Colorectal cancer prognosis and expression of exon-v6-containing CD44 proteins

Mulder, J.; Kruyt, Philip M.; Sewnath, Miguel E.; Oosting, J.; Seldenrijk, Cornelis A.; Weidema, W. F.; Pals, Steven T.

doi:10.1016/s0140-6736(94)90290-9

Cited by 293 publications

(201 citation statements)

References 9 publications

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“…In this study, for the up-regulated mir-21, the genes that belonged to the class of tumor suppressor genes TIMP1, TIMP3 and TMP1 were suppressed. Similar to our data, others found suppression in the tumor suppressor genes, TIPM1 and TIPM3 that played a role in the malignant phenotype (Mulder et al, 1994;Yu et al, 2004). The Suppression of TPM1 has been reported in malignant cells, suggesting a role for these proteins in neoplastic transformation (Raval et al, 2003).…”

Section: Discussionsupporting

confidence: 91%

MicroRNAs and Metastasis-related Gene Expression in Egyptian Breast Cancer Patients

Hafez

Hassan²,

Zekri³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Section: Discussionsupporting

confidence: 91%

MicroRNAs and Metastasis-related Gene Expression in Egyptian Breast Cancer Patients

Hafez

Hassan²,

Zekri³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…4 CD44 has been extensively studied in several cancer types, although its role in carcinogenesis remains controversial. In some types of cancer it can act as a tumor suppressor, as in prostate carcinomas or neuroblastomas, 5,6 whereas in others it can act as a tumor promoter, as in breast cancer, [7][8][9] colorectal cancer 10,11 or non-Hodgkin's lymphomas. 12 Recently, in gastric carcinoma (GC), it was shown that the CD44( þ ) subpopulations of gastric malignant cell lines give rise to xenograft tumors in SCID mice.…”

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confidence: 99%

De novo expression of CD44 variants in sporadic and hereditary gastric cancer

Cunha

Oliveira

Wen

et al. 2010

Laboratory Investigation

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CD44 is the major ubiquitously expressed cell surface receptor for hyaluronate. The CD44 gene encodes several protein isoforms due to extensive alternative splicing and post-translational modifications. Some of these CD44 variable isoforms have been foreseen as key players in malignant transformation and their expression is highly restricted and highly specific, unlike the canonical CD44 standard isoform. In this study, we aimed at dissecting the mRNA splicing pattern of CD44 in normal stomach and gastric cancer (GC) cell lines (n ¼ 9) using cloning and quantitative mRNA amplification assays. Moreover, we assessed the RNA levels and protein expression pattern of relevant splicing forms in distinct premalignant and malignant gastric lesions (sporadic (n ¼ 43) and hereditary (n ¼ 3) forms) using real-time RT-PCR and immunohistochemistry. We also explored the association of CD44 and E-cadherin expression by immunohistochemistry, as E-cadherin has a pivotal functional role in GC. We established the pattern of CD44 variant forms in normal stomach and gastric malignancy. We observed that although exon v6-containing isoforms were rarely expressed in normal gastric mucosa, they became increasingly expressed both in gastric premalignant (hyperplastic polyps, complete and incomplete intestinal metaplasia, low-and high-grade dysplasia) and malignant lesions (cell lines derived from GCs, primary sporadic GCs and hereditary diffuse GCs (HDGCs)). Moreover, we verified that whenever E-cadherin expression was absent, exon v6-containing CD44 isoforms were overexpressed. The lack of expression of CD44 isoforms containing exon v6 in the surface and foveolar epithelia of normal stomach and, its de novo expression in premalignant, as well as in sporadic and hereditary malignant lesions of the stomach, pinpoint CD44 v6-containg isoforms as potential biomarkers for early transformation of the gastric mucosa. Further, our results raise the hypothesis of using CD44v6 as a marker of early invasive intramucosal carcinoma in HDGC CDH1 mutation carriers that lack CDH1 expression in their tumors.

