Graphical abstract Epigenetic activation of WNT5A expression contributes to glioblastoma tumor recurrence by promoting differentiation of glioma-derived stem cells into endothelial cells.

HER2 is an important predictive marker for response to trastuzumab and lapatinib in breast cancer. It is also a powerful prognostic marker in node-positive patients. Although standardized assays are used to help select patients for anti-HER2 therapy, there are no standardized criteria for assessing HER2 as a prognostic marker. Recent data using quantitative image analysis suggest that both high and low HER2 expression are associated with poor clinical outcome. Using the immunohistochemical scoring criteria currently recommended by the College of American Pathologists and American Society of Clinical Oncology to help select patients for trastuzumab, we evaluated HER2 protein expression in tumor tissue microarrays of 91 node-positive patients with invasive breast carcinoma treated with mastectomy and doxorubicin-based chemotherapy without trastuzumab and without irradiation with a median follow-up of 12.5 years. A wide range of HER2 expression (HER2 ≥ 1 +) in the primary tumor was significantly associated with decreased locoregional recurrence-free survival (P = 0.014), decreased disease-specific survival (P = 0.001), and decreased overall survival (P = 0.001). Even in the subset considered HER2 negative by current College of American Pathologists and American Society of Clinical Oncology guidelines, HER2 = 1 + was associated with worse outcome than HER2 = 0 in this patient cohort. The association between HER2 ≥ 1 + and worse outcome had the greatest statistical significance in the hormone receptor-positive subset of patients. These findings support the hypothesis that low-level HER2 expression may have significant clinical implications. Although the assessment of HER2 expression is most important for predicting response to anti-HER2 therapy, detection of low-level HER2 expression might also be useful in helping to select a more aggressive treatment regimen for patients ineligible for anti-HER2 therapy.

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Purpose: Nucleolin is a major nucleolar protein that has been shown to be overexpressed in rapidly dividing cells and plays an essential role in cell proliferation and survival. However, the expression and significance of nucleolin in pancreatic ductal adenocarcinoma (PDA) have not been studied.Experimental Design: We used a tissue microarray consisting of 1.0-mm cores of tumor and paired nonneoplastic pancreatic tissue from 69 pancreaticoduodenectomy specimens with stage II PDA. Nucleolin expression was evaluated by immunohistochemistry and scored quantitatively by image analysis. Nucleolin expression was classified as nucleolin-high or nucleolin-low using the median nucleolin labeling index of 3.5% as cutoff. Staining results were correlated with clinicopathologic features and survival.Results: Both PDAs and PDA cell lines showed nucleolar staining for nucleolin. Nucleolin expression was higher in PDAs and PDA cell lines than in nonneoplastic ductal epithelial cells. Among the 69 stage II PDAs, 34 (49%) were nucleolin-high. The median overall survival was 65.2 ± 16.3 months for patients who had nucleolin-high PDAs compared with 19.5 ± 3.3 months for patients whose tumors were nucleolin-low (P = 0.03, log-rank method). No significant correlation between nucleolin expression and other clinicopathologic parameters was found. In multivariate analysis, nucleolin expression was a prognostic factor for overall survival in patients with stage II PDA independent of patient's age, gender, tumor size, differentiation, and lymph node status.Conclusions: Nucleolin was overexpressed in PDAs and PDA cell lines. A high level of nucleolar expression of nucleolin was an independent prognostic marker for better survival for patients with stage II PDAs. Clin Cancer Res; 16(14); 3734-42. ©2010 AACR.Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer death in the United States (1). Only 15% to 20% of patients diagnosed with PDA are surgically resectable and most of the patients who undergo resection have stage II disease. The long-term survival rate of patients who have curative resection is approximately 20%, with a median survival of 18 to 24 months (1). Despite pancreaticoduodenectomy, the disease commonly recurs, with the most common sites of recurrence being the liver, lung, peritoneal cavity, and pancreatic surgery bed; the prognosis is poor (1).Previous studies have shown that multiple genes are frequently altered in PDAs, including the activation of the K-ras oncogene by point mutation (2) and inactivation of the tumor suppressor genes p16 (3), SMAD4/ DPC4 (4, 5), and p53 (6). More recently, it has been shown that telomere shortening occurs at the early stage during the development of PDA. Telomere shortening was detected in 91% of the pancreatic intraepithelial neoplasia 1A (PanIN 1A), the earliest putative precursor lesion for PDAs (7). Telomere length is maintained by the human telomerase complex, which is composed of human telomerase RNA (hTR or TERC), and telomeraseassociated protein 1 ...

Preclinical data indicate that A6B4 integrin signaling through Ras homolog gene family, member A, plays an important role in tumor cell motility. The objective of this study was to determine whether the combined expression of A6B4 integrin and neuroepithelioma transforming gene 1 (Net1), a guanine nucleotide exchange factor specific for Ras homolog gene family member A, is associated with adverse clinical outcome in breast cancer patients. Immunohistochemical expression of each protein was evaluated in a tumor tissue microarray prepared from the primary tumors of 94 node-positive patients with invasive breast carcinoma treated with total mastectomy and doxorubicinbased chemotherapy without radiation with a median follow-up of 12.5 years. Associations between staining results and multiple clinicopathologic variables were investigated. Although there was no significant association between A6B4 integrin or Net1 expression and clinical outcome when each marker was considered individually, coexpression of A6B4 and Net1 was associated with decreased distant metastasis -free survival (P = 0.030). In the subset of patients with hormone receptor -positive tumors, coexpression of A6B4 and Net1 was associated with a decrease in distant metastasis -free and overall survival (P < 0.001 and P = 0.006, respectively). Although an association between human epidermal growth factor receptor 2 expression and coexpression of A6B4 and Net1 (P = 0.008) was observed, coexpression of A6B4 and Net1 (hazard ratio, 1.63; P = 0.02) and lymphovascular invasion (hazard ratio, 2.35; P = 0.02) were the only factors independently associated with the development of distant metastasis in multivariate analysis. These findings suggest that coexpression of A6B4 integrin and Net1 could be a useful biomarker for aggressive disease in node-positive breast cancer patients. (Cancer Epidemiol Biomarkers Prev 2009;18(1):80 -6)