Juszczynski P, Ouyang J, Monti S, Rodig SJ, Takeyama K, Abramson J et al.. The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci USA 104: 13134-13139

Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2007; 104(32):13134-9. DOI: 10.1073/pnas.0706017104
Source: PubMed


Classical Hodgkin lymphomas (cHLs) contain small numbers of neoplastic Reed-Sternberg (RS) cells within an extensive inflammatory infiltrate that includes abundant T helper (Th)-2 and T regulatory (Treg) cells. The skewed nature of the T cell infiltrate and the lack of an effective host antitumor immune response suggest that RS cells use potent mechanisms to evade immune attack. In a screen for T cell-inhibitory molecules in cHL, we found that RS cells selectively overexpressed the immunoregulatory glycan-binding protein, galectin-1 (Gal1), through an AP1-dependent enhancer. In cocultures of activated T cells and Hodgkin cell lines, RNAi-mediated blockade of RS cell Gal1 increased T cell viability and restored the Th1/Th2 balance. In contrast, Gal1 treatment of activated T cells favored the secretion of Th2 cytokines and the expansion of CD4+CD25high FOXP3+ Treg cells. These data directly implicate RS cell Gal1 in the development and maintenance of an immunosuppressive Th2/Treg-skewed microenvironment in cHL and provide the molecular basis for selective Gal1 expression in RS cells. Thus, Gal1 represents a potential therapeutic target for restoring immune surveillance in cHL.

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Available from: Stefano Monti, Oct 05, 2015
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    • "It regulates complex signaling pathways involved in tumor–host interaction (101) and angiogenesis (102). Tumor secretion of Gal-1 contributes to the immunosuppressive potential of a wide range of tumors by limiting T-cell survival and impairing DC function (103–105). NB tumors, particularly those with poor prognosis, express high levels of Gal-1 (106). The neurotrophin receptor TrkB is also expressed in NB with poor prognosis, conferring invasive and metastatic potential to the tumor cells as well as enhancing therapy resistance. "
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    ABSTRACT: Neuroblastoma (NB), accounting for 10% of childhood cancers, exhibits aberrant cell-surface glycosylation patterns. There is evidence that changes in glycolipids and protein glycosylation pathways are associated to NB biological behavior. Polysialic acid (PSA) interferes with cellular adhesion, and correlates with NB progression and poor prognosis, as well as the expression of sialyltransferase STX, the key enzyme responsible for PSA synthesis. Galectin-1 and gangliosides, overexpressed and actively shedded by tumor cells, can modulate normal cells present in the tumor microenvironment, favoring angiogenesis and immunological escape. Different glycosyltransferases are emerging as tumor markers and potential molecular targets. Immunotherapy targeting disialoganglioside GD2 rises as an important treatment option. One anti-GD2 antibody (ch14.18), combined with IL-2 and GM-CSF, significantly improves survival for high-risk NB patients. This review summarizes our current knowledge on NB glycobiology, highlighting the molecular basis by which carbohydrates and protein-carbohydrate interactions impact on biological behavior and patient clinical outcome.
    Frontiers in Oncology 07/2014; 4:114. DOI:10.3389/fonc.2014.00114
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    • "Once migrated into the tumor mass, lymphocytes are addressed toward Th2 and T-reg differentiation (in particular, a Tr1 phenotype)28 acquiring the ability (together with HRS cells) to produce and secrete TGF-β and IL-10, able to suppress CTL function. Thus, T-regs regulate the production of IL-2 and limit CTL activation,23 while Th2 cells induce the expression of several cyclins and cyclin-dependent kinases 29 and of antiapoptotic markers, such as Bcl-Xl and Mcl1,30 with overexpression of STAT3 in HRS cells, activation of cyclin D1 and Bclx expression, and a down-regulation of STAT1, a tumor suppressor factor.17,18,31 "
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    ABSTRACT: Classic Hodgkin Lymphoma (cHL) has a unique histology since only a few neoplastic cells are surrounded by inflammatory accessory cells that in the last years have emerged as crucial players in sustaining the course of disease. In addition, recent studies suggest that the abnormal activity of these inflammatory cells (such as deregulation in regulatory T cells signaling, expansion of myeloid derived suppressor cells, HLA-G signaling and natural killer cells dysfunction) may have prognostic significance. This review is focused on summarizing recent advanced in immunological defects in cHL with translational implications.
    Mediterranean Journal of Hematology and Infectious Diseases 06/2014; 6(1):e2014039. DOI:10.4084/MJHID.2014.039
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    • "Galectin-1 is differentially expressed by various normal and pathological tissues and appears to be functionally polyvalent, with a wide range of biological activity, including modulation of cells apoptosis, migration, adhesion, malignant transformation, tumor angiogenesis and tumor immunosuppression[12], [30], [31], [32], [33]. Regarding PDAC, Galectin-1 has been proved to be a PDAC related protein[8], [17], [34]. "
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    ABSTRACT: Galectin-1, a member of carbohydrate-binding proteins with a polyvalent function on tumor progression, was found strongly expressed in pancreatic satellite cells (PSCs), which partner in crime with cancer cells and promote the development of pancreatic ductal adenocarcinoma (PDAC). We evaluated the effects of PSCs derived Galectin-1 on the progression of PDAC, as well as the tumor establishment and development in mouse xenografts. The relationship between immunohistochemistry staining intensity of Galectin-1 and clinicopathologic variables were assessed in 66 PDAC tissues, 18 chronic pancreatitis tissues and 10 normal controls. The roles of PSCs isolated from PDAC and normal pancreas on the proliferative activity, MMP2 and MMP9 expression, and the invasion of CFPAC-1 in the co-cultured system, as well as on the tumor establishment and development in mouse xenografts by mixed implanting with CFPAC-1 subcutaneously were evaluated. Galectin-1 expression was gradually increased from normal pancreas (negative), chronic pancreatitis (weak) to PDAC (strong), in which Galectin-1 expression was also increased from well, moderately to poorly differentiated PDAC. Galectin-1 staining intensity of pancreatic cancer tissue was associated with increase in tumor size, lymph node metastasis, perineural invasion and differentiation and UICC stage, and served as the independent prognostic indicator of poor survival of pancreatic cancer. In vitro and in vivo experiments indicated that TGF-β1 upregulated Galectin-1 expression in PSCs, which could further promotes the proliferative activity, MMP2 and MMP9 expression, and invasion of pancreatic cancer cells, as well as the tumor establishment and growth. Galectin-1 expression in stromal cells of pancreatic cancer suggests that this protein plays a role in the promotion of cancer cells invasion and metastasis and provides a therapeutic target for the treatment of pancreatic cancer.
    PLoS ONE 03/2014; 9(3):e90476. DOI:10.1371/journal.pone.0090476 · 3.23 Impact Factor
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