Journal of Molecular Medicine

, Volume 91, Issue 4, pp 497–506 | Cite as

Radiation-induced galectin-1 by endothelial cells: a promising molecular target for preferential drug delivery to the tumor vasculature

  • Meenakshi Upreti
  • Azemat Jamshidi-Parsian
  • Scott Apana
  • Marc Berridge
  • Daniel A. Fologea
  • Nathan A. Koonce
  • Ralph L. Henry
  • Robert J. Griffin
Original Article


The present study reports on a new strategy for selective, radiation therapy-amplified drug delivery using an antiangiogenic 33-a.a., tumor vasculature-targeting ligand, anginex, to improve the therapeutic ratio for strategies developed against solid tumors. Our findings indicate that galectin-1 is (a) one of the major receptors for anginex (b) overexpressed by tumor neovasculature and (c) further specifically upregulated in endothelial cells in response to radiation exposure as low as 0.5 Gy. An investigation of [18]-F-labeled anginex biodistribution in SCK tumors indicates that anginex is an effective targeting molecule for image and radiation-guided therapy of solid tumors. An anginex-conjugated liposome capable of being loaded with drug was shown to selectively target endothelial cells post-radiation. The presence of endothelial cells in a three-dimensional co-culture system with tumor cells developed to study tumor/endothelial cell interactions in vitro led to higher levels of galectin-1 and showed a further increase in expression upon radiation exposure when compared to tumor cell spheroids alone. Similar increase in galectin-1 was observed in tumor tissue originating from the tumor‐endothelial cell spheroids in vivo and radiation exposure further induced galectin-1 in these tumors. The overall results suggest feasibility of using a clinical or subclinical radiation dose to increase expression of the galectin-1 receptor on the tumor microvasculature to promote delivery of therapeutics via the anginex peptide. This approach may reduce systemic toxicity, overcome drug resistance, and improve the therapeutic efficacy of conventional chemo/radiation strategies.


Galectin-1 Endothelial cells Tumor vasculature Anginex Tumor‐endothelial cell spheroids 



We gratefully acknowledge the research support from National Cancer Institute Grants CA44114 and CA107160 and the Arkansas Biosciences Institute.

Conflict of interest

No potential conflicts of interest were disclosed.

Supplementary material

109_2012_965_MOESM1_ESM.pdf (198 kb)
ESM 1 (PDF 197 kb)


