Abstract B8: Galectin-1 expressed in human melanoma is bound to cancer stem cells: A driver for metastatic progression and target for antimetastatic cancer therapy (2013)

Abstract Galectin-1 has been shown as a major protein secreted by the majority of cancer types. It plays important roles in the tumor microenvironment protecting against immune cell attack, from reactive oxygen species production and promotes metastasis. Galectin-1 binds at high levels to the surfaces of human endothelial cell lines and binding is inhibited by pre-treatment with inhibitory disaccharides. Galectin blockade in this manner can be used to inhibit growth of primary cancers in murine models. We have shown galectin-1 is highly expressed within hypoxic domains of primary human melanoma, associated with cancer stem cell markers, but is widely expressed at high levels in metastases from the same patients. Using siRNA knockdown or binding inhibitors, galectin-1 expression is shown to be critical for protecting endothelial cells in tumor angiogenesis and for promoting tumor metastasis. More recently, it has been shown that galectin blockade using small drug molecules significantly enhanced the permeability and access of other chemotherapies inside tumors by promoting vascular leakiness, increasing cytotoxic efficacy and immune cell killing in-situ detected by TUNEL assays inside tumors. Galectin-1 blockade or siRNA knockdown also significantly inhibits metastases to the lung in the 4T1 murine breast cancer model. When used in combination as a triple therapy with whole cancer cell vaccines subjected to IFN and expressing CD80 together with anti-CTLA4 Ig treatment, galectin-1 blockade produced synergistic enhancements increasing CD8+ CTL anticancer responses to inhibit cancer growth in a range of different mouse tumor models including the CT26 colon and 4T-1 breast cancers. These results together with flow cytometric analysis showed that the melanoma stem cell markers, CD271 and ABCB5 co-localized with bound galectin-1 in hypoxic regions of melanomas, suggesting that galectin-1 may play a role in cancer stem cell function, promoting their mobilization and metastasis. Published References: 1. Galectin-1 as a potent target for cancer therapy: role in the tumor microenvironment. Ito K, Stannard K, Gabutero E, Clark AM, Neo SY, Onturk S, Blanchard H, Ralph SJ. Cancer Metastasis Rev. 2012 Dec;31(3-4):763-78. 2. Inhibiting galectin-1 reduces murine lung metastasis with increased CD4(+) and CD8 (+) T cells and reduced cancer cell adherence. Ito K, Ralph SJ. Clin Exp Metastasis. 2012 Aug;29(6):561-72. 3. Thiodigalactoside inhibits murine cancers by concurrently blocking effects of galectin-1 on immune dysregulation, angiogenesis and protection against oxidative stress. Ito K, Scott SA, Cutler S, Dong LF, Neuzil J, Blanchard H, Ralph SJ. Angiogenesis. 2011 Sep;14(3):293-307. 4. Galectin inhibitory disaccharides promote tumour immunity in a breast cancer model. Stannard KA, Collins PM, Ito K, Sullivan EM, Scott SA, Gabutero E, Darren Grice I, Low P, Nilsson UJ, Leffler H, Blanchard H, Ralph SJ. Cancer Lett. 2010 Dec 28;299(2):95-110. Citation Format: Koichi Ito, Selda Onturk, Katie Powell, Beatrice Philip, James Wilmott, Richard Scolyer, Peter Hersey, Stephen J. Ralph. Galectin-1 expressed in human melanoma is bound to cancer stem cells: A driver for metastatic progression and target for antimetastatic cancer therapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B8.