Journal of Urology

1995

DOI: 10.1016/s0022-5347(01)66923-4

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Isolation and Characterization of Metastatic Variants from Human Transitional Cell Carcinoma Passaged by Orthotopic Implantation in Athymic Nude Mice

Colin P.N. Dinney

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Rakesh K. Singh

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et al.

Abstract: This reproducible model of human bladder cancer offers the opportunity to study cellular properties associated with tumor progression and metastasis and is suitable for the evaluation of new therapeutic strategies for invasive bladder cancer.

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Cited by 143 publications

(78 citation statements)

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“…We next examined the effect of IQGAP1 depletion on subcutaneous mouse xenograft growth kinetics using 253J and T24 cells, both of which have poor subcutaneous tumorigenicity and growth in immunocompromised mice (13, 14). In T24 implanted mice the shIQGAP1 cohort reached IACUC protocol limits on tumor size at day 47 post-implant.…”

Section: Resultsmentioning

confidence: 99%

Patient Mutation Directed shRNA Screen Uncovers Novel Bladder Tumor Growth Suppressors

Duex²,

et al. 2015

Molecular Cancer Research

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Next generation sequencing (NGS) of human bladder cancer has revealed many gene alterations compared with normal tissue, with most being predicted to be “loss of function”. However, given the high number of alterations, evaluating the functional impact of each is impractical. Here we develop and use a high-throughput, in vivo strategy to determine which alterations are loss of function in tumor growth suppressors. Genes reported as altered by NGS in bladder cancer patients were bioinformatically processed by MutationTaster and MutationAssessor, with 283 predicted as loss of function. A shRNA lentiviral library targeting these genes was transduced into T24 cells, a non-tumorigenic human bladder cancer cell line, followed by injection into mice. Tumors that arose were sequenced and the dominant shRNA constructs were found to target IQGAP1, SAMD9L, PCIF1, MED1 and KATNAL1 genes. In vitro validation experiments revealed that shRNA molecules directed at IQGAP1 showed the most profound increase in anchorage-independent growth of T24 cells. The clinical relevance of IQGAP1 as a tumor growth suppressor is supported by the finding that its expression is lower in bladder cancer compared with benign patient urothelium in multiple independent datasets. Lower IQGAP1 protein expression associated with higher tumor grade and decreased patient survival. Finally, depletion of IQGAP1 leads to increased TGFBR2 with TGFβ signaling, explaining in part how reduced IQGAP1 promotes tumor growth. These findings suggest IQGAP1 is a bladder tumor growth suppressor that works via modulating TGFβ signaling and is a potentially clinically useful biomarker. Implications This study used gene mutation information from patient-derived bladder tumor specimens to inform the development of a screen used to identify novel tumor growth suppressors. This included identification of the protein IQGAP1 as a potent bladder cancer growth suppressor.

“…We next examined the effect of IQGAP1 depletion on subcutaneous mouse xenograft growth kinetics using 253J and T24 cells, both of which have poor subcutaneous tumorigenicity and growth in immunocompromised mice (13, 14). In T24 implanted mice the shIQGAP1 cohort reached IACUC protocol limits on tumor size at day 47 post-implant.…”

Section: Resultsmentioning

confidence: 99%

Patient Mutation Directed shRNA Screen Uncovers Novel Bladder Tumor Growth Suppressors

Duex²,

et al. 2015

Molecular Cancer Research

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Next generation sequencing (NGS) of human bladder cancer has revealed many gene alterations compared with normal tissue, with most being predicted to be “loss of function”. However, given the high number of alterations, evaluating the functional impact of each is impractical. Here we develop and use a high-throughput, in vivo strategy to determine which alterations are loss of function in tumor growth suppressors. Genes reported as altered by NGS in bladder cancer patients were bioinformatically processed by MutationTaster and MutationAssessor, with 283 predicted as loss of function. A shRNA lentiviral library targeting these genes was transduced into T24 cells, a non-tumorigenic human bladder cancer cell line, followed by injection into mice. Tumors that arose were sequenced and the dominant shRNA constructs were found to target IQGAP1, SAMD9L, PCIF1, MED1 and KATNAL1 genes. In vitro validation experiments revealed that shRNA molecules directed at IQGAP1 showed the most profound increase in anchorage-independent growth of T24 cells. The clinical relevance of IQGAP1 as a tumor growth suppressor is supported by the finding that its expression is lower in bladder cancer compared with benign patient urothelium in multiple independent datasets. Lower IQGAP1 protein expression associated with higher tumor grade and decreased patient survival. Finally, depletion of IQGAP1 leads to increased TGFBR2 with TGFβ signaling, explaining in part how reduced IQGAP1 promotes tumor growth. These findings suggest IQGAP1 is a bladder tumor growth suppressor that works via modulating TGFβ signaling and is a potentially clinically useful biomarker. Implications This study used gene mutation information from patient-derived bladder tumor specimens to inform the development of a screen used to identify novel tumor growth suppressors. This included identification of the protein IQGAP1 as a potent bladder cancer growth suppressor.

