Cell Cycle Markers in the Evaluation of Bladder Cancer

Abstract

Bladder cancer (BC) is a heterogeneous neoplasia characterized by a high number of recurrences. Standardized clinical and morphological parameters are not always sufficient to predict individual tumor behavior. The aim of this study was to evaluate the expression of cell cycle regulators proteins as potential adjuvant in prognosis and monitoring of this disease. Block paraffin samples from patients with urothelial bladder carcinoma treated by transurethral resection (TUR) were collected to immunohistochemistry analysis for proteins p16, p21, p27, p53, pRb and Ki-67. Chisquare, logistic regression and Kaplan-Meier curve were used to analyze the prognostic value of these markers. Of the 93 patients included in the study, the main categories of staging observed were T1 (53%) and Ta (29%), and the distribution between tumor grades was 58% of patients with low grade to 42% of patients with high grade. The expressions of p16, p21, p27, p53, pRb and Ki-67 were altered in 31%, 42%, 60%, 91%, 27% and 56% of patients, respectively. The immunohistochemical expression of Ki-67 was associated with tumor histological grade (p = 0.016), and expression of pRb with recurrence-free survival (p = 0.035), but no isolated marker was significant associated with recurrence and progression in multivariate analysis. More than two markers abnormally expressed were associated with presence of recurrence (p = 0.005) and lower recurrence-free surviva (p = 0.004). Our panel marker has important prognostic value for BC, especially when more than two have altered expression predicting good clinical recurrence implication.

Alterations of p53 and Rb Pathways Are Associated with High Proliferation in Bladder Urothelial Carcinomas

“…In the present study, high expression (>10% of neoplastic cells) levels of p53, cyclin A, cyclin B1 and Ki67 proteins were inversely correlated with the papillary morphology of the tumor and positively correlated with tumor grade and pTstage. These results are in keeping with previous studies (25,32,37) and show that high expression of cell cycle proteins such as p53, cyclin A, cyclin B1 and Ki67 is associated with adverse histopathological parameters.…”

“…Interestingly, concomitant alterations of various cell-cycle regulators have been associated with tumor recurrence and aggressive behavior of BUC (5,19,24,37), but the impact of such concurrent alterations on tumor cell proliferation, to the best of our knowledge, has not been analyzed so far. Thus, the expression of p53, p21, pRb, p16, p27, cyclin D1, cyclin A, cyclin B1 and Ki67 proteins in 122 cases of BUC were investigated in order: a) to search for immunohistochemical alterations of these cell cycle regulatory proteins, b) to determine the proliferation status (expression of cyclin A, cyclin B1, Ki67), c) to analyze the impact of concurrent immunohistochemical alterations of p53 and Rb growth suppressor pathways on tumor cell proliferation and d) to correlate the findings with histopathological parameters.…”

A Comprehensive Bioinformatics Analysis of Notch Pathways in Bladder Cancer

“…Various well-known cancer-related pathways are involved in carcinogenesis, such as Wnt, Hedgehog, hypoxia, and TGF/BMP pathways, which potentially affect Notch signaling [ 14 ]. Furthermore, some pathways have been shown to play a critical role in the BCa, e.g., tuberous sclerosis complex–mammalian target of rapamycin (TSC-mTOR) pathway (TSC/mTOR) [ 15 ], receptor tyrosine kinase signaling (RTK) [ 16 ], Ras/mitogen activated protein kinase pathway (RAS/MAPK) [ 17 ], epithelial–mesenchymal transition (EMT) [ 18 ], DNA damage response [ 18 ], cell cycle [ 19 ], and apoptosis pathways [ 20 , 21 ]. Whether the crosstalk with the well-known cancer-related pathways can affect the dichotomous function of Notch signaling in BCa is still unclear.…”

Deduction of Novel Genes Potentially Involved in Upper Tract Urothelial Carcinoma Using Next-Generation Sequencing and Bioinformatics Approaches

“…The characteristic feature of mature urothelium is quiescent with low mitotic index and turnover rate, and the homeostasis of urothelial cell regeneration upon injury relies on epithelial-mesenchymal crosstalk, local secreted growth factors, and epigenetic regulation 34. Similar molecular signatures of cell cycle and proliferative tissue markers between UC of bladder and upper urinary tract origin has been reported, and Ki-67, pRb, p53, and CDCA5 are of prognostic values 10,15,35-38. Using DAVID and GSEA for pathway enrichment analysis, MKI67 , a gene encoding nuclear protein Ki-67, was identified as one of the top dysregulated genes related to cell proliferation and cell cycle checkpoint pathways in our UTUC dataset.…”