N-glycans and metastasis in galectin-3 transgenic mice

More, Shyam K.; Srinivasan, Nithya; Budnar, Srikanth; Bane, Sanjay M.; Upadhya, Archana; Thorat, Rahul; Ingle, Arvind; Chiplunkar, Shubhada V.; Kalraiya, Rajiv D.

doi:10.1016/j.bbrc.2015.03.030

Cited by 14 publications

(10 citation statements)

References 24 publications

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“…A study using B16F1 melanoma cells, a variant of B16 melanoma possessing lower metastatic potential than B16F10 cells, demonstrated that C57/BL6 Lgals3−/− mice were more competent in terms of their anti-tumor immunity when compared to Lgals3+/+ mice and, presented enhanced NK-cell activity and lower metastasis [ 19 , 24 ]. In contrast, More SK, 2015 [ 25 ] found that C57/BL6 Lgals3−/− mice showed similar extent of B16F10 melanoma metastatic colonies in the lung as the Lgals3+/+ mice. Another group described that Lgals3−/− mice facilitated B16F10 lung metastasis as a result of decreased NK cytotoxicity and disturbed serum Th1, Th2 and Th17 cytokines [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

The deficiency of galectin-3 in stromal cells leads to enhanced tumor growth and bone marrow metastasis

et al. 2016

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BackgroundGalectin-3 is a multifunctional β-galactoside-binding lectin that once synthesized, is expressed in the nucleus, cytoplasm, cell surface and in the extracellular environment. Because of its unique structure, galectin-3 can oligomerize forming lattice upon binding to multivalent oligossacharides and influence several pathologic events such as tumorigenesis, invasion and metastasis.MethodsIn our study, balb/c Lgals3+/+ and Lgals3−/− female mice were inoculated in the fourth mammary fat pad with 4T1 breast cancer cell line. The primary tumor, inguinal lymph nodes and iliac bone marrow were evaluated 15, 21 and 28 days post-injection. The primary tumor growth was evaluated by measuring the external diameter, internal growth by ultrasound and weight of the excised tumor. The presence of cancer cells in the draining lymph nodes and iliac crest bone marrow were performed by immunohistochemistry, PCR and clonogenic metastatic assay.ResultsIn this study we demonstrated that the deletion of galectin-3 in the host affected drastically the in vivo growth rate of 4T1 tumors. The primary tumors in Lgals3−/− mice displayed a higher proliferative rate (p < 0,05), an increased necrotic area (p < 0,01) and new blood vessels with a wider lumen in comparison with tumors from Lgals3+/+ mice (P < 0,05). Moreover, we detected a higher number of 4T1-derived metastatic colonies in the lymph nodes and the bone marrow of Lgals3−/− mice (p < 0,05). Additionally, healthy Lgals3−/− control mice presented an altered spatial distribution of CXCL12 in the bone marrow, which may explain at least in part the initial colonization of this organ in Lgals3−/− injected with 4T1 cells.ConclusionsTaken together, our results demonstrate for the first time that the absence of galectin-3 in the host microenvironment favors the growth of the primary tumors, the metastatic spread to the inguinal lymph nodes and bone marrow colonization by metastatic 4T1 tumor cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2679-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The deficiency of galectin-3 in stromal cells leads to enhanced tumor growth and bone marrow metastasis

et al. 2016

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“…48 Galectin-3 is also known to bind N-glycans. 49 Moreover, Galectin-3 binds MUC1 via O-glycans of the VNTR. 20,[49][50][51] Therefore, we investigated whether galectin-3 may be a critical mediator of TRPV5 upregulation by MUC1.…”

Section: Muc1 Requires Trpv5 N-glycan and Galectin-3 For Channel Uprementioning

confidence: 99%

“…49 Moreover, Galectin-3 binds MUC1 via O-glycans of the VNTR. 20,[49][50][51] Therefore, we investigated whether galectin-3 may be a critical mediator of TRPV5 upregulation by MUC1. We found that reduction of galectin-3 by using galectin-3 siRNA abrogated the increase in TRPV5 current density mediated by MUC1 ( Figure 8C).…”

Section: Muc1 Requires Trpv5 N-glycan and Galectin-3 For Channel Uprementioning

confidence: 99%

Mucin-1 Increases Renal TRPV5 Activity In Vitro, and Urinary Level Associates with Calcium Nephrolithiasis in Patients