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“…11 Overexpression of CD44v6 in tumors has been correlated with reduced survival of patients with breast and colon cancer and with non-Hodgkin's lymphoma. [12][13][14] These data indicate that CD44v6 is an attractive target for MAb-based therapy, especially for the treatment of HNSCC in which the level of expression is very favorable. Since HNSCCs are intrinsically radiosensitive, RIT might be particularly suitable.…”

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confidence: 99%

Tumor targeting properties of monoclonal antibodies with different affinity for target antigen CD44V6 in nude mice bearing head‐and‐neck cancer xenografts

Verel

Heider

Siegmund

et al. 2002

Intl Journal of Cancer

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The CD44 protein family consists of isoforms with tissuespecific expression, which are encoded by standard exons and up to 9 alternatively spliced variant exons (v2-v10) of the same gene. The murine MAbs U36 and BIWA-1, directed against overlapping epitopes within the v6 region of CD44, have previously been shown to efficiently target HNSCC. We herein report on the construction of 1 chimeric (BIWA-2) and 2 humanized (BIWA-4 and BIWA-8) derivatives of BIWA-1. Together with U36 and BIWA-1, these new antibodies were evaluated for affinity to the antigen in vitro as well as for biodistribution and efficacy in RIT using nude mice bearing the HNSCC xenograft line HNX-OE. As determined by surface plasmon resonance, the MAbs bound to CD44v6 with an up to 46-fold difference in affinity (K d ranging from 1.1 ؋ 10 -8 to 2.4 ؋ 10 -10 M) with the following ranking: mMAb U36 < hMAb BIWA-4 < hMAb BIWA-8 < mMAb BIWA-1 ϳ cMAb BIWA-2. To evaluate their in vivo tumortargeting properties, 2 MAbs with identical murine or human isotype were labeled with either 131 I or 125 I and administered simultaneously (50 g/10 Ci each) as pairs showing a stepwise decrease in the difference in affinity: U36 vs. BIWA-1 (35.0-fold difference), BIWA-4 vs. BIWA-2 (14.0-fold) and BIWA-4 vs. BIWA-8 (4.0-fold). Biodistribution was assessed at 1, 2, 3 or 4 and 7 days after injection. Remarkably, for all 3 MAb pairs tested, the lower-affinity MAb showed a higher degree and specificity of tumor localization. The difference in tumor localization was more pronounced when the difference in affinity was larger. For example, 3 days after injection, the lower-affinity mMAb U36 showed a 50% higher tumor uptake than the higher-affinity mMAb BIWA-1, while blood levels and uptake in organs were similar. After labeling with 186 Re (300 or 400 Ci), the same MAb pairs showed RIT efficacy consistent with the biodistribution data: 186 The use of radiolabeled MAbs has been recognized as a realistic option for improvement of diagnosis and treatment of cancer. While in the last decade MAbs have been administered to thousands of patients with various types of tumor for both diagnostic and therapeutic purposes, the application of MAbs in head-andneck oncology has not kept pace. One of the main reasons for this slow progress has been the lack of MAbs with a high specificity for head-and-neck cancer, in particular for HNSCC, which accounts for approximately 90% of head-and-neck tumors.In recent years, a panel of MAbs has been developed that is capable of selective HNSCC targeting, as demonstrated in clinical radioimmunoscintigraphy/biodistribution studies with HNSCC patients. Among the best-qualified antibodies are the mMAbs U36 and BIWA-1 (formerly VFF18). 1,2 U36 and BIWA-1 bind to overlapping epitopes in the variable domain v6 of the cell-surface antigen CD44 and have been characterized extensively. 3,4 CD44 isoforms, which arise from differential splicing of up to 9 variant exons, show a tissue-specific expression pattern. Homogenous expression of v6-containing CD44 isofo...

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Colorectal cancer prognosis and expression of exon-v6-containing CD44 proteins

Cited by 293 publications

References 9 publications

MicroRNAs and Metastasis-related Gene Expression in Egyptian Breast Cancer Patients

MicroRNAs and Metastasis-related Gene Expression in Egyptian Breast Cancer Patients

De novo expression of CD44 variants in sporadic and hereditary gastric cancer

Tumor targeting properties of monoclonal antibodies with different affinity for target antigen CD44V6 in nude mice bearing head‐and‐neck cancer xenografts

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