  1. 1.
    Maduro JH, de Vries EG, Meersma GJ, Hougardy BM, van der Zee AG, de Jong S (2008) Targeting pro-apoptotic trail receptors sensitizes HeLa cervical cancer cells to irradiation-induced apoptosis. Int J Radiat Oncol Biol Phys 72:543–552PubMedCrossRefGoogle Scholar
  2. 2.
    Roses RE, Xu M, Koski GK, Czerniecki BJ (2008) Radiation therapy and Toll-like receptor signaling: implications for the treatment of cancer. Oncogene 27:200–207PubMedCrossRefGoogle Scholar
  3. 3.
    Camby I, Le Mercier M, Lefranc F, Kiss R (2006) Galectin-1: a small protein with major functions. Glycobiology 16:137R–157RPubMedCrossRefGoogle Scholar
  4. 4.
    Nagy N, Legendre H, Engels O, Andre S, Kaltner H, Wasano K, Zick Y, Pector JC, Decaestecker C, Gabius HJ et al (2003) Refined prognostic evaluation in colon carcinoma using immunohistochemical galectin fingerprinting. Cancer 97:1849–1858PubMedCrossRefGoogle Scholar
  5. 5.
    van den Brule FA, Waltregny D, Castronovo V (2001) Increased expression of galectin-1 in carcinoma-associated stroma predicts poor outcome in prostate carcinoma patients. J Pathol 193:80–87PubMedCrossRefGoogle Scholar
  6. 6.
    Cindolo L, Benvenuto G, Salvatore P, Pero R, Salvatore G, Mirone V, Prezioso D, Altieri V, Bruni CB, Chiariotti L (1999) Galectin-1 and galectin-3 expression in human bladder transitional-cell carcinomas. Int J Cancer 84:39–43PubMedCrossRefGoogle Scholar
  7. 7.
    Gabius HJ, Brehler R, Schauer A, Cramer F (1986) Localization of endogenous lectins in normal human breast, benign breast lesions and mammary carcinomas. Virchows Archiv 52:107–115PubMedCrossRefGoogle Scholar
  8. 8.
    Reynolds AR, Moein Moghimi S, Hodivala-Dilke K (2003) Nanoparticle-mediated gene delivery to tumour neovasculature. Trends Mol Med 9:2–4PubMedCrossRefGoogle Scholar
  9. 9.
    Brannon-Peppas L, Blanchette JO (2004) Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev 56:1649–1659PubMedCrossRefGoogle Scholar
  10. 10.
    Thijssen VL, Barkan B, Shoji H, Aries IM, Mathieu V, Deltour L, Hackeng TM, Kiss R, Kloog Y, Poirier F et al (2011) Tumor cells secrete galectin-1 to enhance endothelial cell activity. Cancer Res 70:6216–6224CrossRefGoogle Scholar
  11. 11.
    Thijssen VL, Hulsmans S, Griffioen AW (2008) The galectin profile of the endothelium: altered expression and localization in activated and tumor endothelial cells. Am J Pathol 172:545–553PubMedCrossRefGoogle Scholar
  12. 12.
    Thijssen VL, Poirier F, Baum LG, Griffioen AW (2007) Galectins in the tumor endothelium: opportunities for combined cancer therapy. Blood 110:2819–2827PubMedCrossRefGoogle Scholar
  13. 13.
    Thijssen VL, Postel R, Brandwijk RJ, Dings RP, Nesmelova I, Satijn S, Verhofstad N, Nakabeppu Y, Baum LG, Bakkers J et al (2006) Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy. Proc Natl Acad Sci U S A 103:15975–15980PubMedCrossRefGoogle Scholar
  14. 14.
    Mayo KH, van der Schaft DW, Griffioen AW (2001) Designed beta-sheet peptides that inhibit proliferation and induce apoptosis in endothelial cells. Angiogenesis 4:45–51PubMedCrossRefGoogle Scholar
  15. 15.
    Griffioen AW, van der Schaft DW, Barendsz-Janson AF, Cox A, Struijker Boudier HA, Hillen HF, Mayo KH (2001) Anginex, a designed peptide that inhibits angiogenesis. Biochem J 354:233–242PubMedCrossRefGoogle Scholar
  16. 16.
    Thijssen VL, Barkan B, Shoji H, Aries IM, Mathieu V, Deltour L, Hackeng TM, Kiss R, Kloog Y, Poirier F et al (2010) Tumor cells secrete galectin-1 to enhance endothelial cell activity. Cancer Res 70:6216–6224PubMedCrossRefGoogle Scholar
  17. 17.
    Kluza E, van der Schaft DW, Hautvast PA, Mulder WJ, Mayo KH, Griffioen AW, Strijkers GJ, Nicolay K (2010) Synergistic targeting of alphavbeta3 integrin and galectin-1 with heteromultivalent paramagnetic liposomes for combined MR imaging and treatment of angiogenesis. Nano Lett 10:52–58PubMedCrossRefGoogle Scholar
  18. 18.
    Kluza E, Jacobs I, Hectors SJ, Mayo KH, Griffioen AW, Strijkers GJ, Nicolay K (2012) Dual-targeting of alphavbeta3 and galectin-1 improves the specificity of paramagnetic/fluorescent liposomes to tumor endothelium in vivo. J Control Release 158:207–214PubMedCrossRefGoogle Scholar
  19. 19.
    Apana SM, Griffin RG, Koonce NA, Webber JS, Dings RPM, Mayo KH, Berridge MS (2011) Synthesis of [18F]anginex with high specific activity [18F]fluorobenzaldehyde for targeting angiogenic activity in solid tumors. J Label Compd Radiaopharmaceuticals. doi: 10.1002/jlcr.1912
  20. 20.