Nie

Bal

Yang

et al. 2016

JASN

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Hypercalciuria is a major risk factor for nephrolithiasis. We previously reported that Uromodulin (UMOD) protects against nephrolithiasis by upregulating the renal calcium channel TRPV5. This channel is crucial for calcium reabsorption in the distal convoluted tubule (DCT). Recently, mutations in the gene encoding Mucin-1 (MUC1) were found to cause autosomal dominant tubulointerstitial kidney disease, the same disease caused by UMOD mutations. Because of the similarities between UMOD and MUC1 regarding associated disease phenotype, protein structure, and function as a cellular barrier, we examined whether urinary MUC1 also enhances TRPV5 channel activity and protects against nephrolithiasis. We established a semiquantitative assay for detecting MUC1 in human urine and found that, compared with controls (n=12), patients (n=12) with hypercalciuric nephrolithiasis had significantly decreased levels of urinary MUC1. Immunofluorescence showed MUC1 in the thick ascending limb, DCT, and collecting duct. Applying whole-cell patch-clamp recording of HEK cells, we found that wild-type but not disease mutant MUC1 increased TRPV5 activity by impairing dynamin-2- and caveolin-1-mediated endocytosis of TRPV5. Coimmunoprecipitation confirmed a physical interaction between TRPV5 and MUC1. However, MUC1 did not increase the activity of N-glycan-deficient TRPV5. MUC1 is characterized by variable number tandem repeats (VNTRs) that bind the lectin galectin-3; galectin-3 siRNA but not galectin-1 siRNA prevented MUC1-induced upregulation of TRPV5 activity. Additionally, MUC1 lacking VNTRs did not increase TRPV5 activity. Our results suggest that MUC1 forms a lattice with the N-glycan of TRPV5 via galectin-3, which impairs TRPV5 endocytosis and increases urinary calcium reabsorption.

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“…SW inhibits mainly the ER and Golgi apparatus α-mannosidases, but also the lysosomal α-mannosidase [4]. It has been demonstrated that SW treatment inhibits tumor cell migration [7,8], modulates of macrophage activity towards M1 phenotype [9–11] and activates of NK cells [12,13].…”

Section: Introductionmentioning

confidence: 99%

Swainsonine, an alpha-mannosidase inhibitor, may worsen cervical cancer progression through the increase in myeloid derived suppressor cells population

et al. 2019

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Cervical cancer, caused by high oncogenic risk Human Papillomavirus (HPV) infection, continues to be a public health problem, mainly in developing countries. Using peptide phage display as a tool to identify potential molecular targets in HPV associated tumors, we identified α-mannosidase, among other enriched sequences. This enzyme is expressed in both tumor and inflammatory compartment of the tumor microenvironment. Several studies in experimental models have shown that its inhibition by swainsonine (SW) led to inhibition of tumor growth and metastasis directly and indirectly, through activation of macrophages and NK cells, promoting anti-tumor activity. Therefore, the aim of this work was to test if swainsonine treatment could modulate anti-tumor immune responses and therefore interfere in HPV associated tumor growth. Validation of our biopanning results showed that cervical tumors, both tumor cells and leukocytes, expressed α-mannosidase. Ex vivo experiments with tumor associated macrophages showed that SW could partially modulate macrophage phenotype, decreasing CCL2 secretion and impairing IL-10 and IL-6 upregulation, which prompted us to proceed to in vivo tests. However, in vivo , SW treatment increased tumor growth. Investigation of the mechanisms leading to this result showed that SW treatment significantly induced the accumulation of myeloid derived suppressor cells in the spleen of tumor bearing mice, which inhibited T cell activation. Our results suggested that SW contributes to cervical cancer progression by favoring proliferation and accumulation of myeloid cells in the spleen, thus exacerbating these tumors systemic effects on the immune system, therefore facilitating tumor growth.

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N-glycans and metastasis in galectin-3 transgenic mice

Cited by 14 publications

References 24 publications

The deficiency of galectin-3 in stromal cells leads to enhanced tumor growth and bone marrow metastasis

The deficiency of galectin-3 in stromal cells leads to enhanced tumor growth and bone marrow metastasis

Mucin-1 Increases Renal TRPV5 Activity In Vitro, and Urinary Level Associates with Calcium Nephrolithiasis in Patients

Swainsonine, an alpha-mannosidase inhibitor, may worsen cervical cancer progression through the increase in myeloid derived suppressor cells population

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