More Shyam K, Srinivasan Nithya, Budnar Srikanth, Bane Sanjay M, Upadhya Archana, Thorat Rahul A, Ingle Arvind D, Chiplunkar Shubhada V, Kalraiya Rajiv D
Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Sector 22, Kharghar, Navi Mumbai 410210, India.
Division of Molecular Cell Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia.
Biochem Biophys Res Commun. 2015 May 1;460(2):302-7. doi: 10.1016/j.bbrc.2015.03.030. Epub 2015 Mar 17.
Poly-N-acetyl-lactosamine (polyLacNAc) on N-glycans facilitate lung specific metastasis of melanoma cells by serving as high affinity ligands for galectin-3, expressed in highest amounts in the lungs, on almost all its tissue compartments including on the surface of vascular endothelium. PolyLacNAc not only aids in initial arrest on the organ endothelium but in all the events of extravasation. Inhibition of polyLacNAc synthesis, or competitive inhibition of its interaction with galectin-3 all inhibited these processes and experimental metastasis. Transgenic galectin-3 mice, viz., gal-3(+/+) (wild type), gal-3(+/-) (hemizygous) and gal-3(-/-) (null) have been used to prove that galectin-3/polyLacNAc interactions are indeed critical for lung specific metastasis. Gal-3(+/-) mice which showed <50% expression of galectin-3 on the lungs also showed proportionate decrease in the number of B16F10 melanoma metastatic colonies affirming that galectin-3 and polyLacNAc interactions are indeed key determinants of lung metastasis. However, surprisingly, the number and size of metastatic colonies in gal-3(-/-) mice was very similar as that seen in gal-3(+/+) mice. The levels of lactose binding lectins on the lungs and the transcripts of other galectins (galectin-1, -8 and -9) which are expressed on lungs and have similar sugar binding specificities as galectins-3, remain unchanged in gal-3(+/+) and gal-3(-/-) mice. Further, inhibition of N-glycosylation with Swainsonine (SW) which drastically reduces metastasis of B16F10 cells in gal-3(+/+) mice, did not affect lung metastasis when assessed in gal-3(-/-) mice. Together, these results rule out the possibility of some other galectin taking over the function of galectin-3 in gal-3(-/-) mice. Chimeric mice generated to assess if absence of any effect on metastasis is due to compromised tumor immunity by replacing bone marrow of gal-3(-/-) mice with that from gal-3(+/+) mice, also failed to impact melanoma metastasis. As galectin-3 regulates several immune functions including maturation of different immune cells, compromised tumor immunity could be the major determinant of melanoma metastasis in gal-3(-/-) mice and warrants thorough investigation.
N-聚糖上的多聚N-乙酰乳糖胺（polyLacNAc）通过作为半乳糖凝集素-3的高亲和力配体促进黑色素瘤细胞的肺特异性转移，半乳糖凝集素-3在肺中表达量最高，几乎在其所有组织区室中都有表达，包括血管内皮表面。PolyLacNAc不仅有助于在器官内皮上的初始滞留，还参与了外渗的所有过程。抑制polyLacNAc合成或竞争性抑制其与半乳糖凝集素-3的相互作用均抑制了这些过程和实验性转移。转基因半乳糖凝集素-3小鼠，即gal-3(+/+)（野生型）、gal-3(+/-)（杂合子）和gal-3(-/-)（纯合子）已被用于证明半乳糖凝集素-3/polyLacNAc相互作用确实对肺特异性转移至关重要。肺中半乳糖凝集素-3表达量<50%的gal-3(+/-)小鼠，其B16F10黑色素瘤转移瘤的数量也相应减少，这证实了半乳糖凝集素-3和polyLacNAc相互作用确实是肺转移的关键决定因素。然而，令人惊讶的是，gal-3(-/-)小鼠中转移瘤的数量和大小与gal-3(+/+)小鼠中所见非常相似。肺中乳糖结合凝集素的水平以及其他在肺中表达且与半乳糖凝集素-3具有相似糖结合特异性的半乳糖凝集素（半乳糖凝集素-1、-8和-9）的转录本，在gal-3(+/+)和gal-3(-/-)小鼠中保持不变。此外，用苦马豆素（SW）抑制N-糖基化可显著降低gal-3(+/+)小鼠中B16F10细胞的转移，但在gal-3(-/-)小鼠中评估时对肺转移没有影响。总之，这些结果排除了在gal-3(-/-)小鼠中其他半乳糖凝集素取代半乳糖凝集素-3功能的可能性。通过用gal-3(+/+)小鼠的骨髓替换gal-3(-/-)小鼠的骨髓来评估对转移无任何影响是否是由于肿瘤免疫受损而产生的嵌合小鼠，也未能影响黑色素瘤转移。由于半乳糖凝集素-3调节多种免疫功能，包括不同免疫细胞的成熟，肿瘤免疫受损可能是gal-3(-/-)小鼠中黑色素瘤转移的主要决定因素，值得深入研究。
