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Aberrant glycosylation promotes lung cancer metastasis through adhesion to galectins in the metastatic niche.

ABSTRACT: Metastasis is the leading cause of cancer-associated deaths. Although dissemination of tumor cells likely occurs early in tumorigenesis, the constituents of the microenvironment play essential rate-limiting roles in determining whether these cells will form clinically relevant tumors. Recent studies have uncovered many molecular factors that contribute to the establishment of a protumorigenic metastatic niche. Here, we demonstrate that galectin-3, whose expression has clinical associations with advanced malignancy and poor outcome, contributes to metastatic niche formation by binding to carbohydrates on metastatic cells. We show that galectin-3 is expressed early during tumorigenesis by both CD11b(+)Gr-1(+) and CD11b(+)Ly-6C(hi) leukocytes. Tumors mobilize these myeloid populations through secretion of soluble factors, including IL6. We find that metastatic cancer cells exhibit elevated presentation of the oncofetal galectin-3 carbohydrate ligand, the Thomsen-Friedenreich antigen, on their surfaces as a result of altered C2GnT2 and St6GalNAc4 glycosyltransferase activity that inhibits further glycosylation of this carbohydrate motif and promotes metastasis.Although clinical observations of elevated serum galectin-3 levels and altered glycosylation have been associated with malignancy, we identify novel roles for glycosyltransferases in promoting adhesion to galectins in the metastatic niche. This identification of a cytokine-leukocyte-glycosylation axis in metastasis provides mechanistic explanations for clinical associations between malignancy and aberrant glycosylation.

SUBMITTER: Reticker-Flynn NE

PROVIDER: S-EPMC4367955 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Aberrant glycosylation promotes lung cancer metastasis through adhesion to galectins in the metastatic niche.

Reticker-Flynn Nathan E NE Bhatia Sangeeta N SN

Cancer discovery 20141124 2

<h4>Unlabelled</h4>Metastasis is the leading cause of cancer-associated deaths. Although dissemination of tumor cells likely occurs early in tumorigenesis, the constituents of the microenvironment play essential rate-limiting roles in determining whether these cells will form clinically relevant tumors. Recent studies have uncovered many molecular factors that contribute to the establishment of a protumorigenic metastatic niche. Here, we demonstrate that galectin-3, whose expression has clinical ...[more]

PMID: 25421439

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Aberrant glycosylation promotes lung cancer metastasis through adhesion to galectins in the metastatic niche.

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Aberrant glycosylation promotes lung cancer metastasis through adhesion to galectins in the metastatic niche.

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