Claudin-7 Regulates EpCAM-Mediated Functions in Tumor Progression

Nübel, Tobias; Preobraschenski, Julia; Tuncay, Hüseyin; Weiss, Tobias; Kühn, Sebastian; Ladwein, Markus; Langbein, Lutz; Zöller, Margot

doi:10.1158/1541-7786.mcr-08-0200

Cited by 104 publications

(90 citation statements)

References 54 publications

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“…The origin of NETs is still debated, but the expression of this carcinoma-associated antigen adds evidence to an epithelial origin rather than being derived from the neural crest as was once originally thought (10,19). EpCAM upregulates c-myc and cyclins, promoting cell cycling and enhancing proliferation (20)(21)(22)(23)(24). Anti-EpCAM therapy has been trialed in metastatic breast cancer, colorectal cancer, and in malignant ascites (25)(26)(27)(28)(29)(30) and EpCAM expression in NETs presents an opportunity for EpCAM directed therapy (9).…”

Section: Discussionmentioning

confidence: 99%

Circulating Tumor Cells and EpCAM Expression in Neuroendocrine Tumors

Khan

Tsigani

Rashid

et al. 2011

Clinical Cancer Research

103

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Purpose: Neuroendocrine tumors (NET) are heterogeneous tumors with widely variable survival. It is unknown whether they express EpCAM (epithelial cell adhesion molecule) and thus whether NET circulating tumor cells (CTC) are detectable. We systematically investigated EpCAM expression and CTC detection in patients with metastatic NETs and evaluated the potential of CTCs to predict radiological progression.Experimental Design: EpCAM protein expression was evaluated in 74 samples of formalin-fixed, paraffin-embedded NET tissue by immunohistochemistry. Seventy-nine patients with metastatic NETs (42 midgut, 5 unknown primary, 19 pancreatic, 13 bronchopulmonary) had blood samples drawn for CTC isolation and enumeration utilizing the CellSearch platform. Patients were classified as having progressive or nonprogressive disease on the basis of serial imaging.Results: Strong homogeneous, membranous EpCAM expression was observed in all ileal (n ¼ 26) and pancreatic NETs (n ¼ 16), whereas variable EpCAM expression was observed in bronchopulmonary NETs (n ¼ 13). Forty-three percent of midgut and 21% of pancreatic NETs had CTCs detected with a range of 0-62 and 0-11, respectively. The absence of CTCs was strongly associated with stable disease (P < 0.001). There was a moderate correlation between CTC levels and urinary 5-hydroxyindole acetic acid (r ¼ 0.5, P ¼ 0.007) and between CTC levels and burden of liver metastases (B ¼ 8.91, P < 0.001). There was no or low correlation between CTC levels and Ki-67 (r ¼ 0.08, P ¼ 0.59) and serum chromogranin A (r ¼ 0.246, P ¼ 0.03).Conclusions: This is the first systematic analysis showing EpCAM expression and CTC detection in NETs. CTCs seem to be associated with progressive disease and may provide useful prognostic information given the variable survival rates in these tumors.

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Section: Discussionmentioning

confidence: 99%

Circulating Tumor Cells and EpCAM Expression in Neuroendocrine Tumors

Khan

Tsigani

Rashid

et al. 2011

Clinical Cancer Research

103

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“…Although the direct interaction of EpCAM with claudin-7 has not been formally demonstrated, the relative paucity of other proteins in preparative anti-EpCAM immunoprecipitates from Caco-2 cells suggests that this is the case (12,38). Previous studies have demonstrated that EpCAMclaudin-7 interactions are strongly influenced by amino acid substitutions at 2 positions within the EpCAM transmembrane domain (39). We have confirmed these results (12) but currently have no insights into mechanisms that might link N-terminal cleavage of EpCAM to conformational changes in the EpCAM transmem- Figure 7.…”

Section: Methodsmentioning

confidence: 99%

Matriptase-mediated cleavage of EpCAM destabilizes claudins and dysregulates intestinal epithelial homeostasis