    Jia D, Koonce NA, Halakatti R, Li X, Yaccoby S, Swain FL, Suva LJ, Hennings L, Berridge MS, Apana SM et al (2010) Repression of multiple myeloma growth and preservation of bone with combined radiotherapy and anti-angiogenic agent. Radiat Res 173:809–817PubMedCrossRefGoogle Scholar
  21. 21.
    Upreti M, Jamshidi-Parsian A, Koonce NA, Webber JS, Sharma SK, Asea AA, Mader MJ, Griffin RJ (2011) Tumor-endothelial cell three-dimensional spheroids: new aspects to enhance radiation and drug therapeutics. Transl Oncol 4:365–376PubMedGoogle Scholar
  22. 22.
    Gupta K, Kshirsagar S, Li W, Gui L, Ramakrishnan S, Gupta P, Law PY, Hebbel RP (1999) VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling. Exp Cell Res 247:495–504PubMedCrossRefGoogle Scholar
  23. 23.
    Wu X, Lensch MW, Wylie-Sears J, Daley GQ, Bischoff J (2007) Hemogenic endothelial progenitor cells isolated from human umbilical cord blood. Stem Cells (Dayton, Ohio) 25:2770–2776CrossRefGoogle Scholar
  24. 24.
    Ma CM, Coffey CW, DeWerd LA, Liu C, Nath R, Seltzer SM, Seuntjens JP (2001) AAPM protocol for 40–300 kV X-ray beam dosimetry in radiotherapy and radiobiology. Med Phys 28:868–893PubMedCrossRefGoogle Scholar
  25. 25.
    Wahl RL, Jacene H, Kasamon Y, Lodge MA (2009) From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med 50(Suppl 1):122S–150SPubMedCrossRefGoogle Scholar
  26. 26.
    Dings RP, Arroyo MM, Lockwood NA, van Eijk LI, Haseman JR, Griffioen AW, Mayo KH (2003) Beta-sheet is the bioactive conformation of the anti-angiogenic anginex peptide. Biochem J 373:281–288PubMedCrossRefGoogle Scholar
  27. 27.
    He J, Baum LG (2004) Presentation of galectin-1 by extracellular matrix triggers T cell death. J Biol Chem 279:4705–4712PubMedCrossRefGoogle Scholar
  28. 28.
    He J, Baum LG (2006) Endothelial cell expression of galectin-1 induced by prostate cancer cells inhibits T-cell transendothelial migration. Lab Investig; A J Tech Methods Pathol 86:578–590Google Scholar
  29. 29.
    Rabinovich GA, Ariel A, Hershkoviz R, Hirabayashi J, Kasai KI, Lider O (1999) Specific inhibition of T-cell adhesion to extracellular matrix and proinflammatory cytokine secretion by human recombinant galectin-1. Immunology 97:100–106PubMedCrossRefGoogle Scholar
  30. 30.
    van den Brule F, Califice S, Garnier F, Fernandez PL, Berchuck A, Castronovo V (2003) Galectin-1 accumulation in the ovary carcinoma peritumoral stroma is induced by ovary carcinoma cells and affects both cancer cell proliferation and adhesion to laminin-1 and fibronectin. Laboratory Investig; A J Tech Methods Pathol 83:377–386Google Scholar
  31. 31.
    Le QT, Shi G, Cao H, Nelson DW, Wang Y, Chen EY, Zhao S, Kong C, Richardson D, O’Byrne KJ et al (2005) Galectin-1: a link between tumor hypoxia and tumor immune privilege. J Clin Oncol 23:8932–8941PubMedCrossRefGoogle Scholar
  32. 32.
    Moeller BJ, Dreher MR, Rabbani ZN, Schroeder T, Cao Y, Li CY, Dewhirst MW (2005) Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 8:99–110PubMedCrossRefGoogle Scholar
  33. 33.
    Ahmed MM (2004) Regulation of radiation-induced apoptosis by early growth response-1 gene in solid tumors. Current Cancer Drug Targets 4:43–52PubMedCrossRefGoogle Scholar
  34. 34.
    Fu M, Zhu X, Zhang J, Liang J, Lin Y, Zhao L, Ehrengruber MU, Chen YE (2003) Egr-1 target genes in human endothelial cells identified by microarray analysis. Gene 315:33–41PubMedCrossRefGoogle Scholar
  35. 35.
    Moeller BJ, Cao Y, Li CY, Dewhirst MW (2004) Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5:429–441PubMedCrossRefGoogle Scholar
  36. 36.
    Zhao XY, Chen TT, Xia L, Guo M, Xu Y, Yue F, Jiang Y, Chen GQ, Zhao KW (2019) Hypoxia inducible factor-1 mediates expression of galectin-1: the potential role in migration/invasion of colorectal cancer cells. Carcinogenesis 31:1367–1375CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Meenakshi Upreti
    • 1
  • Azemat Jamshidi-Parsian
    • 2
  • Scott Apana
    • 3
  • Marc Berridge
    • 3
  • Daniel A. Fologea
    • 4
  • Nathan A. Koonce
    • 2
  • Ralph L. Henry
    • 5
  • Robert J. Griffin
    • 2
  1. 1.College of PharmacyUniversity of KentuckyLexingtonUSA
  2. 2.Department of Radiation OncologyUniversity of Arkansas for Medical SciencesLittle RockUSA
  3. 3.Department of RadiologyUniversity of Arkansas for Medical SciencesLittle RockUSA
  4. 4.Department of PhysicsBoise State UniversityBoiseUSA
  5. 5.Department of Biological SciencesUniversity of ArkansasFayettevilleUSA

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