Aberrant P-cadherin expression is a feature of clonal expansion in the gastrointestinal tract associated with repair and neoplasia

Sanders, D. S. A.; Perry, Ian; Hardy, Richard J.; Jankowski, Janusz

doi:10.1002/(sici)1096-9896(200004)190:5<526::aid-path564>3.0.co;2-9

Cited by 35 publications

(33 citation statements)

References 32 publications

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“…Studies have shown the upregulation of P-cadherin during wound healing and the early stages of colon cancer, but the expression of this molecule seems to disappear in poorly differentiated tumors. 44 P-cadherin has also been reported to promote the motility of pancreas cancer, 45 and its expression is an indicator of poor outcome in breast cancer. 46 Cox-2 is a rate-limiting enzyme in the production of prostaglandins.…”

Section: Discussionmentioning

confidence: 99%

Co-Activation of Epidermal Growth Factor Receptor and c-MET Defines a Distinct Subset of Lung Adenocarcinomas

Matsubara

Ishikawa

Oguni

et al. 2010

The American Journal of Pathology

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Epidermal growth factor receptor (EGFR) and MET are molecular targets for lung cancer treatment. The relationships between expression, activation, and gene abnormalities of these two targets are currently unclear. Here, we demonstrate that a panel of 40 lung cancer cell lines could be classified into two groups. Group I was characterized by (1) high phosphorylations of MET and EGFR, (2) frequent mutation or amplification of EGFR, MET, and human epidermal growth factor receptor-2 (HER2), (3) high expressions of bronchial epithelial markers (thyroid transcription factor-1 (TTF-1), MUC1, and Cytokeratin 7 (CK7)); and (4) high expressions of MET, human epidermal growth factor receptor-3, E-cadherin, cyclooxygenase-2, and laminin gamma2. In contrast, Group II exhibited little or no phosphorylation of MET and EGFR; no mutation or amplification of EGFR, MET, and HER2; were triple-negative for TTF-1, MUC1, and CK7; and showed high expressions of vimentin, fibroblast growth factor receptor-1, and transcription factor 8. Importantly, Group I was more sensitive to gefitinib and more resistant to cisplatin and paclitaxel than Group II. The clinical relevance was confirmed in publicly available data on 442 primary lung adenocarcinoma patients; survival benefits by postoperative chemotherapy were seen in only patients with tumors corresponding to Group II. Overall, co-activation of EGFR and MET defines a distinct subgroup of lung carcinoma with characteristic genetic abnormalities, gene expression pattern , and response to chemotherapeutic reagents. (Am J

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Section: Discussionmentioning

confidence: 99%

Co-Activation of Epidermal Growth Factor Receptor and c-MET Defines a Distinct Subset of Lung Adenocarcinomas

Matsubara

Ishikawa

Oguni

et al. 2010

The American Journal of Pathology

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“…S5C and D) models, showed no antitumor response to PF-03732010; these results suggest that PF-03732010 only inflicts efficacy in tumors with high P-cadherin expression. P-cadherin is frequently upregulated in a diverse panel of malignancies (15,33,34) and often associated with high histologic grade, invasiveness, and poor survival rate (14,35). The broad spectrum activity of PF-03732010 provides rationale and opportunity in the clinical development of the antibody for treating patients with tumors with high P-cadherin expression.…”

Section: Discussionmentioning

confidence: 99%

PF-03732010: A Fully Human Monoclonal Antibody against P-Cadherin with Antitumor and Antimetastatic Activity

