Lactoferrin in Malignant Human Tumours: New Insights from an Immunohistochemical Meta-Analysis
DOI:
https://doi.org/10.6000/1927-7229.2013.02.01.3Keywords:
Immunohistochemistry, Lactoferrin, Cancer, Humans.Abstract
Lactoferrin (LF), an iron-binding glycoprotein, is well known to have different physiological activities in humans; in normal conditions, it has been found in milk, blood, urine as well as in many external and mucosal secretions. Herein we have performed a meta-analysis regarding LF immunohistochemical expression as well as its localization pattern in human malignant tumours obtained from personal observations and literature suggestions. The observed heterogeneity in LF immunoexpression between different malignancies as well as inside the same tumour was also discussed in order to acquire a possible explanation for its presence and function.
We suggest that neoplastic elements should be able to produce LF in order to make a greater amount of iron available for their turnover; alternatively, the localization of LF in malignant cells may not reflect an intracellular synthesis, reflecting instead the degree of trans-membranous iron transfer as the consequence of defective or functionally impaired LF-receptors, already documented elsewhere on the surface of target cells as well as in human neoplastic cell lines.
References
Steijns JM, Van Hooijdonk AC. Occurrence, structure, biochemkical properties and technological characteristics of lactoferrin. Brit J Nutr 2000; 84 Suppl 1: 11-17. http://dx.doi.org/10.1017/S0007114500002191
Van der Strate BW, Beljaars L, Molema G, Harmsen MC, Meijer DK. Antiviral activities of lactoferrin. Antiviral Res 2001; 52: 225-39. http://dx.doi.org/10.1016/S0166-3542(01)00195-4
Oztas Yesim ER, Ozgunes N. Lactoferrin: a multifunctional protein. Adv Mol Med 2005; 1: 149-54. http://dx.doi.org/10.1007/s10238-011-0156-3
García-Montoya IA, Cendón TS, Arévalo-Gallegos S, Rascón-Cruz Q. Lactoferrin a multiple bioactive protein: an overview. Biochim Biophys Acta 2012; 1820: 226-36. http://dx.doi.org/10.1016/j.bbagen.2011.06.018
Gonzalez-Chavez SA, Arevalo-Gallegos S, Rascon-Cruz Q. Lactoferrin: structure, function and applications. Int Journal Antimicrob Agents 2009; 33: 301-9. http://dx.doi.org/10.1016/j.ijantimicag.2008.07.020
Brock JH. Lactoferrin 50 years on. Biochem Cell Biol 2012; 90: 245-51. http://dx.doi.org/10.1139/o2012-018
Lonnerdal B, Iyer S. Lactoferrin: Molecular structure and biological function. Ann Rev Nutr 1995; 15: 93-110. http://dx.doi.org/10.1146/annurev.nu.15.070195.000521
Cirioni O, Giacometti A, Barchesi F, Scalise G. Inhibition of growth of Pneumocystis carinii by loactoferrins alone and in combination with pyrimethanime, clarithromycin and minocycline. J Antimicrob Chemother 2000; 46: 577-82. http://dx.doi.org/10.1093/jac/46.4.577
Andersen JH, Osbakk SA, Vorland LH, Traavik T, Gutteberg TJ. Lactoferrin and cyclic lactoferricin inhibit the entry of human cytomegalovirus into human fibroblasts. Antiviral Res 2001; 51: 141-49. http://dx.doi.org/10.1016/S0166-3542(01)00146-2
Tuccari G, Villari D, Giuffrè G, Simone A, Squadrito G, Raimondo G, Barresi G. Immunohistochemical evidence of lactoferrin in hepatic biopsies of patients with viral or cryptogenetic chronic liver disease. Histol Histopathol 2002; 17: 1077-83. http://www.hh.um.es/pdf/Vol_17/17_4/Tuccari-17-1077-1083-2002.pdf
Takakura N, Wakabayashi H, Ishibashi H, Teraguchi S, Tamura Y, Yamaguchi H et al. Oral lactoferrin treatment of experimental oral candidiasis in mice. Antimicrob Agents Chemother 2003; 47: 2619-23. http://dx.doi.org/10.1128/AAC.47.8.2619-2623.2003
Yamauchi K, Wakabayashi H, Shin K, Takase M. Bovine lactoferrin: benefits and mechanism of action against infections. Biochem Cell Biol 2006; 84: 291-96. http://dx.doi.org/10.1139/o06-054
Zarember KA, Sugui JA, Chang YC, Kwon-Chung KJ, Gallin JI. Human polymorphonuclear leukocytes inhibit Aspergillus fumigatus conidial growth by lactoferrin-mediated iron depletion. J Immunol 2007; 178: 6367-73. http://www.jimmunol.org/content/178/10/6367
Brock JH, Lamont A, Boyle DJ et al. Antibodies to lactoferrin. A possible link between cow's milk intolerance and autoimmune disease. Adv Exp Med Biol 1998; 443: 305-11.
