Current Preclinical Models for the Advancement of Translational Bladder Cancer Research

DeGraff, David J.; Robinson, Victoria; Shah, Jay B.; Brandt, William D.; Sonpavde, Guru; Kang, Yibin; Liebert, Monica; Wu, Xianwei; Taylor, John A.

doi:10.1158/1535-7163.mct-12-0508

Cited by 26 publications

(19 citation statements)

References 93 publications

(75 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To determine whether the tumor-barrier effects of p53 upregulation by oncogenic HRAS* in urothelial cells were coincidental or causative, we introduced oncogenic HRAS* along with sh-RNA of p53 into cultured RT4 cells, which were originally derived from a human low-grade, superficial papillary bladder tumor (27) and lacked RAS or p53 mutation/deletion (30). Enforced expression of oncogenic HRAS* in RT4 elicited a marked upregulation of p53 and p21 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Oncogenic HRAS Activates Epithelial-to-Mesenchymal Transition and Confers Stemness to p53-Deficient Urothelial Cells to Drive Muscle Invasion of Basal Subtype Carcinomas

Melamed

Tang

et al. 2015

Cancer Research

Self Cite

View full text Add to dashboard Cite

Muscle-invasive urothelial carcinomas of the bladder (MIUCB) exhibit frequent receptor tyrosine kinase alterations but the precise nature of their contributions to tumor pathophysiology is unclear. Using mutant HRAS (HRAS*) as an oncogenic prototype, we obtained evidence in transgenic mice that RTK/RAS pathway activation in urothelial cells causes hyperplasia that neither progresses to frank carcinoma nor regresses to normal urothelium through a period of one year. This persistent hyperplastic state appeared to result from an equilibrium between pro-mitogenic factors and compensatory tumor barriers in the p19-MDM2-p53-p21 axis and a prolonged G2 arrest. Conditional inactivation of p53 in urothelial cells of transgenic mice expressing HRAS* resulted in carcinoma-in-situ and basal-subtype MIUCB with focal squamous differentiation resembling the human counterpart. The transcriptome of microdissected MIUCB was enriched in genes that drive epithelial-mesenchyme transition, the upregulation of which is associated with urothelial cells expressing multiple progenitor/stem cell markers. Taken together, our results provide evidence for RTK/RAS pathway activation and p53 deficiency as a combinatorial theranostic biomarker which may inform the progression and treatment of urothelial carcinoma.

show abstract

Section: Resultsmentioning

confidence: 99%

Oncogenic HRAS Activates Epithelial-to-Mesenchymal Transition and Confers Stemness to p53-Deficient Urothelial Cells to Drive Muscle Invasion of Basal Subtype Carcinomas

Melamed

Tang

et al. 2015

Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Cell lines (UC9, UC14, UC10, T24, SV-HUC1) and primary cells (w81, pa19) were purchased from American Type Culture Collection (ATCC) or derived as previous described (23,24). All cell lines were analyzed and authenticated by targeted genomic and RNA sequencing.…”

Section: Methodsmentioning

confidence: 99%

ATDC/TRIM29 Drives Invasive Bladder Cancer Formation through miRNA-Mediated and Epigenetic Mechanisms

et al. 2015

Self Cite

View full text Add to dashboard Cite

Bladder cancer is a common and deadly malignancy but its treatment has advanced little due to poor understanding of the factors and pathways that promote disease. ATDC/TRIM29 is a highly expressed gene in several lethal tumor types, including bladder tumors, but its role as a pathogenic driver has not been established. Here we show that overexpression of ATDC in vivo is sufficient to drive both non-invasive and invasive bladder carcinoma development in transgenic mice. ATDC-driven bladder tumors were indistinguishable from human bladder cancers, which displayed similar gene expression signatures. Clinically, ATDC was highly expressed in bladder tumors in a manner associated with invasive growth behaviors. Mechanistically, ATDC exerted its oncogenic effects by suppressing miR-29 and subsequent upregulation of DNMT3A, leading to DNA methylation and silencing of the tumor suppressor PTEN. Taken together, our findings established a role for ATDC as a robust pathogenic driver of bladder cancer development, identified downstream effector pathways and implicated ATDC as a candidate biomarker and therapeutic target.

show abstract

“…To determine if CD62L expression is elevated in high grade bladder cancer lines, we screened four cell lines (HTB4, HTB5, HTB9, CRL-1472) representing different tumor grades (2-4) [18], as well as a benign cell line UROtsa. The HTB-9 cell line had a significantly (P<0.001) higher level of CD62L mRNA expression (13-fold) compared to UROtsa cells (Figure 2) .…”

Section: Resultsmentioning

confidence: 99%

Increased expression of L-selectin (CD62L) in high-grade urothelial carcinoma: A potential marker for metastatic disease

Choudhary

Hegde

Voznesensky

et al. 2015

Urologic Oncology: Seminars and Original Investigations

Self Cite

View full text Add to dashboard Cite

Introduction L-selectin (CD62L) is a vascular adhesion molecule constitutively expressed on leucocytes with a primary function of directing leucocyte migration and homing of lymphocytes to lymph nodes (LNs). In a gene expression microarray study comparing laser captured micro-dissected (LCM) high grade muscle invasive bladder cancer (MIBC) without prior treatment and low grade bladder cancer (LGBC) human samples, we found CD62L to be the highest differentially expressed gene. We sought to examine the differential expression of CD62L in MIBCs and its clinical relevance. Methods Unfixed fresh and formalin fixed paraffin-embedded human bladder cancer specimens and serum samples were obtained from the UCHC tumor bank. Tumor cells were isolated from frozen tumor tissue sections by LCM followed by RNA isolation. qPCR was used to validate the level of CD62L transcripts. Immunohistochemistry and ELISA were performed to evaluate the CD62L protein localization and expression level. Flow cytometry was used to identify the relative number of cells expressing CD62L in fresh tumor tissue. In silico studies were performed using the Oncomine Database. Results Immunostaining showed a uniformly higher expression of CD62L in MIBC specimens vs. LGBCs specimens. Further, CD62L localization was seen in foci of metastatic tumor cells in LN specimens from patients with high grade MIBC and known nodal involvement. Upregulated expression of CD62L was also observed by flow cytometric analysis of freshly isolated tumor cells from biopsies of high grade cancers vs. LGBC specimens. Circulating CD62L levels were also found to be higher in serum samples from patients with high grade metastatic vs. high grade non-metastatic MIBC. In addition, in silico analysis of Oncomine Microarray Database showed a significant correlation between CD62L expression and tumor aggressiveness and clinical outcomes. Conclusion These data confirm the expression of CD62L on urothelial carcinoma cells and suggest that CD62L may serve as biomarker to predict the presence of or risk for developing metastatic disease in patients with bladder cancer.

show abstract

Current Preclinical Models for the Advancement of Translational Bladder Cancer Research

Cited by 26 publications

References 93 publications

Oncogenic HRAS Activates Epithelial-to-Mesenchymal Transition and Confers Stemness to p53-Deficient Urothelial Cells to Drive Muscle Invasion of Basal Subtype Carcinomas

Oncogenic HRAS Activates Epithelial-to-Mesenchymal Transition and Confers Stemness to p53-Deficient Urothelial Cells to Drive Muscle Invasion of Basal Subtype Carcinomas

ATDC/TRIM29 Drives Invasive Bladder Cancer Formation through miRNA-Mediated and Epigenetic Mechanisms

Increased expression of L-selectin (CD62L) in high-grade urothelial carcinoma: A potential marker for metastatic disease

Contact Info

Product

Resources

About