Hypoxia Up-Regulates Galectin-3 in Mammary Tumor Progression and Metastasis

The tumor microenvironment encompasses several stressful conditions for cancer cells such as hypoxia, oxidative stress and pH alterations. Galectin-3, a well-studied member of the beta-galactoside-binding animal family of lectins has been implicated in multiple steps of metastasis as cell-cell and cell-ECM adhesion, promotion of angiogenesis, cell proliferation and resistance to apoptosis. However, both its aberrantly up- and down-regulated expression was observed in several types of cancer. Thus, the mechanisms that regulate galectin-3 expression in neoplastic settings are not clear. In order to demonstrate the putative role of hypoxia in regulating galectin-3 expression in canine mammary tumors (CMT), in vitro and in vivo studies were performed. In malignant CMT cells, hypoxia was observed to induce expression of galectin-3, a phenomenon that was almost completely prevented by catalase treatment of CMT-U27 cells. Increased galectin-3 expression was confirmed at the mRNA level. Under hypoxic conditions the expression of galectin-3 shifts from a predominant nuclear location to cytoplasmic and membrane expressions. In in vivo studies, galectin-3 was overexpressed in hypoxic areas of primary tumors and well-established metastases. Tumor hypoxia thus up-regulates the expression of galectin-3, which may in turn increase tumor aggressiveness.

肿瘤微环境（tumor microenvironment）涵盖了癌细胞所面临的多种应激条件，包括缺氧、氧化应激及pH值改变。半乳糖凝集素3（Galectin-3）是一类研究较为深入的β-半乳糖苷结合动物凝集素家族成员，已被证实参与肿瘤转移过程的多个环节，如细胞-细胞黏附、细胞-细胞外基质（extracellular matrix, ECM）黏附、促进血管生成、细胞增殖及抗凋亡调控。然而，在多种癌症类型中均观察到其表达存在异常上调与下调的情况。因此，在肿瘤状态下调控半乳糖凝集素3表达的具体机制仍不明确。为阐明缺氧在犬乳腺肿瘤（canine mammary tumors, CMT）中调控半乳糖凝集素3表达的潜在作用，本研究开展了体外（in vitro）与体内（in vivo）实验。在恶性犬乳腺肿瘤细胞中，缺氧可诱导半乳糖凝集素3的表达，这一效应在经过氧化氢酶处理的CMT-U27细胞中几乎完全被阻断。研究在mRNA水平验证了半乳糖凝集素3的表达上调。在缺氧条件下，半乳糖凝集素3的表达定位从以细胞核为主导转变为细胞质与细胞膜表达。体内实验结果显示，半乳糖凝集素3在原发性肿瘤的缺氧区域及已形成的转移灶中均呈过表达状态。综上，肿瘤缺氧可上调半乳糖凝集素3的表达，进而可能增强肿瘤的侵袭性。