High-Level Expression of EphA2 Receptor Tyrosine Kinase in Prostatic Intraepithelial Neoplasia

Zeng, Gu-Qing; Hu, Zhiqiang; Kinch, Michael S.; Pan, Chong‐Xian; Flockhart, David A.; Kao, Chinghai; Gardner, Thomas A.; Zhang, Shaobo; Li, Lang; Baldridge, Lee Ann; Koch, Michaël; Ulbright, Thomas M.; Eble, John N.; Liu, Cheng

doi:10.1016/s0002-9440(10)63584-5

Cited by 108 publications

(82 citation statements)

References 18 publications

(22 reference statements)

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“…In addition to the EGFR family, an Eph receptor family of tyrosine receptor kinases (RTK) have critical functions in normal growth and development but were shown to be overexpressed in a host of human cancers (Zeng et al, 2003;Surawska et al, 2004;Fox et al, 2006;Taddei et al, 2009). Eph receptors are thought to modulate interactions of cells within the tumour and between tumour cells.…”

Section: Discussionmentioning

confidence: 99%

“…Eph receptors are thought to modulate interactions of cells within the tumour and between tumour cells. They also regulate stroma vasculature interaction and are implicated in PCa progression (Zeng et al, 2003;Fox et al, 2006;Taddei et al, 2009). As limited data are available on the interaction between AR and Eph receptors in androgen-sensitive and independent tumours, we will not discuss this subject further in this review.…”

Section: Discussionmentioning

confidence: 99%

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Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

2009

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Androgen deprivation therapy reduces prostate cancer (PCa) tumour growth; however, disease relapse often ensues independently of androgen stimulation, producing androgen-refractory tumours with increased invasion, proliferation, and malignancy. Androgens downregulate epidermal growth factor receptor (EGFR) in normal prostate but not in PCa. Thus, loss of EGFR regulation and altered signalling may, in part, explain the transition of prostate tumours from androgen dependent to androgen independent. Studies in animal models, PCa cell lines, and tumour specimens suggest that androgens modulate prostate growth and function through mechanisms that involve 'cross-talk' between androgen receptor (AR) and growth factor receptor signalling pathways. The objective of this review is to discuss the paradoxical relationship between androgen regulation of EGFR in normal prostate and PCa. We reviewed the literature from mid-1980s through 2009 to assess the relationship between androgens and EGFR function in modulating the growth of normal prostate and PCa. Loss of androgen regulation of EGFR in PCa may be responsible for increased tumour growth, invasion, and metastasis, with important implications on the clinical management of PCa. We advance the hypothesis that a molecular switch, responsible for downregulating EGFR expression by androgens in the normal prostate, is either lost or modified in PCa.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

2009

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“…32 The strong correlation between EphA2 expression and prostate carcinoma aggressiveness prompted us to select an experimental model to study the role of EphA2 in the regulation of cell motility and invasiveness of prostate carcinoma cells. We therefore selected PC3 prostate tumor cells as a model because of their expression of both EphA2 and ephrinA1 ligand ( Figure 1A).…”

Section: Epha2 Receptor Phosphorylation In Tumor Cells Is Regulated Bmentioning

confidence: 99%

Kinase-Dependent and -Independent Roles of EphA2 in the Regulation of Prostate Cancer Invasion and Metastasis

