Croci DO, Salatino M, Rubinstein N et al.Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi's sarcoma. J Exp Med 209:1985-2000

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: 12.52). 10/2012; 209(11):1985-2000. DOI: 10.1084/jem.20111665


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.

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    • "Interestingly, it has been recently described that TGF-b 1 treatment of fibroblasts increases Gal1 via PI3K/Akt and p38 MAPK and accelerates fibrosis (Lim et al., 2014). Therefore, increased expression of Gal1 in HCC is associated with the development of metastasis, suggesting that, in addition to melanoma (Rubinstein et al., 2004), lung carcinoma (Wu et al., 2009; Croci et al., 2014), Kaposi's sarcoma (Croci et al., 2012), breast carcinoma, (Dalotto-Moreno et al., 2013) and prostate carcinoma (Laderach et al., 2013), HCC represents another tumor type amenable for Gal1 targeting. In conclusion, our results demonstrate that Gal1 is involved in the development of EMT in HCC cells and provide new insights which highlight Gal1 as an important therapeutic target to restrain HCC progression. "
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    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.
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    • "Human LGALS1 contains several putative NFKB consensus sites and the expression of a super-repressor (IkB-a-SR) or pharmacological inhibitor (BAY-117802) prevented hypoxia induction of Gal-1. Furthermore, NFKB-mediated Gal-1 expression under hypoxia was activated by ROS and N-acetylcysteine scavenging of ROS inhibited hypoxia induction of Gal-1 (Croci et al. 2012). "
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    ABSTRACT: Radiation therapy is a main stay in treating solid tumors and plays a significant role in definitive and adjuvant therapy. Unfortunately, local control remains a challenge, in which the success of radiotherapy is largely dictated by tumor hypoxia, DNA damage repair and the antitumor immune response. Extensive efforts have therefore been devoted to targeting the factors that attenuate tumor radiosensitivity, although with limited success. Mounting evidence suggests that tumor and endothelial cells may utilize galectin-1 (Gal-1) for protection against radiation through several mechanisms. Targeting Gal-1 in combination with radiotherapy provides an exciting approach to address several radiation-prohibitive mechanisms.
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    • "This is mainly due to the limited number of PCa animal models available, especially of those that either reflect the entire metastatic cascade—rather than intravenous dissemination models or in situ metastasis microenvironment models—or consider the influence of the immune system (Chauchereau 2011; Grabowska et al. 2014). This last aspect is essential since galectins are major players in cancer immune evasion, endothelial cell activity and metastatic process (Thijssen et al. 2010; Rabinovich and Croci 2012). Since wild-type mice do not spontaneously develop PCa, cooperative endeavors are still required with a view to developing new PCa models using syngenic implantations of murine PCa cells in immune competent animals. "
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    ABSTRACT: Prostate cancer is the second most common cause of cancer and the sixth leading cause of cancer death among men worldwide. While localized prostate cancer can be cured, advanced and metastatic prostate cancer remains a significant therapeutic challenge. Malignant transformation is associated with important modifications of the cellular glycosylation profile, and it is postulated that these changes have a considerable relevance for tumor biology. Metastasis is a multiphasic process that encompasses angiogenesis, the spread of tumor cells and their growth at distant sites from the primary tumor location. Recognition of glycoconjugates by galectins, amongst other lectins, plays a fundamental role in the metastatic spread, tumor immune escape and the neovascularization process. Particularly in prostate cancer, both carbohydrates and galectins have been implicated in many cellular processes such as proliferation, apoptosis, migration and invasion. However, a limited number of studies assessed their potential implications in the induction of metastasis in prostate cancer patients or in animal models. Moreover, the role of galectin-glycan interactions in vivo still remains poorly understood; concerted effort should thus be made in order to shed some light on this question. This review summarizes current evidence on both the expression and role of glycans and galectins in prostate cancer, particularly turning our attention to the angiogenic and metastatic processes.
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