Zhang

Yan²,

Zhang³

et al. 2010

Clinical Cancer Research

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Purpose: P-cadherin is a membrane glycoprotein that functionally mediates tumor cell adhesion, proliferation, and invasiveness. We characterized the biological properties of PF-03732010, a human monoclonal antibody against P-cadherin, in cell-based assays and tumor models.Experimental Design: The affinity, selectivity, and cellular inhibitory activity of PF-03732010 were tested in vitro. Multiple orthotopic and metastatic tumor models were used for assessing the antitumor and antimetastatic activities of PF-03732010. Treatment-associated pharmacodynamic changes were also investigated.Results: PF-03732010 selectively inhibits P-cadherin-mediated cell adhesion and aggregation in vitro. In the P-cadherin-overexpressing tumor models, including MDA-MB-231-CDH3, 4T1-CDH3, MDA-MB-435HAL-CDH3, HCT116, H1650, PC3M-CDH3, and DU145, PF-03732010 inhibited the growth of primary tumors and metastatic progression, as determined by bioluminescence imaging. Computed tomography imaging, H&E stain, and quantitative PCR analysis confirmed the antimetastatic activity of PF-03732010. In contrast, PF-03732010 did not show antitumor and antimetastatic efficacy in the counterpart tumor models exhibiting low P-cadherin expression. Mechanistic studies via immunofluorescence, immunohistochemical analyses, and 3′-[18 F]fluoro-3′-deoxythymidine-positron emission tomography imaging revealed that PF-03732010 suppressed P-cadherin levels, caused degradation of membrane β-catenin, and concurrently suppressed cytoplasmic vimentin, resulting in diminished metastatic capacity. Changes in the levels of Ki67, caspase-3, and 3′-[ 18 F]fluoro-3′-deoxythymidine tracer uptake also indicated antiproliferative activity and increased apoptosis in the tested xenografts. Conclusions: These findings suggest that interrupting the P-cadherin signaling pathway may be a novel therapeutic approach for cancer therapy. PF-03732010 is presently undergoing evaluation in Phase 1 clinical trials. Clin Cancer Res; 16(21); 5177-88. ©2010 AACR.

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“…P-cadherin, another classical cadherin, is expressed in ectodermal tissues, more specifically in the basal layers of stratified epithelia (8,9) and in myoepithelial cells of the breast (10). P-cadherin is implicated in growth and differentiation, as evidenced by knockout mice displaying precocious differentiation of the mammary gland (11), and is aberrantly expressed in mammary carcinomas of high histologic grade and with a poor prognosis (12)(13)(14)(15)(16), as well as in other types of carcinomas and proliferative inflammatory lesions (17)(18)(19). It has been suggested that suppression of the P-cadherin gene is lost during carcinogenesis (9), but the nature of this mechanism and the biological role of the newly acquired P-cadherin remain to be investigated.…”

Section: Introductionmentioning

confidence: 99%

P-Cadherin Is Up-Regulated by the Antiestrogen ICI 182,780 and Promotes Invasion of Human Breast Cancer Cells

Paredes

Stove²,

Stove³

et al. 2004

Cancer Research

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P-cadherin expression in breast carcinomas has been associated with tumors of high histologic grade and lacking estrogen receptor-␣, suggesting a link between these proteins. In the MCF-7/AZ breast cancer cell line, blocking estrogen receptor-␣ signaling with the antiestrogen ICI 182,780 induced an increase of P-cadherin, which coincided with induction of in vitro invasion. Retroviral transduction of MCF-7/AZ cells, as well as HEK 293T cells, showed the proinvasive activity of P-cadherin, which requires the juxtamembrane domain of its cytoplasmic tail. This study establishes a direct link between P-cadherin expression and the lack of estrogen receptor-␣ signaling in breast cancer cells and suggests a role for Pcadherin in invasion, through its interaction with proteins bound to the juxtamembrane domain.

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Aberrant P-cadherin expression is a feature of clonal expansion in the gastrointestinal tract associated with repair and neoplasia

Cited by 35 publications

References 32 publications

Co-Activation of Epidermal Growth Factor Receptor and c-MET Defines a Distinct Subset of Lung Adenocarcinomas

Co-Activation of Epidermal Growth Factor Receptor and c-MET Defines a Distinct Subset of Lung Adenocarcinomas

PF-03732010: A Fully Human Monoclonal Antibody against P-Cadherin with Antitumor and Antimetastatic Activity

P-Cadherin Is Up-Regulated by the Antiestrogen ICI 182,780 and Promotes Invasion of Human Breast Cancer Cells

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