“…7,24,153 The most common routes of administration for the development of bone metastasis are orthotopic and intracardiac injections. In addition, intratibial injections have been used to investigate the local effects of TCC in bone.…”

Section: Animal Modelsmentioning

confidence: 99%

Animal Models of Bone Metastasis

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³

et al. 2015

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Bone is one of the most common sites of cancer metastasis in humans and is a significant source of morbidity and mortality. Bone metastases are considered incurable and result in pain, pathologic fracture, and decreased quality of life. Animal models of skeletal metastases are essential to improve the understanding of the molecular pathways of cancer metastasis and growth in bone and to develop new therapies to inhibit and prevent bone metastases. The ideal animal model should be clinically relevant, reproducible, and representative of human disease. Currently, an ideal model does not exist; however, understanding the strengths and weaknesses of the available models will lead to proper study design and successful cancer research. This review provides an overview of the current in vivo animal models used in the study of skeletal metastases or local tumor invasion into bone and focuses on mammary and prostate cancer, lymphoma, multiple myeloma, head and neck squamous cell carcinoma, and miscellaneous tumors that metastasize to bone.

“…253J cells are low tumorigenic and non-metastatic. 253J-BV cell line is a highly tumorigenic and metastatic line derived from 253J through serial passages of orthotopic 253J tumors in the bladder (19). Therefore, it is a valuable model system to study the contribution of miRNA in tumorigenesis and metastasis.…”

Section: Resultsmentioning

confidence: 99%

“…253 J-BV cells were generously provided by Dr. Ashish Kamat (MD Anderson Cancer Center) (19, 20). 253J cells were maintained in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), penicillin and streptomycin.…”

Section: Methodsmentioning

confidence: 99%

1α,25(OH)2D3 differentially regulates miRNA expression in human bladder cancer cells

¹

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²

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³

et al. 2015

The Journal of Steroid Biochemistry and Molecular Biology

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Bladder cancer is the fourth most commonly diagnosed cancer in men and eighth leading cause of cancer-related death in the US. Epidemiological and experimental studies strongly suggest a role for 1α,25(OH)2D3 in cancer prevention and treatment. The antitumor activities of 1α,25(OH)2D3 are mediated by the induction of cell cycle arrest, apoptosis, differentiation and the inhibition of angiogenesis and metastasis. MiRNAs play important regulatory roles in cancer development and progression. However, the role of 1α,25(OH)2D3 in the regulation of miRNA expression and the potential impact in bladder cancer has not been investigated. Therefore, we studied 1α,25(OH)2D3-regulated miRNA expression profiles in human bladder cancer cell line 253J and the highly tumorigenic and metastatic derivative line 253J-BV by miRNA qPCR panels. 253 J and 253J-BV cells express endogenous vitamin D receptor (VDR) which can be further induced by 1α,25(OH)2D3. VDR target gene 24-hydroxylase was induced by 1α,25(OH)2D3 in both cell lines, indicating functional 1α,25(OH)2D3 signaling. The miRNA qPCR panel assay results showed that 253J and 253J-BV cells have distinct miRNA expression profiles. Further, 1α,25(OH)2D3 differentially regulated miRNA expression profiles in 253J and 253 J-BV cells in a dynamic manner. Pathway analysis of the miRNA target genes revealed distinct patterns of contribution to the molecular functions and biological processes in the two cell lines. In conclusion, 1α,25(OH)2D3 differentially regulates the expression of miRNAs, which may contribute to distinct biological functions, in human bladder 253J and 253J-BV cells.

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