Galectin-3

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Galectin-3 is a member of the lectin family, of which 14 mammalian galectins have been identified.[1] Galectin-3 is approximately 30 kDa and, like all galectins, contains a carbohydrate-recognition-binding domain (CRD) of about 130 amino acids that enable the specific binding of β-galactosides.[1][2][3][4] Galectin-3 is encoded by a single gene, LGALS3, located on chromosome 14, locus q21–q22.[1][5] It is expressed in the nucleus, cytoplasm, mitochondrion, cell surface, and extracellular space.[1][2][3] This protein has been shown to be involved in the following biological processes: cell adhesion, cell activation and chemoattraction, cell growth and differentiation, cell cycle, and apoptosis.[1] Given galectin-3’s broad biological functionality, it has been demonstrated to be involved in cancer, inflammation and fibrosis, heart disease, and stroke.[1][4][6][7] Studies have also shown that the expression of galectin-3 is implicated in a variety of processes associated with heart failure, including myofibroblast proliferation, fibrogenesis, tissue repair, inflammation, and Ventricular remodeling.[6][8][9]

The roles of galectins and galectin-3, in particular, in cancer have been heavily investigated.[10] Of note, galectin-3 has been suggested to play important roles in cancer metastasis.[11]

Role in Disease[edit]

Fibrosis[edit]

Research has shown a definite correlation between galectin-3 expression levels and various types of fibrosis. Galectin-3 is upregulated in cases of liver fibrosis, renal fibrosis, and idiopathic pulmonary fibrosis (IPF). In several studies with mice deficient in or lacking galectin-3, conditions that caused control mice to develop IPF, renal, or liver fibrosis either induced limited fibrosis or failed to induce fibrosis entirely.[12][13][14] Companies have developed galectin modulators that block the binding of galectins to carbohydrate structures. The galectin-3 inhibitor, TD139 has the potential to treat fibrosis.[14]

Galectin-3 inhibitor[edit]

Galectin-3 is upregulated in patients with idiopathic pulmonary fibrosis. The cells that receive galectin-3 stimulation (fibroblasts, epithelial cells, and myofibroblasts) upregulated the formation of fibrosis and collagen formation.[15] Fibrosis is necessary in many aspects of intrabody regeneration. The myocardial lining constantly undergoes necessary fibrosis, and the inhibition of galectin-3 interferes with myocardial fibrogenesis. A study concluded that drugs binding to galectin-3 will benefit those who have too much fibrosis on the heart, but it might potentially backfire for those who need heart restructuring.[15]

Cardiovascular Disease[edit]

Elevated levels of galectin-3 have been found to be significantly associated with higher risk of death in both acute decompensated heart failure and chronic heart failure populations.[16][17][18][19] In normal human, murine, and rat cells galectin-3 levels are low. However as heart disease progresses, significant upregulation of galectin-3 occurs in the myocardium.[20]

Galectin-3 also may be used as a biomarker to identify at risk individuals, and predict patient response to different drugs and therapies. For instance, galectin-3 levels could be used in early detection of failure-prone hearts and lead to intervention strategies including broad spectrum anti-inflammatory agents.[21] One study concluded that individuals with systolic heart failure of ischaemic origin and elevated galectin-3 levels may benefit from statin treatment.[22] Galectin-3 has also been associated as a factor promoting ventricular remodeling following mitral valve repair, and may identify patients requiring additional therapies to obtain beneficial reverse remodeling. [23]

Galectin-3 and Cancer[edit]

The wide variety of effects of galectin-3 on cancerous cells are due to the unique structure and various interaction properties of the molecule. Overexpression and changes in the localization of galectin-3 molecules affects the prognosis of the patient and targeting the actions of galectin-3 poses a promising therapeutic strategy for the development of effective therapeutic agents for cancer treatment.

Overexpression and changes in sub- and inter-cellular localization of galectin-3 are commonly seen in cancerous conditions. The many interaction and binding properties of galectin-3 influence various cell activities based on its location. Altered galectin-3 expression can affect cancer cell growth and differentiation, chemoattraction, apoptosis, immunosuppression, angiogenesis, adhesion, invasion and metastasis.[24]

Biological effects[edit]

Galectin-3 overexpression promotes neoplastic transformation and the maintenance of transformed phenotypes as well as enhances the tumour cell's adhesion to the extracellular matrix and increase metastatic spreading. Galectin-3 can be either an inhibitory or a promoting apoptotic depending on its sub-cellular localization. In immune regulation, galectin-3 can regulate immune cell activities and helps contribute to the tumour cell's evasion of the immune system. Galectin-3 also helps promote angiogenesis.[24]

