CD44 variant isoforms associate with tetraspanins and EpCAM

Schmidt, Dirk-Steffen; Klingbeil, Pamela; Schnölzer, Martina; Zöller, Margot

doi:10.1016/j.yexcr.2004.02.023

Cited by 70 publications

(54 citation statements)

References 82 publications

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“…We assumed that this complex, rather than the individual molecules, might promote tumor progression. The following observations supported this hypothesis: (a) the CD44v6/CO-029/EpCAM/ claudin-7 complex is located in tetraspanin-enriched membrane microdomains (TEM) that serve as a signaling platform (8,9) and (b) the TEM-localized complex supports matrix adhesion, agglomeration, and apoptosis resistance distinctly to the individual components of the complex (6).…”

Section: Introductionmentioning

confidence: 74%

“…Furthermore, the mechanism underlying the unexpected involvement of the cell-cell adhesion molecule EpCAM in tumor progression, as well as that of the tetraspanin CO-029, are unknown. We noted in a rat tumor model that (a) CD44v6 forms a TEM-located complex with D6.1A, EpCAM, and claudin-7 (6, 7), and that (b) complexes expressing rat tumor lines display functional activities different from tumor lines that express only individual components (6). Thus, we hypothesized that only coexpression of these molecules promotes colorectal cancer progression.…”

Section: Resultsmentioning

confidence: 99%

“…Tetraspanins mostly function as molecular facilitators that form complexes between themselves, additional transmembrane and signal-transducing molecules (8,(31)(32)(33)(34)(35). Although integrins are the preferential transmembrane partners (36)(37)(38), EpCAM and CD44 also associate with tetraspanins (6,7,9,31,39). With few exceptions, tetraspanin associations are of low stringency and are not due to a direct protein-protein interaction.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Complex of EpCAM, Claudin-7, CD44 Variant Isoforms, and Tetraspanins Promotes Colorectal Cancer Progression

Kühn

Koch

Nübel

et al. 2007

Molecular Cancer Research

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239

221

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High expression of EpCAM and the tetraspanin CO-029 has been associated with colorectal cancer progression. However, opposing results have been reported on CD44 variant isoform v6 (CD44v6) expression. We recently noted in rat gastrointestinal tumors that EpCAM, claudin-7, CO-029, and CD44v6 were frequently coexpressed and could form a complex. This finding suggested the possibly that the complex, rather than the individual molecules, could support tumor progression. The expression of EpCAM, claudin-7, CO-029, and CD44v6 expression was evaluated in colorectal cancer (n = 104), liver metastasis (n = 66), and tumor-free colon and liver tissue. Coexpression and complex formation of the molecules was correlated with clinical variables and apoptosis resistance. EpCAM, claudin-7, CO-029, and CD44v6 expression was up-regulated in colon cancer and liver metastasis. Expression of the four molecules did not correlate with tumor staging and grading. However, coexpression inversely correlated with disease-free survival. Coexpression was accompanied by complex formation and recruitment into tetraspanin-enriched membrane microdomains (TEM). Claudin-7 contributes to complex formation inasmuch as in the absence of claudin-7, EpCAM hardly associates with CO-029 and CD44v6 and is not recruited into TEMs. Notably, colorectal cancer lines that expressed the EpCAM/claudin-7/CO-029/CD44v6 complex displayed a higher degree of apoptosis resistance than lines devoid of any one of the four molecules. Expression of EpCAM, claudin-7, CO-029, and CD44v6 by themselves cannot be considered as prognostic markers in colorectal cancer. However, claudin-7 -associated EpCAM is recruited into TEM and forms a complex with CO-029 and CD44v6 that facilitates metastasis formation. (Mol Cancer Res 2007;5(6):553 -67)

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Section: Introductionmentioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Complex of EpCAM, Claudin-7, CD44 Variant Isoforms, and Tetraspanins Promotes Colorectal Cancer Progression

Kühn

Koch

Nübel

et al. 2007

Molecular Cancer Research

Self Cite

239

221

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“…Concomitantly, appropriately assembled hyaluronan could act as the initial trigger leading to CD44 clustering. This can be accompanied by relocation of CD44 to specialized membrane microdomains, which serve as signaling platforms (48,49). Work is in progress to evaluate whether CD44v6-initiated apoptosis resistance, indeed, proceeds via assembled hyaluronan (see below) as the initial trigger, which allows CD44v6 to associate with c-Src promoting focal adhesion kinase activation and/or to recruit hepatocyte growth factor/scatter factor for c-Met activation or whether c-Met activation proceeds via activated focal adhesion kinase (50).…”

