Abstract
Analysis of the protein composition of urine has been the subject of much research that has captured the interest of scientific groups over the years. A number of factors have been isolated from urine that possess anti-neoplastic activities as seen both in vitro and in vivo studies. The urine from pregnant women and commercial preparations of crude clinical grade human chorionic gonadotropin contain factors (HAF for hCG associated factor) with anti-Kaposi's sarcoma activity. Also found in urine with activity are eosinophil-derived neurotoxin (EDN), anti-neoplastic urinary protein (ANUP), inhibin, activin A, and angiostatin. The anti-cancer activity of urinary proteins is associated with apoptosis of endothelial cells and of tumor-associated endothelial cells. A better understanding of the biological functions of these various urinary proteins, and of others that remain to be discovered, should provide insights into novel cell regulatory systems operating during pregnancy.
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Edwards JJ, Tollaksen SL, Anderson NG. Proteins of human urine. III. Identification and two-dimensional electrophoretic map positions of some major urinary proteins. Clin Chem 1982; 28: 941–948.
Rasmussen HH, Orntoft TF, Wolf H, Celis JE. Towards a comprehensive database of proteins from urine of patients with bladder cancer. J Urol 1996; 1555: 113–2119.
Perez-Atayde AR, Sallan SE, Tedrow U, Connors S, Allred E, Folkman J. Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am J Pathol 1997; 150: 815–821.
Cathomas G, Tamm M, McGandy CE, et al. Transplantationassociated malignancies: restriction of human herpes virus 8 to Kaposi's sarcoma. Transplantation 1997; 64: 175–178.
Safai B, Johnson KG, Myskowski PL, et al. The natural history of Kaposi's sarcoma in the acquired immunodeficiency syndrome. Ann Intern Med 1985; 103: 744–750.
Mitsuyasu RT. Clinical aspects of AIDS-related Kaposi's sarcoma. Curr Opin Oncol 1993; 5: 835–844.
McNutt NS, Fletcher V, Conant MA. Early lesions of Kaposi's sarcoma in homosexual men. An ultrastructural comparison with other vascular proliferations in skin. Am J Pathol 1983; 111: 62–77.
Nadji M, Morales AR, Ziegles-Weissman J, Penneys NS. Kaposi's sarcoma: immunohistologic evidence for an endothelial origin. Arch Pathol Lab Med 1981; 105: 274–275.
Roth WK, Werner S, Risau W, Remberger K, Hofschneider PH. Cultured, AIDS-related Kaposi's sarcoma cells express endothelial cell markers and are weakly malignant in vitro. Int J Cancer 1988; 42: 767–773.
Regezi JA, MacPhail LA, Daniels TE, DeSouza YG, Greenspan JS, Greenspan D. Human immunodeficiency virus-associated oral Kaposi's sarcoma. A heterogeneous cell population dominated by spindle-shaped endothelial cells. Am J Pathol 1993; 143: 240–249.
Fan J, Bass HZ, Fahey JL. Elevated IFN-gamma and decreased IL-2 gene expression are associated with HIV infection. J Immunol 1993; 151: 5031–5040.
Samaniego F, Markham PD, Gallo RC, Ensoli B. Inflammatory cytokines induce AIDS-Kaposi's sarcoma-derived spindle cells to produce and release basic fibroblast growth factor and enhance Kaposi's sarcoma-like lesion formation in nude mice. J Immunol 1995; 154: 3582–3592.
Masood R, Cai J, Zheng T, Smith DL, Naidu Y, Gill PS. Vascular endothelial growth factor/vascular permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma. Proc Natl Acad Sci USA 1997; 94: 979–984.
Samaniego F, Markham PD, Gendelman R, Gallo RC, Ensoli B. Inflammatory cytokines induce endothelial cells to produce and release basic fibroblast growth factor and to promote Kaposi's sarcoma-like lesions in nude mice. J Immunol 1997; 158: 1887–1894.
Samaniego F, Gallo RC. Immunopathogenesis of Kaposi's sarcoma. In: Gupta S, ed. Immunology of HIV Infection. New York: Plenum 1996: 437–450.
Cesarman E, Nador RG, Bai F, et al. Kaposi's sarcoma-associated herpesvirus contains G protein-coupled receptor and cyclin D homologs which are expressed in Kaposi's sarcoma and malignant lymphoma. J Virol 1996; 70: 8218–8223.
Russo JJ, Bohenzky RA, Chien MC, et al. Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8). Proc Natl Acad Sci USA 1996; 93: 14862–14867.
Moore PS, Boshoff C, Weiss RA, Chang Y. Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science 1996; 274: 1739–1744.
Cheng EH, Nicholas J, Bellows DS, et al. A Bcl-2 homolog encoded by Kaposi sarcoma-associated virus, human herpesvirus 8, inhibits apoptosis but does not heterodimerize with Bax or Bak. Proc Natl Acad Sci USA 1997; 94: 690–694.
Bais C, Santomasso B, Coso O, et al. G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 1998; 391: 86–89.
