CD44 isoforms in prognosis of breast cancer

Friedrichs, Kay; Kugler, G; Franke, Folker E.; Terpe, Hans-Joachim; Arlt, Josef; Regidor, Pedro‐Antonio; Günthert, Ursula

doi:10.1016/s0140-6736(95)92018-8

Cited by 23 publications

(15 citation statements)

References 4 publications

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“…Our analysis would suggest that the major change in CD44 splicing occurs during development of adenocarcinomas, not their metastases and that it may be the over-expression of variant CD44 mRNAs during the neoplastic state which is important for the metastatic process, rather than the production of any mRNA including v6. This di erence may suggest why experiments monitoring inclusion of CD44 variable exons have failed to demonstrate a consistent correlation to disease progression in several clinical studies (Friedrichs et al, 1995;Muller et al, 1997;Tran et al, 1997).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 1999

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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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“…Interest in CD44 was generated by reports implicating CD44 variant and standard (CD44s) isoforms in tumor metastasis in animal models (5,7). Numerous studies of CD44 isoforms as metastasis markers in human cancers, such as colorectal carcinoma (8)(9)(10) and breast cancer (11)(12)(13)(14), produced variable results.…”

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confidence: 99%

Overexpressed human CD44s promotes lung colonization during micrometastasis of murine fibrosarcoma cells: Facilitated retention in the lung vasculature

Kogerman

Sy²,

Culp

1997

Proc. Natl. Acad. Sci. U.S.A.

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Normally nonmetastatic murine sis-transformed BALB͞c 3T3 cells, transfected with human CD44s gene (hCD44s), acquire spontaneous metastatic capacity to the lung. The mechanism(s) of this facilitated micrometastasis was analyzed in an experimental metastasis model. Human CD44s overexpression promoted the earliest stages severalfold (initial implantation and subsequent stabilization of tumor cells) but was irrelevant for later stages (subsequent outgrowth) of lung experimental micrometastasis. By injecting mixed populations of parental (nonmetastatic) and CD44s-transfected cells, it was shown that cell-cell adhesion between tumor and parental cells was not promoted by hCD44s but that promotion of cell-cell adhesion to lung endothelium or specifically between transfected cells (via hyaluronan) are likely mechanisms. Results obtained with hCD44s-negative primary tumor cells and hCD44s-positive or -negative variants of lung micrometastatic cells (after s.c. injection of transfectants) confirmed the importance of CD44s overexpression for early but not late stages of experimental lung metastasis. Therefore, CD44s represents a metastasis-facilitating molecule that is irrelevant for primary tumor outgrowth but that promotes micrometastasis to the lungs at the very earliest stages.Metastasis is a complex cascade of interrelated events (1), successful completion of which depends on the intrinsic variability of tumor cells (2) and host microenvironments (3, 4). This complexity has made the molecular mechanisms of metastasis difficult to analyze. A number of important molecules have been suggested, including CD44, a cell surface receptor for the high molecular weight glycosaminoglycan hyaluronan (HA) (5).CD44 is a heterogeneous family of type I transmembrane glycoproteins with complex alternative-splicing and glycosylation patterns (6). Interest in CD44 was generated by reports implicating CD44 variant and standard (CD44s) isoforms in tumor metastasis in animal models (5, 7). Numerous studies of CD44 isoforms as metastasis markers in human cancers, such as colorectal carcinoma (8-10) and breast cancer (11-14), produced variable results.Studies from our laboratory correlated serum-independent CD44s expression with tumor metastasis in a murine fibrosarcoma͞metastasis model system [i.e., BALB͞c 3T3 cells transformed with sis or ras oncogenes (15-17)]. The involvement of CD44s in metastasis was tested more directly by transfecting the human CD44s gene (hCD44s) into two different nonmetastatic fibrosarcoma cell types. They demonstrated induction of spontaneous metastasis by overexpression of hCD44s (18). In contrast, hCD44s overexpression was selected against during primary tumor outgrowth; this expression was down-regulated in primary tumors by an epigenetic mechanism involving methylation of the human CD44s gene.In this study, the mechanism(s) of induction of metastatic capacity by hCD44s expression was analyzed using tail vein injections into nude mice and quantitation of pulmonary micrometastases by virtue of the drug ...

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CD44 isoforms in prognosis of breast cancer

Cited by 23 publications

References 4 publications

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

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

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

Overexpressed human CD44s promotes lung colonization during micrometastasis of murine fibrosarcoma cells: Facilitated retention in the lung vasculature

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