CD44 variant exon epitopes in primary breast cancer and length of survival

Kaufmann, M.; Minckwitz, Gϋnter von; Heider, Karl Heinz; Ponta, Helmut; Herrlich, Peter; Sinn, Hans‐Peter

doi:10.1016/s0140-6736(95)90521-9

Cited by 331 publications

(242 citation statements)

References 13 publications

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“…CD44 plays an important role in prognosis of many cancers, such as bile duct cancer (Kunlabut et al, 2012), breast cancer (Kaufmann et al, 1995), colorectal cancer (Fan et al, 2012) and so on. CD44 can be expressed as isoforms generated by the alternative splicing of variant exons (Mackay et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Prognostic Value of CD44 Variant exon 6 Expression in Non-Small Cell Lung Cancer: a Meta-analysis

He¹,

Qiu²,

Chen³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Section: Introductionmentioning

confidence: 99%

Prognostic Value of CD44 Variant exon 6 Expression in Non-Small Cell Lung Cancer: a Meta-analysis

He¹,

Qiu²,

Chen³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…Combinations of these variable exons lead to a variety of CD44 isoforms (Screaton et al, 1992;Haynes et al, 1990;Gunthert, 1993). Certain isoforms, especially those including variable exons v5, 6, and 7, have been implicated in the metastasis of several malignancies (East and Hart, 1993;Cannistra et al, 1995;Stickeler et al, 1997;Wielenga et al, 1993) and correlated with survival in human breast cancer (Joensuu et al, 1993;Kaufmann et al, 1995). Recently it has been shown that alternative splicing of CD44 responds to signal transduction.…”

Section: Introductionmentioning

confidence: 99%

Stage-specific changes in SR splicing factors and alternative splicing in mammary tumorigenesis

et al. 1999

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Using a mouse model of mammary gland development and tumorigenesis we examined changes in both alternative splicing and splicing factors in multiple stages of mammary cancer. The emphasis was on the SR family of splicing factors known to in¯uence alternative splicing in a wide variety of genes, and on alternative splicing of the pre-mRNA encoding CD44, for which alternative splicing has been implicated as important in a number of human cancers, including breast cancer. We observed step-wise increases in expression of individual SR proteins and alternative splicing of CD44 mRNA during mammary gland tumorigenesis. Individual preneoplasias di ered as to their expression patterns for SR proteins, often expressing only a sub-set of the family. In contrast, tumors demonstrated a complex pattern of SR expression. Little di erence was observed between neoplasias and their metastases. Alternative splicing of CD44 also changed through the disease paradigm such that tumors produced RNA containing a mixture of variable exons, whereas preneoplasias exhibited a more restricted exon inclusion pattern. In contrast, other standard splicing factors changed little in either concentration or splicing pattern in the same cells. These data suggest alterations in relative concentrations of speci®c splicing factors during early preneoplasia that become more pronounced during tumor formation. Given the ability of SR proteins to a ect alternative processing decisions, our results suggest that a number of pre-mRNAs may undergo changes in alternative splicing during the early and intermediate stages of mammary cancer.

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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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CD44 variant exon epitopes in primary breast cancer and length of survival

Cited by 331 publications

References 13 publications

Prognostic Value of CD44 Variant exon 6 Expression in Non-Small Cell Lung Cancer: a Meta-analysis

Prognostic Value of CD44 Variant exon 6 Expression in Non-Small Cell Lung Cancer: a Meta-analysis

Stage-specific changes in SR splicing factors and alternative splicing in mammary tumorigenesis

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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