Bmi1 regulates human glioblastoma stem cells through activation of differential gene networks in CD133+ brain tumor initiating cells.

PURPOSE: Glioblastoma (GBM) is the most aggressive adult brain cancer, with a 15 month median survivorship attributed to the existence of treatment-refractory brain tumor initiating cells (BTICs). In order to better understand the mechanisms regulating the tumorigenic properties of this population, we studied the role of the polycomb group member BMI1 in our patient-derived GBM BTICs and its relationship with CD133, a well-established marker of BTICs. METHODS: Using gain and loss-of-function studies for Bmi1 in neural stem cells (NSCs) and patient-derived GBM BTICs respectively, we assessed in vitro self-renewal and in vivo tumor formation in these two cell populations. We further explored the BMI1 transcriptional regulatory network through RNA sequencing of different GBM BTIC populations that were knocked down for Bmi1. RESULTS: There is a differential role of BMI1 in CD133-positive cells, notably involving cell metabolism. In addition, we identified pivotal targets downstream of BMI1 in CD133+ cells such as integrin alpha 2 (ITGA2), that may contribute to regulating GBM stem cell properties. CONCLUSIONS: Our work sheds light on the association of three genes with CD133-BMI1 circuitry, their importance as downstream effectors of the BMI1 signalling pathway, and their potential as future targets for tackling GBM treatment-resistant cell populations.

Objective-subjective disparity in cancer-related cognitive impairment: does the use of change measures help reconcile the difference?

OBJECTIVE: Studies to date have found little correlation between subjective and objective measures of cognitive function in cancer patients, making it difficult to interpret the significance of their cognitive complaints. The purpose of this study was to determine if a stronger correlation would be obtained using measures of cognitive change rather than static scores. METHODS: Sixty women with early stage breast cancer underwent repeated cognitive assessment over the course of chemotherapy with a neuropsychological test battery (objective measure) and with the FACT-Cog (subjective measure). Their results were compared to 60 healthy women matched on age and education and assessed at similar intervals. We used multilevel modeling, with FACT-Cog as the dependent measure and ordinary least squares slopes of a neuropsychological summary score as the independent variable, to evaluate the co-variation between the subjective and objective measures over time RESULTS: Measures of both objective and subjective cognitive function declined over the course of chemotherapy in the breast cancer patients but there was no significant relationship between them, even when using change measures. Change in objective cognitive function was not related to change in anxiety or fatigue scores but the decline in perceived cognitive function was associated with greater anxiety and fatigue. CONCLUSIONS: The discrepancy in objective and subjective measures of cognition in breast cancer patients cannot be accounted for in terms of a failure to use change measures. Although the results are negative, we contend that this is the more appropriate methodology for analyzing cancer-related changes in cognition.

Clearing the air: a review of our current understanding of "chemo fog".

An increasing number of cancer survivors has led to a greater interest in the long-term side effects of cancer treatments and their impact on quality of life. In particular, cognitive impairments have been frequently reported by cancer survivors as an adverse effect which they attribute to the neurotoxicity of chemotherapy and have dubbed "chemobrain" or "chemo fog." Research within the past 15-20 years has explored the many factors thought to contribute to cancer-related cognitive decline in an attempt to determine a potential cause. In spite of many confounding factors, there is growing evidence that the neurotoxicity of chemotherapy does contribute to cognitive changes. This review examines the evolution of "chemo fog" research with a look at methodological issues, the status of our current understanding, and suggestions for future research.

A cancer stem cell model for studying brain metastases from primary lung cancer.

BACKGROUND: Brain metastases are most common in adults with lung cancer, predicting uniformly poor patient outcome, with a median survival of only months. Despite their frequency and severity, very little is known about tumorigenesis in brain metastases. METHODS: We applied previously developed primary solid tumor-initiating cell models to the study of brain metastases from the lung to evaluate the presence of a cancer stem cell population. Patient-derived brain metastases (n = 20) and the NCI-H1915 cell line were cultured as stem-enriching tumorspheres. We used in vitro limiting-dilution and sphere-forming assays, as well as intracranial human-mouse xenograft models. To determine genes overexpressed in brain metastasis tumorspheres, we performed comparative transcriptome analysis. All statistical analyses were two-sided. RESULTS: Patient-derived brain metastasis tumorspheres had a mean sphere-forming capacity of 33 spheres/2000 cells (SD = 33.40) and median stem-cell frequency of 1/60 (range = 0-1/141), comparable to that of primary brain tumorspheres (P = .53 and P = .20, respectively). Brain metastases also expressed CD15 and CD133, markers suggestive of a stemlike population. Through intracranial xenotransplantation, brain metastasis tumorspheres were found to recapitulate the original patient tumor heterogeneity. We also identified several genes overexpressed in brain metastasis tumorspheres as statistically significant predictors of poor survival in primary lung cancer. CONCLUSIONS: For the first time, we demonstrate the presence of a stemlike population in brain metastases from the lung. We also show that NCI-H1915 tumorspheres could be useful in studying self-renewal and tumor initiation in brain metastases. Our candidate genes may be essential to metastatic stem cell populations, where pathway interference may be able to transform a uniformly fatal disease into a more localized and treatable one.