EpCAM is predominantly expressed in high grade and advanced stage urothelial carcinoma of the bladder

Brunner, Andrea; Prelog, Martina; Verdorfer, Irmgard; Tzankov, Alexandar; Mikuz, Gregor; Ensinger, Christian

doi:10.1136/jcp.2007.049460

Cited by 78 publications

(82 citation statements)

References 33 publications

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“…For example, monoclonal antibodies against TACSTD1 (EpCAM), discovered here as a lung metastasis-specific target gene (Table 2a) and recently shown to be a marker for cancer stem cell populations, 31 have been used in the clinical trial setting. 32 Our findings, in concert with a recent report of associating TACSTD1 IHC with poor prognosis for human bladder cancer 33 might suggest the preclinical evaluation of such a therapy for patients with lung metastatic bladder cancer. In the case of LAMC2, its EGF-like repeats have been shown to be processed from the protein by matrix metalloproteases and they may agonize the EGFR, 19 a receptor tyrosine kinase now targeted via several therapeutic modalities.…”

Section: Discussionmentioning

confidence: 49%

Profiling Bladder Cancer Organ Site-Specific Metastasis Identifies LAMC2 as a Novel Biomarker of Hematogenous Dissemination

Smith

Nicholson

Nitz

et al. 2009

The American Journal of Pathology

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Little is known about which genes mediate metastasis in bladder cancer, which accounts for much of the mortality of this disease. We used human bladder cancer cell lines to develop models of two clinically common metastatic sites, lung and liver, and evaluated their gene expression with respect to human tumor tissues. Parental cells were injected into either the murine spleen to generate liver metastases or tail vein to generate lung metastases with sequential progeny derived by re-injection and comparisons made of their organ-specific nature by crossed-site injections. Both genomic and transcriptomic analyses of organselected cell lines found salient differences and shared core metastatic profiles, which were then screened against gene expression data from human tumors. The expression levels of laminin V gamma 2 (LAMC2) contained in the core metastatic signature were increased as a function of human tumor stage, and its genomic location was in an area of gain as measured by comparative genomic hybridization. Using immunohistochemistry in a human bladder cancer tissue microarray, LAMC2 expression levels were associated with tumor grade, but inversely with nodal status. In contrast, in node-negative patients, LAMC2 expression was associated with visceral metastatic recurrence. In summary, LAMC2 is a novel biomarker of bladder cancer metastasis that reflects the propensity of cells to metastasize via either lymphatic or hematogenous routes. Metastasis represents a critical event in the natural history of disease for a cancer patient and is associated with significant reduction in patient survival.1 However, although a significant body of research has shed light on this process, less is known about the nature of organspecific metastasis.2,3 In vivo metastasis assays using cancer cell lines passaged through mouse models have been used to discover the role of specific genes relevant to metastatic behavior. 4 For example, in breast cancer, recent reports have addressed the question of the molecular regulation of organ site-specific metastasis. Using the spontaneously metastatic MDA-MB-231 human breast cancer cell line, one group reported the in vivo selection of sublines of differing metastatic potential to bone, lung, and adrenal gland, 5,6 and then evaluated in both animal models and metastatic tumor tissues from patients the gene expression profiles associated with site-specific metastasis. 7Bladder cancer is the fifth most commonly diagnosed cancer in the United States, 8 and the molecular lesions characterizing bladder carcinogenesis and progression are beginning to be better elucidated. 9 However, little is known about the pathways that regulate general metastatic propensity or organ site-specific tropism to lung or liver, which are two common sites of dissemination in this and other tumor types. Our prior work has focused on the discovery and investigation of genes that regulate lung metastasis, such as the metastasis suppressor RhoGDI2, by comparing metastatic T24T cells to their isogenic nonmetastatic relativ...

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Section: Discussionmentioning

confidence: 49%

Profiling Bladder Cancer Organ Site-Specific Metastasis Identifies LAMC2 as a Novel Biomarker of Hematogenous Dissemination

Smith

Nicholson

Nitz

et al. 2009

The American Journal of Pathology

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“…No difference in expression of EPCAM was observed in relation to tumor grade and FGFR3 mutation, but a significant difference was observed in relation to tumor stage, with nonmuscle invasive (Ta-T1) tumors showing an average expression significantly lower than muscle invasive tumors (T2 or higher; P ¼ 0.033), consistent with previous reports Ã , significant (P 0.05) differences from control. (25). Expression of TNC could not be examined in relation to FGFR3 mutation, tumor stage, and tumor grade due to the small number of positive tumors (n ¼ 18).…”

