Differential expression of senescence and cell death factors in non-small cell lung and colorectal tumors showing telomere attrition.

OBJECTIVE: The main aim of this work is to investigate the expression of factors related to senescence and cell death pathways in non-small cell lung cancers (NSCLCs) and colorectal cancers (CRCs) in relation to telomere status. METHODS: We analyzed 158 tissue samples, 36 NSCLCs, 43 CRCs, and their corresponding control tissues obtained from patients submitted to surgery. Telomere function was evaluated by determining telomerase activity and telomere length. Expression of factors related to senescence, cell death pathways, transformation and tumorigenesis was investigated using arrays. Results were validated by real-time quantitative PCR. RESULTS: Considering tumors with telomere shortening, expression for BNIP3, DAPK1, NDRG1, EGFR, and CDKN2A was significantly higher in NSCLC than in CRC, whereas TP53 was overexpressed in CRC with respect to NSCLC. Moreover, compared to nontumor samples, DAPK1, GADD45A, SHC1, and TP53 were downregulated in the group of NSCLCs with telomere shortening, and no significant differences were found in CRC. CONCLUSIONS: In NSCLC, the failure of pathways which involve factors such as DAPK1, GADD45A, SHC1, and TP53, in response to short telomeres, could promote tumor progression. In CRC, the viability of these pathways in response to short telomeres could contribute to limiting tumorigenesis.

Clinicopathological variables, immunophenotype, chromosome 1p36 loss and tumour recurrence of 247 meningiomas grade I and II.

The WHO grading scheme distinguishes benign (grade I), atypical (grade II) and anaplastic (grade III) meningiomas. Both atypical and anaplastic meningiomas exhibited an overall increased rate of recurrence, but between 15-20% benign meningiomas will also exhibit an unfavourable clinical course with recurrence before 10 years despite aggressive surgery. We investigated 247 cases of meningiomas grade I and II. The immunohistochemical expression of 30 different molecular biomarkers of cell adhesion molecules, cell-cycle and apoptosis regulators and checkpoints was analyzed. We also determined apoptosis by in-situ hybridization (APOPDETEKTM) and loss of chromosome 1p36 by FISH. The study revealed a statistically significant co-variation (p<0.05) between meningiomas grade II associated with several clinicopathological features (Simpson grade of clinical resection, necrosis, nuclear atypia, macronucleoli, transition to small cell, sheet-like growth, high cellularity), increased expression of several biomarkers of tumour proliferation (Cyclin A, Cyclin E, MIB-1 or MDM2), proteases (Cathepsin D) or cell-adhesion (CD44) and lower expression of progesterone receptors than meningiomas grade I. The presence of Psammoma bodies or the location at convexity were protective prognostic factors for tumour recurrence while high cellularity and early age of onset (<57 year-old) were indicators of increased recurrence risk. The expression of COX-2, gamma-catenin, Topoisomerase IIa, VEGF and MIB-1 was significantly higher in the cohort of recurrent meningiomas. Meningiomas with chromosome 1p36 loss showed a higher recurrence rate (33.3%) than meningiomas with normal chromosome 1p36 (18%). Increased COX-2 expression in recurrent meningioma may also suggest a putative role of COX-2 inhibitors as a chemopreventive treatment for recurrence.