Davis MA, Sturzl MA, Blasig C, et al. Expression of human herpesvirus 8–encoded cyclin D in Kaposi's sarcoma spindle cells. J Natl Cancer Inst 1997; 89: 1868–1874.
Lee H, Veazey R, Williams K, et al. Deregulation of cell growth by the K1 gene of Kaposi's sarcoma-associated herpesvirus. Nat Med 1998; 4: 435–440.
Siegel B, Levintin-Kriss S, Schiffer A, Sayer J, Engelberg I, Vonsover A, et al. Kaposi's sarcoma in immunosuppression. Possibly the result of a dual viral infection. Cancer 1990; 65: 492–498.
Lunardi-Iskandar, Bryant JL, Zeman RA, et al.Tumorigenesis and metastasis of neoplastic Kaposi's sarcoma cell line in immunodeficient mice blocked by a human pregnancy hormone. Nature 1995; 75: 64–68.
Hermans P. AIDS-related Kaposi's sarcoma patients with visceral manifestations: Response to human chorionic gonadotropin preparations. J Hum Virol 1998; 1: 82–89.
Gill PS, Lunardi-Ishkandar Y, Louie S, et al. The effects of preparations of human chorionic gonadotropin on AIDS-related Kaposi's sarcoma. N Engl J Med 1996; 335: 1261–1269.
Lunardi-Iskandar Y, Bryant JL, Blattner WA, et al. Effects of a urinary factor from women in early pregnancy on HIV-1, SIV and associated disease. Nat Med 1998; 4: 428–434.
Morse JH, Lustbader JW, Harrington JW, Canfield RE. Heterogeneity of proteins in commercial preparations of human chorionic gonadotropin (hCG) demonstrated byWestern blotting. Am J Reprod Immunol Microbiol 1988; 17: 134–140.
Rabkin CS, Chibwe G, Muyunda K, Musaba E. Kaposi's sarcoma in pregnant women [letter]. Nature 1995; 377: 21–22.
Bernstein L, Hanisch R, Sullivan-Halley J, Ross RK.Treatment with human chorionic gonadotropin and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 1995; 4: 437–440.
Samaniego F, Bryant JL, Liu N, et al. Induction of programmed cell death in Kaposi's sarcoma cells by preparations of human chorionic gonadotropin. J Natl Cancer Inst 1999; 91: 135–143.
Hermeking H, Eick D. Mediation of c-myc-induced apoptosis by p53. Science 1994; 265: 2091–2093.
Albini A, Paglieri I, Orengo G, et al. The beta-core fragment of human chorionic gonadotrophin inhibits growth of Kaposi's sarcoma-derived cells and a new immortalized Kaposi's sarcoma cell line. AIDS 1997; 11: 713–721.
Yoshimura M, Nishikawa M, Mori Y, et al. Human chorionic gonadotropin induces c-myc mRNA expression via TSH receptor in FRTL-5 rat thyroid cells. Thyroid 1992; 2: 315–319.
Gillott DJ, Iles RK, Chard T. The effects of beta-human chorionic gonadotrophin on the in vitro growth of bladder cancer cell lines. Br J Cancer 1996; 73: 323–326.
Lee H, Arsura M, Wu M, Duyao M, Buckler AJ, Sonenshein GE. Role of Rel-related factors in control of c-myc gene transcription in receptor-mediated apoptosis of the murine B cell WEHI 231 line. J Exp Med 1995; 181: 1169–1177.
Alarcon RM, Rupnow BA, Graeber TG, Knox SJ, Giaccia AJ. Modulation of c-Myc activity and apoptosis in vivo. Cancer Res 1996; 56: 4315–4319.
Kachra Z, Guo WX, Sairam MR, Antakly T. Low molecular weight components but not dimeric HCG inhibit growth and down-regulate AP-1 transcription factor in Kaposi's sarcoma cells. Endocrinology 1997; 138: 4038–4041.
Srivastava P, Russo J, Mgbonyebi OP, Russo IH. Growth inhibition and activation of apoptotic gene expression by human chorionic gonadotropin in human breast epithelial cells. Anticancer Res 1998; 18: 4003–4010.
Russo IH, Koszalka M, Russo J. Human chorionic gonadotropin and rat mammary cancer prevention. J Natl Cancer Inst 1990; 82: 1286–1289.
Srivastava P, Silva ID, Russo J, Mgbonyebi OP, Russo IH. Identification of new genes differentially expressed in breast carcinoma cells treated with human chorionic gonadotropin. Int J Oncol 1998; 13: 465–469.
Srivastava P, Russo J, Russo IH. Chorionic gonadotropin inhibits rat mammary carcinogenesis through activation of programmed cell death. Carcinogenesis 1997; 18: 1799–1808.
Feldman EJ, Seiter K, Chiao JW, et al. In vitro effects and clinical evaluation of a human chorionic gonadotrophin preparation in acute leukemia. Leukemia 1998; 12: 1749–1755.
Gallo RC, Lunardi-Iskandar Y, Bryant J, Birken S. Mysterious anti-KS activity still a mystery. Nature Medicine 1998; 4: 2.
