The Role of Fucosylation in Leukocyte Adhesion Deficiency II

Vestweber, Dietmar; Lühn, Kerstin; Marquardt, Thorsten; Wild, Martin K.

doi:10.1007/978-3-662-05397-3_4

Cited by 3 publications

(4 citation statements)

References 48 publications

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“…The present results support the evidence that α-L-fucosidase expression is essential to attenuate the malignant and invasive phenotype of thyroid cancer. There is general agreement in considering that protein fucosylation is crucial for leukocyte adhesion to the vasculature, pointing to its role in cell adhesion and motility [ 45 ]. The findings presented here support the idea that increased fucosylation contributes to higher invasive properties of both blood and cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Humanα-L-fucosidase-1attenuates the invasive properties of thyroid cancer

et al. 2017

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Glycans containing α-L-fucose participate in diverse interactions between cells and extracellular matrix. High glycan expression on cell surface is often associated with neoplastic progression. The lysosomal exoenzyme, α-L-fucosidase-1 (FUCA-1) removes fucose residues from glycans. The FUCA-1 gene is down-regulated in highly aggressive and metastatic human tumors. However, the role of FUCA-1 in tumor progression remains unclear. It is speculated that its inactivation perturbs glycosylation of proteins involved in cell adhesion and promotes cancer. FUCA-1 expression of various thyroid normal and cancer tissues assayed by immunohistochemical (IHC) staining was high in normal thyroids and papillary thyroid carcinomas (PTC), whereas it progressively decreased in poorly differentiated, metastatic and anaplastic thyroid carcinomas (ATC). FUCA-1 mRNA expression from tissue samples and cell lines and protein expression levels and enzyme activity in thyroid cancer cell lines paralleled those of IHC staining. Furthermore, ATC-derived 8505C cells adhesion to human E-selectin and HUVEC cells was inhibited by bovine α-L-fucosidase or Lewis antigens, thus pointing to an essential role of fucose residues in the adhesive phenotype of this cancer cell line. Finally, 8505C cells transfected with a FUCA-1 containing plasmid displayed a less invasive phenotype versus the parental 8505C. These results demonstrate that FUCA-1 is down-regulated in ATC compared to PTC and normal thyroid tissues and cell lines. As shown for other human cancers, the down-regulation of FUCA-1 correlates with increased aggressiveness of the cancer type. This is the first report indicating that the down-regulation of FUCA-1 is related to the increased aggressiveness of thyroid cancer.

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Section: Discussionmentioning

confidence: 99%

Humanα-L-fucosidase-1attenuates the invasive properties of thyroid cancer

et al. 2017

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“…FUK activity appears to account for up to 40% of overall fucosylation through the fucose salvage pathway, whereas the remaining 60% is produced by the de novo synthesis pathway, which converts intracellular GDP-D-mannose into GDP-L-fucose (30). Protein fucosylation is crucial for leukocyte adhesion to the vasculature, pointing to its role in cell adhesion and motility (31). Transcriptional silencing of FUK by ATF2 reduced global fucosylation dynamics, which results in enhanced metastatic propensity of melanoma.…”

Section: Introductionmentioning

confidence: 99%

The transcription factor ATF2 promotes melanoma metastasis by suppressing protein fucosylation

et al. 2015

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Melanoma is one of the most lethal skin cancers worldwide, primarily because of its propensity to metastasize. Thus, the elucidation of mechanisms that govern metastatic propensity is urgently needed. We found that protein kinase Cε (PKCε)–mediated activation of activating transcription factor 2 (ATF2) controls the migratory and invasive behaviors of melanoma cells. PKCε-dependent phosphorylation of ATF2 promoted its transcriptional repression of the gene encoding fucokinase (FUK), which mediates the fucose salvage pathway and thus global cellular protein fucosylation. In primary melanocytes and cell lines representing early-stage melanoma, the abundance of PKCε-phosphorylated ATF2 was low, thereby enabling the expression of FUK and cellular protein fucosylation, which promoted cellular adhesion and reduced motility. In contrast, increased expression of the gene encoding PKCε and abundance of phosphorylated, transcriptionally active ATF2 were observed in advanced-stage melanomas and correlated with decreased FUK expression, decreased cellular protein fucosylation, attenuated cell adhesion, and increased cell motility. Restoring fucosylation in mice either by dietary fucose supplementation or by genetic manipulation of murine Fuk expression attenuated primary melanoma growth, increased the number of intratumoral natural killer cells, and decreased distal metastasis in murine isograft models. Tumor microarray analysis of human melanoma specimens confirmed reduced fucosylation in metastatic tumors and a better prognosis for primary melanomas that had high abundance of fucosylation. Thus, inhibiting PKCε or ATF2 or increasing protein fucosylation in tumor cells may improve clinical outcome in melanoma patients.

