title: N-glycans and metastasis in galectin-3 transgenic mice.
abstract: 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.
authors: Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Sector 22, Kharghar, Navi Mumbai 410210, India.
authors: Shyam K
authors: SK
authors: More
authors: Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Sector 22, Kharghar, Navi Mumbai 410210, India.
authors: Nithya
authors: N
authors: Srinivasan
authors: Division of Molecular Cell Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia.
authors: Srikanth
authors: S
authors: Budnar
authors: Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Sector 22, Kharghar, Navi Mumbai 410210, India.
authors: Sanjay M
authors: SM
authors: Bane
authors: SPP School of Pharmacy & Technology Management, SVKM's NMIMS, Mumbai, India.
authors: Archana
authors: A
authors: Upadhya
authors: Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Sector 22, Kharghar, Navi Mumbai 410210, India.
authors: Rahul A
authors: RA
authors: Thorat
authors: Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Sector 22, Kharghar, Navi Mumbai 410210, India.
authors: Arvind D
authors: AD
authors: Ingle
authors: Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Sector 22, Kharghar, Navi Mumbai 410210, India.
authors: Shubhada V
authors: SV
authors: Chiplunkar
authors: Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Sector 22, Kharghar, Navi Mumbai 410210, India. Electronic address: rkalraiya@actrec.gov.in.
authors: Rajiv D
authors: RD
authors: Kalraiya
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D037502:Galectin 3 / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000556:secondary; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D016133:Polymerase Chain Reaction; D011134:Polysaccharides / Q000502:physiology*
chemical_list: D017931:DNA Primers; D037502:Galectin 3; D011134:Polysaccharides
keywords: Galectin-3; Galectin-3 transgenic mice; Organ specific metastasis