Clinical applications[edit]

Galectin-3 is increasingly being used as a diagnostic marker for different cancers. It can be screened for and used as a prognostic factor to predict the progression of the cancer. Galectin-3 has varying effects in different types of cancer.[25] One approach to cancers with high galectin-3 expression is to use small molecule inhibition of galectin-3 to enhance treatment response.[26]

Research on Galectin-3[edit]

Galecto Biotech is a research company focused on developing drugs using galectin-3 in treatment for fibrosis, specifically idiopathic pulmonary fibrosis.[27] Galectin Therapeutics in the United States is also using galectins for their research, finding recently that inhibition of galectin-3 significantly reduces portal hypertension and fibrosis in mice.[28] Chronic heart failure has been found to be indicated by a galectin-3 tests, using the ARCHITECT immunochemistry platform developed by Abbott and BG Medicine, helping to determine which patients are most at risk for the disease.[29] Pecta-Sol C binds to galectin-3 binding sites on the surfaces of cells as a preventative measure created by Isaac Eliaz in conjunction with EcoNugenics.[30]

References[edit]

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  2. ^ a b Liu F, Patterson RJ, Wang JL. (2002). "Intracellular function of galectins.". BBA General Subjects 1572 (2-3): 263–273. doi:10.1016/S0304-4165(02)00313-6. PMID 12223274. 
  3. ^ a b Cooper D. (2002). "Galectinomics: finding themes in complexity.". BBA General Subjects 1572 (2-3): 209–231. doi:10.1016/S0304-4165(02)00310-0. PMID 12223271. 
  4. ^ a b Henderson NC, Sethi T. (2009). "The regulation of inflammation by galectin-3.". Immunol Rev 230 (1): 160–171. doi:10.1111/j.1600-065X.2009.00794.x. PMID 19594635. .
  5. ^ Raimond J, Zimonjic DB, Mignon C, et al. (1997). "Mapping of the galectin-3 gene (LGALS3) to human chromosome 14 at region 14q21—22.". Mamm. Genome 8 (9): 706–707. doi:10.1007/s003359900548. PMID 9271684. 
  6. ^ a b Sharma UC, Pokharel S, van Brakel TJ, et al. (2004). "Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction.". Circulation 110 (19): 3121–3128. doi:10.1161/01.CIR.0000147181.65298.4D. PMID 15520318. 
  7. ^ Yan Y, Lang B, Vemuganti R, et al. (2009). "Galectin-3 mediates post-ischemic tissue remodeling.". Brain Res. 1288: 116–124. doi:10.1016/j.brainres.2009.06.073. PMID 19573520. 
  8. ^ Liu YH, D'Ambrosio M, et al. (2009). "N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth-regulatory lectin.". Am. J. Physiol. Heart Circ. Physiol. 296 (2): H404–12. doi:10.1152/ajpheart.00747.2008. PMC 2643891. PMID 19098114. 
  9. ^ Lin YH, Lin LY, Wu YW, et al. (2009). "The relationship between serum galectin-3 and serum markers of cardiac extracellular matrix turnover in heart failure patients". Clin. Chim. Acta 409 (1-2): 96–99. doi:10.1016/j.cca.2009.09.001. PMID 19747906. 
  10. ^ Liu F, Rabinovich G (2005). "Galectins as modulators of tumour progression.". Nature Reviews Cancer 5 (1): 29–41. doi:10.1038/nrc1527. PMID 15630413. 
  11. ^ Reticker-Flynn NE, et al. (2012). 1122. "A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis.". Nature Communications 3 (3): 1122. doi:10.1038/ncomms2128. PMID 23047680. 
  12. ^ Henderson, Neil; Alison C. Mackinnon (28 March 2006). "Galectin-3 regulates myofibroblast activation and hepatic fibrosis". Proceedings of the National Academy of Sciences of the United States 103 (13): 5060–5065. doi:10.1073/pnas.0511167103. PMC 1458794. Retrieved 28 November 2013. 
  13. ^ Henderson, Neil; Alison C. Mackinnon (February 2008). "Galectin-3 Expression and Secretion Links Macrophages to the Promotion of Renal Fibrosis". The American Journal of Pathology 172 (2): 288–298. doi:10.2353/ajpath.2008.070726. PMC 2312353. Retrieved 28 November 2013. 