Baveye S, Elass E, Mazurier J, Spik G, Legrand D. Lactoferrin: a multifunctional glycoprotein involved in the modulation of the inflammatory process. Clin Chem Lab Med 1999; 37: 281-86.
Guillen C, McInnes IB, Vaughan D, Speekenbrink AB, Brock JH. The effects of local administration of lactoferrin on inflammation in murine autoimmune and infectious arthritis. Arthr Rheum 2000; 43: 2073-80. http://dx.doi.org/10.1002/1529-0131(200009)
Legrand D, Pierce A, Elass E, Carpentier M, Mariller C, Mazurier J. Lactoferrin structure and functions. Adv Exp Med Biol 2008; 606: 163-194. http://dx.doi.org/10.1007/978-0-387-74087-4_6
Lonnerdal B. Nutritional roles of lactoferrin. Curr Op Clin Nutr Metab Care 2009; 12: 293-7. http://dx.doi.org/10.1097/MCO.0b013e328328d13e
Pierce A, Legrand D, Mazurier J. Lactoferrin: a multifunctional protein. Med Sci 2009; 25: 361-9. http://dx.doi.org/10.1051/medsci/2009254361
Furmanski P, Li ZP, Fortuna MB, Swamy CV, Das MR. Multiple molecular forms of human lactoferrin. Identification of a class of lactoferrins that possess ribonuclease activity and lack iron-binding capacity. J Exp Med 1989; 170: 415-29. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189405/pdf/je1702415.pdf
Qiu J, Hendrixson DR, Baker EN, Murphy TF, St Geme JW 3rd, Plaut AG. Human milk lactoferrin inactivates two putative colonization factors expressed by Haemophilus influenzae. Proc Natl Acad Sci USA 1998; 95: 12641-6. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC22884/pdf/pq012641.pdf
Ye XY, Wang HX, Liu F, Ng TB. Ribonuclease, cell-free translation-inhibitory and superoxide radical scavenging activities of the iron-binding protein lactoferrin from bovine milk. Int J Biochem Cell Biol 2000; 32: 235-41. http://dx.doi.org/10.1016/S1357-2725(99)00131-4
Kanyshkova TG, Babina SE, Semenov DV, Isaeva N, Vlassov AV, Neustroev KN et al. Multiple enzymatic activities of human milk lactoferrin. Eur J Biochem 2003; 270: 3353-61. http://dx.doi.org/10.1046/j.1432-1033.2003.03715.x
Ward PP, Paz E, Conneelly OM. Multifunctional roles of lactoferrin: a critical overview. Cell Mol Life Sci 2005; 62: 2540-8. http://dx.doi.org/10.1007/s00018-005-5369-8
Giuffrè G, Barresi V, Skliros C, Barresi G, Tuccari G. Immunoexpression of lactoferrin in human sporadic renal cell carcinomas. Oncology Reports 2007; 17: 1021-6.
Damiens E, El Yazidi I, Mazurier J, Duthille I, Spik G, Boilly-Marer Y. Lactoferrin inhibits G1 cyclin-dependent kinases during growth arrest of human breast carcinoma cells. J Cell Biochem 1999; 74: 486-98. http://dx.doi.org/10.1002/(SICI)1097-4644(19990901)
Norrby K, Mattsby-Baltzer I, Innocenti M, Tuneberg S. Orally administered bovine lactoferrin systematically inhibits VEGF165-mediated angiogenesis in the rat. Int J Cancer 2001; 91: 236-40. http://dx.doi.org/10.1002/1097-0215(200002)
Barresi G, Tuccari G. Lactoferrin in benign hypertrophy and carcinomas of the prostatic gland. Virch Arch Pathol Anat Histol 1984; 403: 59-66.