Taddei

Parri

Angelucci

et al. 2009

The American Journal of Pathology

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Ligand-activated Eph tyrosine kinases regulate cellular repulsion, morphology, adhesion, and motility. EphA2 kinase is frequently up-regulated in several different types of cancers, including prostate, breast, colon, and lung carcinomas, as well as in melanoma. The existing data do not clarify whether EphA2 receptor phosphorylation or its simple overexpression, which likely leads to Eph kinase-independent responses, plays a role in the progression of malignant prostate cancer. In this study, we address the role of EphA2 tyrosine phosphorylation in prostate carcinoma cell adhesion, motility, invasion, and formation of metastases. Tumor cells expressing kinase-deficient EphA2 mutants, as well as an EphA2 variant lacking the cytoplasmic domain, are defective in ephrinA1-mediated cell rounding, retraction fiber formation, de-adhesion from the extracellular matrix, RhoA and Rac1 GTPase regulation, three-dimensional matrix invasion, and in vivo metastasis, suggesting a key role for EphA2 kinase activity. Nevertheless, EphA2 regulation of cell motility and invasion, as well as the formation of bone and visceral tumor colonies, reveals a component of both EphA2 kinase-dependent and -independent features. These results uncover a differential requirement for EphA2 kinase activity in the regulation of prostate carcinoma metastasis outcome, suggesting that although the kinase activity of EphA2 is required for the regulation of cell adhesion and cytoskeletal rearrangement, some distinct kinase-dependent and -independent pathways likely cooperate to drive cancer cell migration, invasion, and metastasis outcome.

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“…[35][36][37] Primary rabbit polyclonal antibodies were used for evaluation of chromogranin A expression (DAKO, Carpinteria, CA; prediluted antibody).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Molecular Genetic Evidence for a Common Clonal Origin of Urinary Bladder Small Cell Carcinoma and Coexisting Urothelial Carcinoma

Liu

Jones

McCarthy

et al. 2005

The American Journal of Pathology

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172

105

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In most cases, small-cell carcinoma of the urinary bladder is admixed with other histological types of bladder carcinoma. To understand the pathogenetic relationship between the two tumor types, we analyzed histologically distinct tumor cell populations from the same patient for loss of heterozygosity (LOH) and X chromosome inactivation (in female patients). We examined five polymorphic microsatellite markers located on chromosome 3p25-26 (D3S3050), chromosome 9p21 (IFNA and D9S171), chromosome 9q32-33 (D9S177), and chromosome 17p13 (TP53) in 20 patients with small-cell carcinoma of the urinary bladder and concurrent urothelial carcinoma. DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-assisted microdissection. A nearly identical pattern of allelic loss was observed in the two tumor types in all cases, with an overall frequency of allelic loss of 90% (18 of 20 cases). Three patients showed different allelic loss patterns in the two tumor types at a single locus; however, the LOH patterns at the remaining loci were identical. Similarly, the same pattern of nonrandom X chromosome inactivation was present in both carcinoma components in the four cases analyzed. Concordant genetic alterations and X chromosome inactivation between small-cell carcinoma and coexisting urothelial carcinoma suggest that both tumor compo- Small-cell carcinoma of the urinary bladder histologically resembles that occurring in the lung and has been reported with an increasing frequency in recent years. [1][2][3][4][5][6][7][8][9][10] It has been estimated to represent 0.5% of bladder malignancies and develops more frequently in older men, with hematuria as the most common presenting symptom. 8 Small-cell carcinoma of the urinary bladder behaves aggressively, often with locally advanced or metastatic disease at the time of presentation. 11 Over the years, three principal theories have been proposed to account for the development of small-cell carcinoma in the urinary bladder. The first theory is that small-cell carcinomas originate from multipotential, undifferentiated cells or stem cells in the urothelium. 5,8,12,13 The frequent association of this tumor with coexisting urothelial carcinoma supports this theory. The second theory is that these tumors arise from neuroendocrine cells within normal or metaplastic urothelium. 14 The third theory is that small-cell carcinomas are derived from an undefined population of submucosal neuroendocrine cells. 1 In this study, we investigated the clonal relationships between small-cell carcinoma and coexisting urothelial carcinoma using loss of heterozygosity (LOH) and X chromosome inactivation analysis. Materials and Methods PatientsTwenty patients with small-cell carcinoma of the urinary bladder and concurrent urothelial carcinoma were included in our study. Archival materials from the 20 cases

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High-Level Expression of EphA2 Receptor Tyrosine Kinase in Prostatic Intraepithelial Neoplasia

Cited by 108 publications

References 18 publications

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

Kinase-Dependent and -Independent Roles of EphA2 in the Regulation of Prostate Cancer Invasion and Metastasis

Molecular Genetic Evidence for a Common Clonal Origin of Urinary Bladder Small Cell Carcinoma and Coexisting Urothelial Carcinoma

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