Lang ME, Lottersberger C, Roth B, et al. Induction of apoptosis in Kaposi's sarcoma spindle cell cultures by the subunits of human chorionic gonadotropin. AIDS 1997; 11: 1333–1340.
Keutmann HT, Charlesworth MC, Mason KA, Ostrea T, Johnson L, Ryan RJ. A receptor-binding region in human choriogonadotropin/ lutropin beta subunit. Proc Natl Acad Sci USA 1987; 84: 2038–2042.
Griffiths SJ, Adams DJ, Talbot SJ. Ribonuclease inhibits Kaposi's sarcoma [letter]. Nature 1997; 390: 568.
Newton DL, Rybak SM. Unique recombinant human ribonuclease and inhibition of Kaposi's sarcoma cell growth. J Natl Cancer Inst 1998; 90: 1787–1791.
Newton DL, Xue Y, Boque L, Wlodawer A, Kung HF, Rybak SM. Expression and characterization of a cytotoxic human-frog chimeric ribonuclease: potential for cancer therapy. Protein Eng 1997; 10: 463–470.
Wu Y, Mikulski SM, Ardelt W, Rybak SM, Youle RJ. A cytotoxic ribonuclease. Study of the mechanism of onconase cytotoxicity. J Biol Chem 1993; 268: 10686–10693.
Mikulski SM, Viera A, Deptala A, Darzynkiewicz Z. Enhanced in vitro cytotoxicity and cytostasis of the combination of onconase with a proteasome inhibitor. Int J Oncol 1998; 13: 633–644.
Juan G, Ardelt B, Li X, et al. G1 arrest of U937 cells by onconase is associated with suppression of cyclin D3 expression, induction of p16INK4A,p21WAF1/CIP1 and p27KIP and decreased pRb phosphorylation. Leukemia 1998; 12: 1241–1248.
Darzynkiewicz Z. The butler did it: search for killer(s) of Kaposi's sarcoma cells in preparations of human chorionic gonadotropin [editorial]. J Natl Cancer Inst 1999; 91:104–106.
Sloane NH, Lynn WR, Macleod RM, Hade EP, Pottathil R, Kyriazis AP. Studies on an antineoplastic fraction from human urine. Characterization of the major protein in this fraction. Biochem J 1986; 234: 355–362.
Ridge RJ, Sloane NH. Partial N-terminal amino acid sequence of the anti-neoplastic urinary protein (ANUP) and the antitumour effect of the N-terminal nonapeptide of the unique cytokine present in human granulocytes. Cytokine 1996; 8: 1–5.
Masood R, McGarvey ME, Zheng T, et al. Antineoplastic urinary protein inhibits Kaposi's sarcoma and angiogenesis in vitro and in vivo. Blood 1999; 93: 1038–1044.
Folkman J. Tumor angiogenesis. Adv Cancer Res 1974; 19: 331–358.
Folkman J. Clinical applications of research on angiogenesis. [Seminars in Medicine of the Beth Israel Hospital, Boston]. N Engl J Med 1995; 333: 1757–1763.
O'Reilly MS, Holmgren L, Shing Y, et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994; 79: 315–328.
ClarkWH,Jr., Elder DE, Guerry D 4th, et al. Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst 1989; 81: 1893–1904.
Claesson-Welsh L, Welsh M, Ito N, et al. Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RGD. Proc Natl Acad Sci USA 1998; 95: 5579–5583.
Lucas R, Holmgren L, Garcia I, et al. Multiple forms of angiostatin induce apoptosis in endothelial cells. Blood 1998; 92: 4730–4741.
O'Reilly MS, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88: 277–285.
Dhanabal M, Ramchandran R, Waterman MJ, et al. Endostatin induces endothelial cell apoptosis. J Biol Chem 1999; 274: 11721–11726.
Petraglia F, Zanin E, Faletti A, Reis FM. Inhibins: paracrine and endocrine effects in female reproductive function. Curr Opin Obstet Gynecol 1999; 11: 241–247.
Wang EY, Draper LB, Lee E, et al. Identification of naturally occurring follistatin complexes in human biological fluids. Biol Reprod 1999; 60: 8–13.
Jenkin G, McFarlane J, de Kretser DM. Inhibin and activin in embryonic and fetal development in ruminants. J Reprod Fertil [Suppl] 1995; 49: 177–186.
Nishihara T, Okahashi N, Ueda N. ActivinAinduces apoptotic cell death. Biochem Biophys Res Commun 1993; 197: 985–991.
Wang QF, Tilly KI, Tilly JL, et al. Activin inhibits basal and androgen-stimulated proliferation and induces apoptosis in the human prostatic cancer cell line, LNCaP. Endocrinology 1996; 137: 5476–5483.
Zhou Y, Fisher SJ, Janatpour M, et al. Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion? J Clin Invest 1997; 99: 2139–2151.
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Pati, S., Lee, Y. & Samaniego, F. Urinary proteins with pro-apoptotic and antitumor activity. Apoptosis 5, 21–28 (2000). https://doi.org/10.1023/A:1009629424297
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DOI: https://doi.org/10.1023/A:1009629424297