  14. ^ a b MacKinnon, Alison; Michael A. Gibbons (1 March 2012). "Regulation of Transforming Growth Factor-β1–driven Lung Fibrosis by Galectin-3". American Journal of Respiratory and Critical Care Medicine 185 (5): 537–546. doi:10.1164/rccm.201106-0965OC. PMC 3410728. Retrieved 28 November 2013. 
  15. ^ a b Yu, L (2013). "Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial fibrogenesis". Circulation: Heart Failure 6 (1): 107–117. doi:10.1161/circheartfailure.112.971168. 
  16. ^ van Kimmenade RR, Januzzi JL, Ellinor PT, et al. (2006). "Utility of amino-terminal pro-brain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure.". J Am Coll Cardiol 48 (6): 1217–24. doi:10.1016/j.jacc.2006.03.061. PMID 16979009. 
  17. ^ Lok D, van der Meer P, de La Porte PM, et al. Galectin-3, a novel marker of macrophage activity, predicts outcome in patients with stable chronic heart failure. J. Am. Coll. Cardiol. 2007;49:98A.
  18. ^ van Veldhuisen DJ, Lok DJ, Damman K, et al. (2009). "Clinical and prognostic value of galectin-3, a novel fibrosis-associated biomarker, in patients with chronic heart failure.". J Card Fail 15 (9): 814. doi:10.1016/j.cardfail.2009.10.013. 
  19. ^ DeFilippi C, Christenson R, Shah R, et al. (2009). "Clinical validation of a novel assay for galectin-3 for risk assessment in acutely destabilized heart failure.". J Card Fail 15 (6): S9. doi:10.1016/j.cardfail.2009.06.405. 
  20. ^ de Boer , R. A., Voors, A. A., Muntendam, P., van Gilst, W. H., & van Veldhuisen, D. J. (2009). "Galectin-3: a novel mediator of heart failure development and progression.". European journal of heart failure 11 (9): 811–817. doi:10.1093/eurjhf/hfp097. PMID 19648160. 
  21. ^ Sharma, U. C., Pokharel, S., van Brakel, T. J., van Berlo (2004). "Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction.". [[Circulation (journal)|]] 110 (19): 3121–31288. doi:10.1161/01.CIR.0000147181.65298.4D. PMID 15520318. 
  22. ^ Gullestad, L., Ueland, T., Kjekshus, J. (2012). "Galectin-3 predicts response to statin therapy in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)". European heart journal 33 (18): 2290–2296. doi:10.1093/eurheartj/ehs077. PMID 22513778. 
  23. ^ Kortekaas, K. A., Hoogslag, G. E., de Boer (2013). "Galectin-3 and left ventricular reverse remodelling after surgical mitral valve repair.". European journal of heart failure 15 (9): 1011–1018. doi:10.1093/eurjhf/hft056. PMID 23576289. 
  24. ^ a b Newlaczyl, Anna U; Yu, Lu-Gang (September 2011). "Galectin-3--a jack-of-all-trades in cancer". Cancer Letters 313 (2): 123–128. doi:10.1016/j.canlet.2011.09.003. PMID 21974805. 
  25. ^ Idikio, Halliday A. (19 October 2011). "Using Galectin-3 and Beclin1/Atg6 Genes In Human Cancers: Using cDNA Tissue Panel, qRT-PCR, and Logistic Regression Model to Identify Cancer Cell Biomarkers". PLoS ONE 6 (10): 1–8. doi:10.1371/journal.pone.0026150. PMID 22039439. 
  26. ^ Çay, Tuğçe (March 2011). "Immunohistochemical Expression of Galectin-3 in Cancer: A Review of the Literature". Turk Patoloji Derg. 1 10 (1): 1–10. doi:10.5146/tjpath.2012.01090. PMID 22207425. 
  27. ^ Garber, K (2013). "Galecto Biotech". Nature Biotechnology 31 (6): 481. doi:10.1038/nbt0613-481. 
  28. ^ "Galectin Therapeutics' Preclinical Data Published in PLOS ONE Show Its Galectin Inhibitors Reverse Cirrhosis and Significantly Reduce Fibrosis and Portal Hypertension". Globe Newswire. Retrieved 28 November 2013. 
  29. ^ Ross, D. "Abbott's Galectin-3 Test Provides Doctors in Europe with New Tool for Assessing the Prognosis of Chronic Heart Failure Patient". Retrieved 28 November 2013. 
  30. ^ Brechka, Nicole (2009). Putting the Squeeze on Cancer. Retrieved 28 November 2013. 

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