Tuccari G, Barresi G. Immunohistochemical demonstration of lactoferrin in follicular adenomas and thyroid carcinomas. Virch Arch Pathol Anat Histol 1985; 406: 67-74.
Merlino G, Barresi G, Tuccari G, Bussolati G. Histogenesis of anaplastic carcinomas of the thyroid, giant cell variety: immunocytochemical investigation. Appl Pathol 1985; 3: 150-8.
Barresi G, Tuccari G Iron-binding proteins in thyroid tumours. An immunocytochemical study. Pathol Res Pract 1987; 182: 344-51.
Tedeschi A, Tuccari G, Magazzù G, Arena F, Ricciardi R, Barresi G. Immunohistochemical localization of lactoferrin in duodenojejunal mucosa from celiac children. J Pediatr Gastroenterol Nutr 1987; 6: 328-34.
Tuccari G, Barresi G, Arena F, Inferrera C. Immunocyto- chemical detection of lactoferrin in human gastric carcinomas and adenomas. Arch Pathol Lab Med 1989; 113: 912-5.
Tuccari G, Rizzo A, Crisafulli C, Barresi G. Iron-binding proteins in human colorectal adenomas and carcinomas: an immunocytochemical investigation. Histol Histopathol 1992; 7: 543-7.
Tuccari G, Rossiello R, Barresi G. Iron binding proteins in gallbladder carcinomas. An immunocytochemical investigation. Histol Histopathol 1997; 12: 671-6.
Tuccari G, Giuffrè G, Crisafulli C, Barresi G. Immunohisto- chemical detection of lactoferrin in human astrocytomas and multiforme glioblastomas. Eur J Histochem 1999; 43: 317-22.
Tuccari G, Giuffrè G, Scarfì R, Simone A, Todaro P, Barresi G. Immunolocalization of lactoferrin in surgically resected pigmented skin lesions. Eur J Histochem 2005; 49: 33-8.
Giuffrè G, Arena F, Scarfì R, Simone A, Todaro P, Tuccari G. Lactoferrin immunoexpression in endometrial carcinomas: relationships with sex steroid hormone receptors (ER and PR), proliferation indices (Ki-67 and AgNOR) and survival. Oncology Reports 2006; 16: 257-63.
Ieni A, Barresi V, Grosso M, Rosa MA, Tuccari G. Lactoferrin immuno-expression in human normal and neoplastic bone tissue. J Bone Min Metab 2009a; 27: 364-71. http://dx.doi.org/10.1007%2Fs00774-009-0044-z
Ieni A, Barresi V, Grosso M, Rosa MA, Tuccari G. Immunolocalization of lactoferrin in cartilage-forming neoplasms. J Orthopaed Sci 2009b; 14: 732-7. http://dx.doi.org/10.1007%2Fs00776-009-1396-x
Ieni A, Barresi V, Grosso M, Rosa MA, Tuccari G. Immunohistochemical evidence of lactoferrin in human embryo-fetal bone and cartilage tissues. Cell Biol Int 2010; 34: 845-9. http://dx.doi.org/10.1042/CBI20090358
Ieni A, Barresi V, Grosso M, Speciale G, Rosa MA, Tuccari G. Does lactoferrin behave as an immunohistochemical oncofetal marker in bone and cartilage human neoplasms? Path Oncol Res 2011; 17: 287-93. http://dx.doi.org/10.1007%2Fs12253-010-9311-5
Garré C, Bianchi-Scarrá G, Sirito M, Musso M, Ravazzolo R. Lactoferrin binding sites and nuclear localization in K562(S) cells. J Cell Physiol 1992; 153: 477-82.
Penco S, Scarfi S, Giovine M, Damonte G, Millo E, Villaggio B et al. Identification of an import signal for, and the nuclear localization of, human lactoferrin. Biotechnol Appl Biochem 2001; 34: 151-9. http://www.babonline.org/bab/034/0151/0340151.pdf
Legrand D, Vigié K, Said EA, Elass E, Masson M, Slomianny MC et al. Surface nucleolin participates in both the binding and endocytosis of lactoferrin in target cells. Eur J Biochem 2004; 271: 303-17.