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“…As mentioned above, clinical-grade L-fucose has been implemented as an experimental treatment for leukocyte adhesion deficiency-II (LAD-II), a rare genetic disorder in children driven by mutations in the de novo GDP-fucose synthetic pathway that abrogates fucosylation in leukocyte precursors, impairing their ability to extravasate from the vasculature. 91 Oral administration of L-fucose, which increases fucosylation via the fucose salvage pathway, is sufficient to compensate for cellular fucosylation that is suppressed by de novo pathway mutations in LAD-II patients, at least partially reverting symptoms of this pathology, demonstrating the potential clinical utility and the safety of L-fucose supplementation. 50 In the context of cancer, preclinical in vivo mouse models of breast cancer, Ehrlich carcinoma, and melanoma have demonstrated antitumorigenic effects of L-fucose.…”

Section: Targeting Fucosylation In Cancermentioning

confidence: 99%

“…In contrast to the efforts aimed at inhibiting fucosylation for the treatment of cancers, increasing fucosylation has also been reported to elicit therapeutically potent antitumor effects with the potential to augment immunotherapies. As mentioned above, clinical‐grade l ‐fucose has been implemented as an experimental treatment for leukocyte adhesion deficiency‐II (LAD‐II), a rare genetic disorder in children driven by mutations in the de novo GDP‐fucose synthetic pathway that abrogates fucosylation in leukocyte precursors, impairing their ability to extravasate from the vasculature 91 . Oral administration of l ‐fucose, which increases fucosylation via the fucose salvage pathway, is sufficient to compensate for cellular fucosylation that is suppressed by de novo pathway mutations in LAD‐II patients, at least partially reverting symptoms of this pathology, demonstrating the potential clinical utility and the safety of l ‐fucose supplementation 50 …”

Section: Targeting Fucosylation In Cancermentioning

confidence: 99%

L‐fucose, a sugary regulator of antitumor immunity and immunotherapies

Adhikari

Liu

Burton

et al. 2022

Molecular Carcinogenesis

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l‐fucose is a dietary sugar that is used by cells in a process called fucosylation to posttranslationally modify and regulate protein behavior and function. As fucosylation plays essential cellular functions in normal organ and immune developmental and homeostasis, it is perhaps not surprising that it has been found to be perturbed in a number of pathophysiological contexts, including cancer. Increasing studies over the years have highlighted key roles that altered fucosylation can play in cancer cell‐intrinsic as well as paracrine signaling and interactions. In particular, studies have demonstrated that fucosylation impact tumor:immunological interactions and significantly enhance or attenuate antitumor immunity. Importantly, fucosylation appears to be a posttranslational modification that can be therapeutically targeted, as manipulating the molecular underpinnings of fucosylation has been shown to be sufficient to impair or block tumor progression and to modulate antitumor immunity. Moreover, the fucosylation of anticancer agents, such as therapeutic antibodies, has been shown to critically impact their efficacy. In this review, we summarize the underappreciated roles that fucosylation plays in cancer and immune cells, as well as the fucosylation of therapeutic antibodies or the manipulation of fucosylation and their implications as new therapeutic modalities for cancer.

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The Role of Fucosylation in Leukocyte Adhesion Deficiency II

Cited by 3 publications

References 48 publications

Humanα-L-fucosidase-1attenuates the invasive properties of thyroid cancer

Humanα-L-fucosidase-1attenuates the invasive properties of thyroid cancer

The transcription factor ATF2 promotes melanoma metastasis by suppressing protein fucosylation

L‐fucose, a sugary regulator of antitumor immunity and immunotherapies

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