Growth factors and receptors as prognostic markers in urothelial carcinoma

Black, Peter C.; Dinney, Colin P.

doi:10.1007/s11934-008-0011-6

Cited by 48 publications

(30 citation statements)

References 38 publications

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“…Increased EGF signaling is associated with progression of superficial bladder lesions carrying p53 or Rb mutations to an invasive phenotype (36). Development of invasiveness entails sequential activation of distinct biochemical pathways that lead to disruption of the extracellular matrix and increased cell motility (37,38). The role of EFGR in this pathway is unclear.…”

Section: Discussionmentioning

confidence: 99%

PTPD1 Supports Receptor Stability and Mitogenic Signaling in Bladder Cancer Cells

Carlucci

Porpora

Garbi

et al. 2010

Journal of Biological Chemistry

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PTPD1, a cytosolic non-receptor protein-tyrosine phosphatase, stimulates the Src-EGF transduction pathway. Localization of PTPD1 at actin cytoskeleton and adhesion sites is required for cell scattering and migration. Here, we show that during EGF stimulation, PTPD1 is rapidly recruited to endocytic vesicles containing the EGF receptor. Endosomal localization of PTPD1 is mediated by interaction with KIF16B, an endosomal kinesin that modulates receptor recycling at the plasma membrane. Silencing of PTPD1 promotes degradation of EGF receptor and inhibits downstream ERK signaling. We also found that PTPD1 is markedly increased in bladder cancer tissue samples. PTPD1 levels positively correlated with the grading and invasiveness potential of these tumors. Transgenic expression of an inactive PTPD1 mutant or genetic knockdown of the endogenous PTPD1 severely inhibited both growth and motility of human bladder cancer cells. These findings identify PTPD1 as a novel component of the endocytic machinery that impacts on EGF receptor stability and on growth and motility of bladder cancer cells.

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Section: Discussionmentioning

confidence: 99%

PTPD1 Supports Receptor Stability and Mitogenic Signaling in Bladder Cancer Cells

Carlucci

Porpora

Garbi

et al. 2010

Journal of Biological Chemistry

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“…As mentioned, activating FGFR3 mutations have been linked to the development of SKs as well as, more recently, epidermal nevi, another type of benign lesions characterized mainly by epidermal thickening with hyperpigmentation (26). Importantly, identical FGFR3 mutations have also been associated, in other epithelial tumors including bladder carcinomas, with good prognosis and lack of malignant progression (27)(28)(29). Conversely, the same FGFR3 activations have been linked with disease progression of some hematopoietic malignancies, including multiple myeloma (30,31).…”

Section: Figurementioning

confidence: 98%

A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans

Mandinova¹,

Kolev²,

Neel³

et al. 2009

J. Clin. Invest.

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Seborrheic keratoses (SKs) are common, benign epithelial tumors of the skin that do not, or very rarely, progress into malignancy, for reasons that are not understood. We investigated this by gene expression profiling of human SKs and cutaneous squamous cell carcinomas (SCCs) and found that several genes previously connected with keratinocyte tumor development were similarly modulated in SKs and SCCs, whereas the expression of others differed by only a few fold. In contrast, the tyrosine kinase receptor FGF receptor-3 (FGFR3) and the transcription factor forkhead box N1 (FOXN1) were highly expressed in SKs, and close to undetectable in SCCs. We also showed that increased FGFR3 activity was sufficient to induce FOXN1 expression, counteract the inhibitory effect of EGFR signaling on FOXN1 expression and differentiation, and induce differentiation in a FOXN1-dependent manner. Knockdown of FOXN1 expression in primary human keratinocytes cooperated with oncogenic RAS in the induction of SCC-like tumors, whereas increased FOXN1 expression triggered the SCC cells to shift to a benign SK-like tumor phenotype, which included increased FGFR3 expression. Thus, we have uncovered a positive regulatory loop between FGFR3 and FOXN1 that underlies a benign versus malignant skin tumor phenotype.

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“…EGFR is commonly targeted either by small molecule tyrosine kinase inhibitors specific to EGFR such as gefitinib or erlotinib or by a chimeric human-mouse monoclonal antibody, cetuximab. EGFR is known to be overexpressed in bladder cancers and several immunohistochemical studies have correlated EGFR expression with poor prognosis (2). A phase II trial combining cetuximab with standard chemotherapies is currently underway in bladder cancer (3).…”

Section: Introductionmentioning

confidence: 99%

Dual Kinase Inhibition of EGFR and HER2 Overcomes Resistance to Cetuximab in a Novel In Vivo Model of Acquired Cetuximab Resistance

Quesnelle

Grandis

2011

Clinical Cancer Research

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Purpose Acquired resistance to cetuximab, a chimeric EGFR-targeting monoclonal antibody, is a widespread problem in the treatment of solid tumors. The paucity of preclinical models has limited investigations to determine the mechanism of acquired therapeutic resistance thereby limiting the development of effective treatments. The purpose of this study was to generate cetuximab-resistant tumors in vivo to characterize mechanisms of acquired resistance. Experimental Design We generated cetuximab-resistant clones from a cetuximab-sensitive bladder cancer cell line in vivo by exposing cetuximab-sensitive xenografts to increasing concentrations of cetuximab followed by validation of the resistant phenotype in vivo and in vitro using invasion assays. A candidate-based approach was used to examine the role of HER2 on mediating cetuximab resistance both in vitro and in vivo. Results We generated a novel model of cetuximab resistance and, for the first time in the context of EGFR-inhibitor resistance, we identified increased phosphorylation of a c-terminal fragment of HER2 (611-CTF) in cetuximab-resistant cells. Afatinib (BIBW-2992), an irreversible kinase inhibitor targeting EGFR and HER2, successfully inhibited growth of the cetuximab-resistant cells in vitro. When afatinib was combined with cetuximab in vivo, we observed an additive growth inhibitory effect in cetuximab-resistant xenografts. Conclusions These data suggest that the use of dual EGFR-HER2 kinase inhibitors can enhance responses to cetuximab, perhaps in part due to downregulation of 611-CTF. This study in a novel in vivo model provides a mechanistic rationale for ongoing phase I clinical trials using this combination treatment modality.

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Growth factors and receptors as prognostic markers in urothelial carcinoma

Cited by 48 publications

References 38 publications

PTPD1 Supports Receptor Stability and Mitogenic Signaling in Bladder Cancer Cells

PTPD1 Supports Receptor Stability and Mitogenic Signaling in Bladder Cancer Cells

A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans

Dual Kinase Inhibition of EGFR and HER2 Overcomes Resistance to Cetuximab in a Novel In Vivo Model of Acquired Cetuximab Resistance

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