Article

Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi’s sarcoma

Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, 1428 Buenos Aires, Argentina.
Journal of Experimental Medicine (Impact Factor: 13.91). 10/2012; 209(11):1985-2000. DOI: 10.1084/jem.20111665

ABSTRACT Kaposi’s sarcoma (KS), a multifocal vascular neoplasm linked to human herpesvirus-8 (HHV-8/KS-associated herpesvirus [KSHV])
infection, is the most common AIDS-associated malignancy. Clinical management of KS has proven to be challenging because of
its prevalence in immunosuppressed patients and its unique vascular and inflammatory nature that is sustained by viral and
host-derived paracrine-acting factors primarily released under hypoxic conditions. We show that interactions between the regulatory
lectin galectin-1 (Gal-1) and specific target N-glycans link tumor hypoxia to neovascularization as part of the pathogenesis
of KS. Expression of Gal-1 is found to be a hallmark of human KS but not other vascular pathologies and is directly induced
by both KSHV and hypoxia. Interestingly, hypoxia induced Gal-1 through mechanisms that are independent of hypoxia-inducible
factor (HIF) 1α and HIF-2α but involved reactive oxygen species–dependent activation of the transcription factor nuclear factor
κB. Targeted disruption of Gal-1–N-glycan interactions eliminated hypoxia-driven angiogenesis and suppressed tumorigenesis
in vivo. Therapeutic administration of a Gal-1–specific neutralizing mAb attenuated abnormal angiogenesis and promoted tumor
regression in mice bearing established KS tumors. Given the active search for HIF-independent mechanisms that serve to couple
tumor hypoxia to pathological angiogenesis, our findings provide novel opportunities not only for treating KS patients but
also for understanding and managing a variety of solid tumors.

1 Follower
 · 
150 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neoplastic transformation results in a wide variety of cellular alterations that impact the growth, survival, and general behavior of affected tissue. Although genetic alterations underpin the development of neoplastic disease, epigenetic changes can exert an equally significant effect on neoplastic transformation. Among neoplasia-associated epigenetic alterations, changes in cellular glycosylation have recently received attention as a key component of neoplastic progression. Alterations in glycosylation appear to not only directly impact cell growth and survival but also facilitate tumor-induced immunomodulation and eventual metastasis. Many of these changes may support neoplastic progression, and unique alterations in tumor-associated glycosylation may also serve as a distinct feature of cancer cells and therefore provide novel diagnostic and even therapeutic targets.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Galectin-1 (Gal1), a β-galactoside-binding protein abundantly expressed in tumor microenvironments, is associated with the development of metastasis in hepatocellular carcinomas (HCC). However, the precise roles of Gal1 in HCC cell invasiveness and dissemination are uncertain. Here, we investigated whether Gal1 mediate epithelial-mesenchymal transition (EMT) in HCC cells, a key process during cancer progression. We used the well-differentiated and low invasive HepG2 cells and performed 'gain-of-function' and 'loss-function' experiments by transfecting cells with Gal1 cDNA constructs or by siRNA strategies, respectively. Epithelial and mesenchymal markers expression, changes in apico-basal polarity, independent-anchorage growth and activation of specific signaling pathways were studied using Western blot, fluorescence microscopy, soft-agar assays and FOP/TOP flash reporter system. Gal1 up-regulation in HepG2 cells induced down-regulation of the adherens junction protein E-cadherin and increased expression of the transcription factor Snail, one of the main inducers of EMT in HCC. Enhanced Gal1 expression facilitated the transition from epithelial cell morphology towards a fibroblastoid phenotype and favored up-regulation of the mesenchymal marker vimentin in HCC cells. Cells overexpressing Gal1 showed enhanced anchorage-independent growth and loss of apico-basal polarity. Remarkably, Gal1 promoted Akt activation, β-catenin nuclear translocation, TCF4/LEF1 transcriptional activity and increased cyclin D1 and c-Myc expression, suggesting activation of the Wnt pathway. Furthermore, Gal1 overexpression induced E-cadherin downregulation through a PI3K/Akt-dependent mechanism. Our results provide the first evidence of a role of Gal1 as an inducer of EMT in HCC cells, with critical implications in HCC metastasis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Physiology 06/2015; 230(6). DOI:10.1002/jcp.24865 · 3.87 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Galectins are a family of proteins that bind to specific glycans thereby deciphering the information captured within the glycome. In the last two decades, several galectin family members have emerged as versatile modulators of tumor progression. This has initiated the development and preclinical assessment of galectin-targeting compounds. With the first compounds now entering clinical trials it is pivotal to gain insight in the diagnostic and prognostic value of galectins in cancer as this will allow a more rational selection of the patients that might benefit most from galectin-targeted therapies. Here, we present a systematic review of galectin expression in human cancer patients. Malignant transformation is frequently associated with altered galectin expression, most notably of galectin-1 and galectin-3. In most cancers, increased galectin-1 expression is associated with poor prognosis while elevated galectin-9 expression is emerging as a marker of favorable disease outcome. The prognostic value of galectin-3 appears to be tumor type dependent and the other galectins require further investigation. Regarding the latter, additional studies using larger patient cohorts are essential to fully unravel the diagnostic and prognostic value of galectin expression. Furthermore, to better compare different findings, consensus should be reached on how to assess galectin expression, not only with regard to localization within the tissue and within cellular compartments but also regarding alternative splicing and genomic variations. Finally, linking galectin expression and function to aberrant glycosylation in cancer cells will improve our understanding of how these versatile proteins can be exploited for diagnostic, prognostic and even therapeutic purposes in cancer patients. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 03/2015; DOI:10.1016/j.bbcan.2015.03.003 · 4.66 Impact Factor

Full-text (2 Sources)

Download
132 Downloads
Available from
May 15, 2014