Section: Mutant Fgfr3 Dysregulates Genes Involved In Cell Adhesion Anmentioning

confidence: 99%

Alteration of Cell–Cell and Cell–Matrix Adhesion in Urothelial Cells: An Oncogenic Mechanism for Mutant FGFR3

Martino

Kelly

Roulson

et al. 2015

Molecular Cancer Research

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Activating mutations of FGFR3 are a common and early event in bladder cancer. Ectopic expression of mutant FGFR3 in normal urothelial cells has both pro-proliferative and antiapoptotic effects at confluence, suggesting that mutant cells are insensitive to cell-cell contact inhibition. Herein, detailed analysis revealed that these cells have reduced cell-cell adhesion, with large intercellular spaces observable at confluence, and diminished cell-substrate adhesion to collagen IV, collagen I, and fibronectin. These phenotypic alterations are accompanied by changes in the expression of genes involved in cell adhesion and extracellular matrix remodeling. Silencing of endogenous mutant FGFR3 in bladder cancer cells induced converse changes in transcript levels of CDH16, PLAU, MMP10, EPCAM, TNC, and HAS3, confirming them as downstream gene targets of mutant FGFR3. Overexpression of EPCAM, HAS3, and MMP10 transcripts was found in a large fraction of primary bladder tumors analyzed, supporting their key role in bladder tumorigenesis in vivo. However, no correlation was found between their protein and/or mRNA expression and FGFR3 mutation status in tumor specimens, indicating that these genes may be targeted by several converging oncogenic pathways. Overall, these results indicate that mutant FGFR3 favors the development and progression of premalignant bladder lesions by altering key genes regulating the cell-cell and cell-matrix adhesive properties of urothelial cells. Implications:The ability of mutant FGFR3 to drive transcriptional expression profiles involved in tumor cell adhesion suggests a mechanism for expansion of premalignant urothelial lesions. Mol Cancer Res; 13(1); 138-48. Ó2014 AACR.

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“…126 A significant association exists between positive EpCAM expression and survival rate in esophageal cancer, 127 clear-cell renal cell carcinoma, 122,128 moderately differentiated colon cancer, 129 and thyroid carcinoma 123 ; however, EpCAM expres-sion has also been associated with a worse prognosis in different types of breast cancer, [130][131][132] pancreatic cancer, 133 gallbladder carcinoma, 134 esophageal squamous cell carcinoma, 135 and urothelial carcinoma of the bladder. 136 For epithelial ovarian cancers, 137 lung cancer, 129,30 prostate cancer, and well and poorly differentiated colon cancers, no clear correlation with survival rates has been observed (Fig). 129 These contradictory data highlight the need to discover other phenotypic markers to more precisely identify CTCs. The CellSearch method could use alternative capture approaches beyond antigens to EpCAM, but these methods would be considered experimental approaches and not readily available to patients.…”

Section: Limitationsmentioning

confidence: 99%

Circulating Tumor Cells: A Window into Tumor Development and Therapeutic Effectiveness

2015

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Background Circulating tumor cells (CTCs) are an important diagnostic tool for understanding the metastatic process and the development of cancer. Methods This review covers the background, relevance, and potential limitations of CTCs as a measurement of cancer progression and how information derived from CTCs may affect treatment efficacy. It also highlights the difficulties of characterizing these rare cells due to the limited cell surface molecules unique to CTCs and each particular type of cancer. Results The analysis of cancer in real time, through the measure of the number of CTCs in a “liquid” biopsy specimen, gives us the ability to monitor the therapeutic efficacy of treatments and possibly the metastatic potential of a tumor. Conclusions Through novel and innovative techniques yielding encouraging results, including microfluidic techniques, isolating and molecularly analyzing CTCs are becoming a reality. CTCs hold promise for understanding how tumors work and potentially aiding in their demise.

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EpCAM is predominantly expressed in high grade and advanced stage urothelial carcinoma of the bladder

Cited by 78 publications

References 33 publications

Profiling Bladder Cancer Organ Site-Specific Metastasis Identifies LAMC2 as a Novel Biomarker of Hematogenous Dissemination

Profiling Bladder Cancer Organ Site-Specific Metastasis Identifies LAMC2 as a Novel Biomarker of Hematogenous Dissemination

Alteration of Cell–Cell and Cell–Matrix Adhesion in Urothelial Cells: An Oncogenic Mechanism for Mutant FGFR3

Circulating Tumor Cells: A Window into Tumor Development and Therapeutic Effectiveness

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