Colorectal cancer hepatic metastases resection margins outcomes: a single-centre retrospective cohort study.

Background: Surgical resection is the most efficient treatment for isolated colorectal cancer hepatic metastases. Among the known prognostic factors of this procedure, the impact of the resection margin width is still a controversial matter in the literature. Methods: A retrospective cohort study was performed including 170 patients who underwent surgical resection of colorectal cancer liver metastases (CRLMs) between 2006 and 2016 in our hepatobiliary unit. Resection margin width was determined histologically by measuring the distance from the tumour in millimetres or centimetres. Patients' clinical characteristics were also collected. Patients were then stratified in two tumour margin groups: below 5 mm (group A) and equal to or above 5 mm (group B). Overall survival (OS) and disease-free survival (DFS) were the primary outcomes. Results: Kaplan-Meier curves showed significantly better outcomes for cases having resection margins above 5 mm for both DFS with 1508.7 days (range 1151.2-1866.2) in group A, compared to 2463.9 days (range 2021.3-2906.5) in group B (P=0.049), and OS with 1557.8 days (range 1276.3-1839.3) for group A and 2303.8 days (range 1921.2--2686.4) for group B (P=0.020). This survival benefit was not significant for patients presenting with stage IV CRC at diagnosis or cases where extended (7+ segments) resections were performed. Conclusion: Five-millimetre margins provide a significant survival advantage and should be aimed for in the treatment of CRLMs. Further research on the cause for this finding, including tumour biology's impact on survival, is required.

Brain cancer stem cells: current status on glioblastoma multiforme.

Glioblastoma multiforme (GBM), an aggressive brain tumor of astrocytic/neural stem cell origin, represents one of the most incurable cancers. GBM tumors are highly heterogeneous. However, most tumors contain a subpopulation of cells that display neural stem cell characteristics in vitro and that can generate a new brain tumor upon transplantation in mice. Hence, previously identified molecular pathways regulating neural stem cell biology were found to represent the cornerstone of GBM stem cell self-renewal mechanism. GBM tumors are also notorious for their resistance to radiation therapy. Notably, GBM "cancer stem cells" were also found to be responsible for this radioresistance. Herein, we will analyze the data supporting or not the cancer stem cell model in GBM, overview the current knowledge regarding GBM stem cell self-renewal and radioresistance molecular mechanisms, and discuss the potential therapeutic application of these findings.

BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery.

Glioblastoma multiforme (GBM) is an aggressive brain tumor that is resistant to all known therapies. Within these tumors, a CD133-positive cancer-initiating neural stem cell (NSC) population was shown to be resistant to gamma radiation through preferential activation of the DNA double-strand break (DSB) response machinery, including the ataxia-telangiectasia-mutated (ATM) kinase. The polycomb group protein BMI1 is enriched in CD133-positive GBM cells and required for their self-renewal in an INK4A/ARF-independent manner through transcriptional repression of alternate tumor suppressor pathways. We report here that BMI1 copurifies with DNA DSB response and nonhomologous end joining (NHEJ) repair proteins in GBM cells. BMI1 was enriched at the chromatin after irradiation and colocalized and copurified with ATM and the histone gammaH2AX. BMI1 also preferentially copurified with NHEJ proteins DNA-PK, PARP-1, hnRNP U, and histone H1 in CD133-positive GBM cells. BMI1 deficiency in GBM cells severely impaired DNA DSB response, resulting in increased sensitivity to radiation. In turn, BMI1 overexpression in normal NSCs enhanced ATM recruitment to the chromatin, the rate of gammaH2AX foci resolution, and resistance to radiation. BMI1 thus displays a previously uncharacterized function in controlling DNA DSB response and repair. Pharmacological inhibition of BMI1 combined with radiation therapy may provide an effective mean to target GBM stem cells.

BMI1 sustains human glioblastoma multiforme stem cell renewal.

Glioblastoma multiforme (GBM) is one of the most common and aggressive types of brain tumors. In GBM, a subpopulation of CD133-positive cancer initiating cells displays stem cell characteristics. The Polycomb group (PcG) and oncogene BMI1 is part of the Polycomb repressive complex 1 (PRC1) that regulates gene expression by modifying chromatin organization. Here we show that BMI1 is expressed in human GBM tumors and highly enriched in CD133-positive cells. Stable BMI1 knockdown using short hairpin RNA-expressing lentiviruses resulted in inhibition of clonogenic potential in vitro and of brain tumor formation in vivo. Cell biology studies support the notion that BMI1 prevents CD133-positive cell apoptosis and/or differentiation into neurons and astrocytes, depending on the cellular context. Gene expression analyses suggest that BMI1 represses alternate tumor suppressor pathways that attempt to compensate for INK4A/ARF/P53 deletion and PI(3)K/AKT hyperactivity. Inhibition of EZH2, the main component of the PRC2, also impaired GBM tumor growth. Our results reveal that PcG proteins are involved in GBM tumor growth and required to sustain cancer initiating stem cell renewal.