and establishes a previously unidentified cellular target for more effective cancer therapies.

Human brain tumors appear to have a hierarchical cellular organization suggestive of a stem cell foundation. In vitro expansion of the putative cancer stem cells as stable cell lines would provide a powerful model system to study their biology. Here, we demonstrate routine and efficient derivation of adherent cell lines from malignant glioma that display stem cell properties and initiate high-grade gliomas following xenotransplantation. Significantly, glioma neural stem (GNS) cell lines from different tumors exhibit divergent gene expression signatures and differentiation behavior that correlate with specific neural progenitor subtypes. The diversity of gliomas may, therefore, reflect distinct cancer stem cell phenotypes. The purity and stability of adherent GNS cell lines offer significant advantages compared to "sphere" cultures, enabling refined studies of cancer stem cell behavior. A proof-of-principle live cell imaging-based chemical screen (450 FDA-approved drugs) identifies both differential sensitivities of GNS cells and a common susceptibility to perturbation of serotonin signaling.

Male BC is usually ER, PR and AR-positive, Luminal B-like/HER2-negative. Of note, 56% patients had T1 tumors but only 4% had BCS. ER was highly positive in >90% of cases but only 77% received adjuvant ET. ER, PR and AR were associated with OS and RFS, whereas grade, Ki67 and IHC surrogates were not. Significant improvement in survival over time was observed.

Glioblastoma (GBM) is a cancer comprised of morphologically, genetically, and phenotypically diverse cells. However, an understanding of the functional significance of intratumoral heterogeneity is lacking. We devised a method to isolate and functionally profile tumorigenic clones from patient glioblastoma samples. Individual clones demonstrated unique proliferation and differentiation abilities. Importantly, naïve patient tumors included clones that were temozolomide resistant, indicating that resistance to conventional GBM therapy can preexist in untreated tumors at a clonal level. Further, candidate therapies for resistant clones were detected with clone-specific drug screening. Genomic analyses revealed genes and pathways that associate with specific functional behavior of single clones. Our results suggest that functional clonal profiling used to identify tumorigenic and drug-resistant tumor clones will lead to the discovery of new GBM clone-specific treatment strategies.cancer | glioblastoma | clonal heterogeneity | genomic analysis | functional analysis

Background: Previous reports identifying discordance between multiparameter tests at the

The recent description of novel recurrent gene fusions in approximately 80% of prostate cancer (PCa) cases has generated increased interest in the search for new translocations in other epithelial cancers and emphasizes the importance of understanding the origins and biologic implications of these genomic rearrangements. Analysis of 15 PCa cases by reverse transcription-polymerase chain reaction was used to detect six ERG-related gene fusion transcripts with TMPRSS2. No TMPRSS2/ETV1 chimeric fusion was detected in this series. Three-color fluorescence in situ hybridization confirms that TMPRSS2/ERG fusion may be accompanied by a small hemizygous sequence deletion on chromosome 21 between ERG and TMPRSS2 genes. Analysis of genomic architecture in the region of genomic rearrangement suggests that tracts of microhomology could facilitate TMPRSS2/ERG fusion events.

The epithelial to mesenchymal transition (EMT) is a cellular program that is involved in embryonic development; wound healing, but also in tumorigenesis. Breast carcinoma (BC) is the most common cancer in women worldwide, and the majority of deaths (90%) are caused by invasion and metastasis. The EMT plays an important role in invasion and subsequent metastasis. Several distinct biological events integrate a cascade that leads not only to a change from an epithelial to mesenchymal phenotype, but allows for detachment, migration, invasion and ultimately, colonization of a second site. Understanding the biological intricacies of the EMT may provide important insights that lead to the development of therapeutic targets in pre-invasive and invasive breast cancer, and could be used as biomarkers identifying tumor subsets with greater chances of recurrence, metastasis and therapeutic resistance leading to death.

Conventional cytogenetic and comparative genomic hybridization (CGH) studies have shown that osteosarcomas (OSs) are characterized by complex structural and numerical chromosomal alterations and gene amplification. In this study, we used high-resolution CGH to investigate recurrent patterns of genomic imbalance by use of DNA derived from nine OS tumors hybridized to a 19,200-clone cDNA microarray. In six OSs, there was copy number gain or amplification of 6p, with a minimal region of gain centering on segment 6p12.1. In seven OSs, the pattern of amplification affecting chromosome arm 8q showed high-level gains of 8q12-21.3 and 8q22-q23, with amplification of the MYC oncogene at 8q24.2. Seven OSs showed copy number gain or amplification of 17p between the loci bounded by GAS7 and PMI (17p11.2-17p12), and three of these tumors also showed small losses at 17p13, including the region containing TP53. An in silico analysis of the distribution of segmental duplications (duplicons) in this region identified a large number of tracts consisting of paralogous sequences mapping to the 17p region, encompassing the region of deletions and amplifications in OS. Interestingly, within this same region there were clusters of duplicons and several genes that are expressed during bone morphogenesis and in OS. In summary, microarray CGH analysis of the chromosomal imbalances of OS confirm the overall pattern observed by use of metaphase CGH and provides a more precise refinement of the boundaries of genomic gains and losses that characterize this tumor.