Weinberg ED. Iron withholding: a defense against infection and neoplasia. Physiol Rev 1984; 64: 65-102.
Roiron D, Amouric M, Marvaldi J, Figarella C. Lactoferrin-binding sites at the syurface of HT29-D4 cells. Comparison with transferrin. Eur J Biochem 1989; 186: 367-73. http://dx.doi.org/10.1111/j.1432-1033.1989.tb15218.x
Suzuki Y, Lonnerdal B. Characterization of mammalian receptors for lactoferrin. Biochem Cell Biol 2002; 80: 75-80.
Suzuki YA, Lopez V, Lonnerdal B. Mammalian lactoferrin receptors: structure and function. Cell Mol Life Sci 2005; 62: 2560-575. http://dx.doi.org /10.1007%2Fs00018-005-5371-1
Caselitz J, Jaup T, Seifert G. Lactoferrin and lysozyme in carcinomas of the parotid gland. A comparative immunocytochemical study with the occurrence in normal and inflamed tissue. Virch Arch Pathol Anat Histol 1981; 394: 61-73.
Charpin C, Lachard A, Pourreau-Schneider N, Jacquemier J, Lavaut MN, Andonian C et al. Localization of lactoferrin and nonspecific cross-reacting antigen in human breast carcinomas. An immunohistochemical study using the avidin-biotin-peroxidase complex method. Cancer 1985; 55: 2612-7.
Cabaret V, Vilain MO, Delobelle-Deroide A, Vanseymortier L. Immunohistochemical demonstration of ceruloplasmin and lactoferrin in a series of 59 thyroid tumors. Ann Pathol 1992; 12: 347-52.
Wang WP, Iigo M, Sato J, Sekine K, Adachi I, Tsuda H. Activation of intestinal mucosa immunity in tumor-bearing mice by lactoferrin. Jpn J Cancer Res 2000; 91: 1022-7.
Wolf JS, Li D, Taylor RJ, O'Malley BW Jr. Lactoferrin inhibits growth of malignant tumors of the head and neck. J Oto-Rhino-Laryngol Rel Spec 2003; 65: 245-9. http://dx.doi.org/10.1159/000075220
Rodrigues L, Teixeira J, Schmitt F, Paulsson M, Månsson HL. Lactoferrin and cancer disease prevention. Crit Rev Food Sci Nutr 2009; 49: 203-17. http://dx.doi.org/10.1080/10408390701856157
de Mejia EG, Dia VP. The role of nutraceutical proteins and peptides in apoptosis, angiogenesis, and metastasis of cancer cells. Cancer Met Rev 2010; 29(3): 511-28. http://dx.doi.org/10.1007/s10555-010-9241-4
Fujita K, Matsuda E, Sekine K, Iigo M, Tsuda H. Lactoferrin enhances Fas expression and apoptosis in the colon muciosa of azoxymethane-treated rats. Carcinogenesis 2004; 25: 1961-6. http://dx.doi.org/10.1093/carcin/bgh205
Norrby K. Human apo-lactoferrin enhances angiogenesis mediated by vascular endothelial growth factor A in vivo. J Vasc Res 2004; 41: 293-304. http://dx.doi.org/10.1159/000078927
Shimamura M, Yamamoto Y, Ashino H, Oikawa T, Hazato T, Tsuda H et al. Bovine lactoferrin inhibits tumor induced angiogenesis. Int J Cancer 2004; 111: 111-6. http://dx.doi.org/10.1002/ijc.20187
Xiao Y, Monitto CL, Minhas KM, Sidransky D. Lactoferrin down-regulates G1 cyclin-dependent kinases during growth arrest of head and neck cancer cells. Clin Cancer Res 2004; 10: 8683-6. http://dx.doi.org/10.1158/1078-0432.CCR-04-0988
Son KN, Park J, Chung CK, Chung DK, Yu DY, Lee KK et al. Human lactoferrin activates transcription of IL-beta gene in mammalian cells. Biochem Biophys Res Comm 2002; 290: 236-41. http://dx.doi.org/10.1006/bbrc.2001.6181