Section: Cd44v and Apoptosis Protectionmentioning

confidence: 99%

CD44 Variant Isoforms Promote Metastasis Formation by a Tumor Cell-Matrix Cross-talk That Supports Adhesion and Apoptosis Resistance

Klingbeil

Marhaba

Jung

et al. 2009

Molecular Cancer Research

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CD44 designates a large family of proteins with a considerable structural and functional diversity, which are generated from one gene by alternative splicing. As such, the overexpression of CD44 variant isoform (CD44v) has been causally related to the metastatic spread of cancer cells. To study the underlying mechanism, stable knockdown clones with deletion of exon v7 containing CD44 isoforms (CD44v kd ) of the highly metastatic rat adenocarcinoma line BSp73ASML (ASML wt ) were established. ASML-CD44v kd clones hardly form lung metastases after intrafootpad application and the metastatic load in lymph nodes is significantly reduced. Rescuing, albeit at a reduced level, CD44v expression in ASML-CD44v kd cells (ASML-CD44v rsc ) restores the metastatic potential. The following major differences in ASML wt , ASML-CD44v kd , and ASML-CD44v rsc clones were observed: (a) ASML wt cells produce and assemble a matrix in a CD44v-dependent manner, which supports integrin-mediated adhesion and favors survival. This feature is lost in the ASML-CD44v kd cells. (b) CD44v cross-linking initiates phosphatidylinositol 3-kinase/Akt activation in ASML wt cells. Accordingly, apoptosis resistance is strikingly reduced in ASML-CD44v kd cells. The capacity to generate an adhesive matrix but not apoptosis resistance is restored in ASML-CD44v rsc cells. These data argue for a 2-fold effect of CD44v on metastasis formation: CD44v-mediated matrix formation is crucial for the settlement and growth at a secondary site, whereas apoptosis resistance supports the efficacy of metastasis formation.

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“…Protein partners of EpCAM include tetraspanins CD9 and 14.1, claudin 7, and CD44 (42)(43)(44). These protein-protein interactions may reduce the accessibility of EpCAM on the surface of normal tissue and leave only few epitopes for recognition by antibodies.…”

Section: Murine-specific Epcam Bitementioning

confidence: 99%

Therapeutic Window of MuS110, a Single-Chain Antibody Construct Bispecific for Murine EpCAM and Murine CD3

Amann¹,

Brischwein²,

Lutterbuese³

et al. 2008

Cancer Research

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EpCAM (CD326) is one of the most frequently and highly expressed tumor-associated antigens known and recently has also been found on cancer stem cells derived from human breast, colon, prostate, and pancreas tumors. However, like many other tumor-associated antigens used for antibodybased immunotherapeutic approaches, EpCAM is expressed on normal tissues including epithelia of pancreas, colon, lung, bile ducts, and breast. To assess the therapeutic window of an EpCAM/CD3-bispecific single-chain antibody construct of the bispecific T-cell engager (BiTE) class, we constructed murine surrogate of MT110 (muS110) from single-chain antibodies specific for murine EpCAM and CD3 antigens. Immunhistochemical analysis showed that, with minor differences, the expression of EpCAM protein on a large variety of tissues from man and mouse was similar with respect to distribution and level. MuS110 exhibited significant antitumor activity at as low as 5 Mg/kg in both syngeneic 4T1 orthotopic breast cancer and CT-26 lung cancer mouse models. Dosing of muS110 for several weeks up to 400 Mg/kg by intraanimal dose escalation was still tolerated, indicating existence of a significant therapeutic window for an EpCAM-specific BiTE antibody in mice. MuS110 was found to have similar in vitro characteristics and in vivo antitumor activity as MT110, a human EpCAM/human CD3-bispecific BiTE antibody that currently is in formal preclinical development. [Cancer Res 2008;68(1):143-51]

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CD44 variant isoforms associate with tetraspanins and EpCAM

Cited by 70 publications

References 82 publications

A Complex of EpCAM, Claudin-7, CD44 Variant Isoforms, and Tetraspanins Promotes Colorectal Cancer Progression

A Complex of EpCAM, Claudin-7, CD44 Variant Isoforms, and Tetraspanins Promotes Colorectal Cancer Progression

CD44 Variant Isoforms Promote Metastasis Formation by a Tumor Cell-Matrix Cross-talk That Supports Adhesion and Apoptosis Resistance

Therapeutic Window of MuS110, a Single-Chain Antibody Construct Bispecific for Murine EpCAM and Murine CD3

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