Wu¹,

Xu²,

Lu³

et al. 2017

Journal of Clinical Investigation

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Congenital tufting enteropathy (CTE) is a severe autosomal recessive human diarrheal disorder with characteristic intestinal epithelial dysplasia. CTE can be caused by mutations in genes encoding EpCAM, a putative adhesion molecule, and HAI-2, a cell surface protease inhibitor. A similar phenotype occurs in mice whose intestinal epithelial cells (IECs) fail to express the tight junction-associated protein claudin-7. EpCAM stabilizes claudin-7 in IECs, and HAI-2 regulates the cell surface serine protease matriptase, a known modifier of intestinal epithelial physiology. Therefore, we hypothesized that HAI-2, matriptase, EpCAM, and claudin-7 were functionally linked. Herein we have demonstrated that active matriptase cleaves EpCAM after Arg80 and that loss of HAI-2 in IECs led to unrestrained matriptase activity and efficient cleavage of EpCAM. Cleavage of EpCAM decreased its ability to associate with claudin-7 and targeted it for internalization and lysosomal degradation in conjunction with claudin-7. CTE-associated HAI-2 mutant proteins exhibited reduced ability to inhibit matriptase and also failed to efficiently stabilize claudin-7 in IECs. These results identify EpCAM as a substrate of matriptase and link HAI-2, matriptase, EpCAM, and claudin-7 in a functionally important pathway that causes disease when it is dysregulated.

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“…1-4 Although EpCAM can be detected on the basolateral membrane of various normal epithelial tissues, including colon, small intestine, and hepatoblasts, 5 , 6 it is believed to be less accessible to traditional antibody constructs due to sequestration within tight cellular junctions. 7 , 8 The univalent EpCAM antibodies edrecolomab and adecatumumab have shown modest single-agent activity in the treatment of colon, prostate, and breast cancer. 9-11 …”

Section: Introductionmentioning

confidence: 99%

A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors

Kebenko

Goebeler

Wolf³

et al. 2018

OncoImmunology

126

106

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We assessed the tolerability and antitumor activity of solitomab, a bispecific T-cell engager (BiTE®) antibody construct targeting epithelial cell adhesion molecule (EpCAM). Patients with relapsed/refractory solid tumors not amenable to standard therapy received solitomab as continuous IV infusion in a phase 1 dose-escalation study with six different dosing schedules. The primary endpoint was frequency and severity of adverse events (AEs). Secondary endpoints included pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity. Sixty-five patients received solitomab at doses between 1 and 96 µg/day for ≥28 days. Fifteen patients had dose-limiting toxicities (DLTs): eight had transient abnormal liver parameters shortly after infusion start or dose escalation (grade 3, n = 4; grade 4, n = 4), and one had supraventricular tachycardia (grade 3); all events resolved with solitomab discontinuation. Six patients had a DLT of diarrhea: four events resolved (grade 3, n = 3; grade 4, n = 1), one (grade 3) was ongoing at the time of treatment-unrelated death, and one (grade 3) progressed to grade 5 after solitomab discontinuation. The maximum tolerated dose was 24 µg/day. Overall, 95% of patients had grade ≥3 treatment-related AEs, primarily diarrhea, elevated liver parameters, and elevated lipase. Solitomab half-life was 4.5 hours; serum levels plateaued within 24 hours. One unconfirmed partial response was observed. In this study of a BiTE® antibody construct targeting solid tumors, treatment of relapsed/refractory EpCAM-positive solid tumors with solitomab was associated with DLTs, including severe diarrhea and increased liver enzymes, which precluded dose escalation to potentially therapeutic levels.

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Claudin-7 Regulates EpCAM-Mediated Functions in Tumor Progression

Cited by 104 publications

References 54 publications

Circulating Tumor Cells and EpCAM Expression in Neuroendocrine Tumors

Circulating Tumor Cells and EpCAM Expression in Neuroendocrine Tumors

Matriptase-mediated cleavage of EpCAM destabilizes claudins and dysregulates intestinal epithelial homeostasis

A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors

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