Skip to main content
SpringerLink
Log in

Relaxin-Like Ligand-Receptor Systems Are Autocrine/Paracrine Effectors in Tumor Cells and Modulate Cancer Progression and Tissue Invasiveness

  • Chapter
Relaxin and Related Peptides

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 612))

Abstract

Relaxin and INSL3 are novel autocrine/paracrine insulin-like hormones in tumor biology. Both effectors can bind to and activate the leucine-rich G-protein coupled receptors LGR7 (relaxin receptor) or LGR8 (relaxin/INSL3 receptor). These relaxin-like ligand-receptor systems modulate cellular functions and activate signaling cascades in a tumor-specific context leading to changes in tumor cell proliferation, altered motility/migration and enhanced production/secretion of potent proteolytic enzymes. Matrix-metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP) and acid hydrolases such as cathepsins can facilitate tissue degradation and represent important proteolytic mediators of relaxin-like actions on tumor cell invasion and metastasis. This review presents recent new findings and emphasises the important functions of the relaxin/INSL3 ligand-receptor system as novel autocrine/paracrine effectors influencing tumor progression and tissue invasiveness.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Tashima LS, Mazoujian G, Bryant-Greenwood GD. Human relaxins in normal, benign and neoplastic breast tissue. J Mol Endocrinol 1994; 12:351–364.

    Article  PubMed  CAS  Google Scholar 

  2. Mazoujian G, Bryant-Greenwood GD. Lancet 1990; 335:298–299.

    Article  PubMed  CAS  Google Scholar 

  3. Bongers-Binder S, Burgardt A, Seeger H et al. Distribution of immunoreactive relaxin in the genital tract and in the mammary gland of nonpregnant women. Clin Exp Obstet Gynecol 1991; 18:161–164.

    PubMed  CAS  Google Scholar 

  4. Hombach-Klonisch S, Buchmann J, Sarun S et al. Relaxin-like factor (RLF) is differentially expressed in the normal and neoplastic human mammary gland. Cancer 2000; 89:2161–2168.

    Article  PubMed  CAS  Google Scholar 

  5. Alfonso P, Nunez A, Madoz-Gurpide J et al. Proteomic expression analysis of colorectal cancer by two-dimensional differential gel electrophoresis. Proteomics 2005; 5:2601–2611.

    Article  CAS  Google Scholar 

  6. Stemmermann GN, Mesiona W, Greenwood FC. Immunocytochemical identification of a relaxin-like protein in gastrointestinal epithelium and carcinoma: a preliminary report. J Endocrinol 1994; 140:321–325.

    Article  PubMed  CAS  Google Scholar 

  7. Hombach-Klonisch S, Hoang-Vu C, Kehlen A et al. INSL3 is expressed in human hyperplastic and neoplastic thyrocytes. Int J Oncol 2003; 22:993–1001.

    PubMed  CAS  Google Scholar 

  8. Ivell R, Hunt N, Khan-Dawood F et al. Expression of the human relaxin gene in the corpus luteum of the menstrual cycle and in the prostate. Mol Cell Endocrinol 1989; 66:251–255.

    Article  PubMed  CAS  Google Scholar 

  9. Klonisch T, Hombach-Klonisch S, Buchmann J et al. Relaxin-like factor (RLF) is expressed in human ovarian Sertoli-Leydig cell tumors. Fertil Steril 1999; 72:546–548.

    Article  PubMed  CAS  Google Scholar 

  10. Klonisch T, Ivell R, Balvers M et al. Expression of relaxin-like factor is down-regulated in human testicular Leydig cell neoplasia. Mol Hum Reprod 1999; 5:104–108.

    Article  PubMed  CAS  Google Scholar 

  11. Bartsch O, Bartlick B, Ivell R. Relaxin signalling links tyrosine phosphorylation to phosphodiesterase and adenylyl cyclase activity. Mol Hum Reprod 2001; 7:799–809.

    Article  PubMed  CAS  Google Scholar 

  12. Nguyen BT, Yang L, Sanborn BM et al. Phosphoinositide 3-kinase activity is required for biphasic stimulation of cyclic adenosine 3′, 5′-monophosphate by relaxin. Mol Endocrinol 2003; 17:1075–1084.

    Article  PubMed  CAS  Google Scholar 

  13. Nguyen BT, Dessauer CW. Relaxin Stimulates Protein Kinase C {zeta} Translocation: Requirement for Cyclic Adenosine 3′, 5′-Monophosphate Production. Mol Endocrinol 2005; 19:1012–1023.

    Article  PubMed  CAS  Google Scholar 

  14. Parsell DA, Mak JY, Amento EP et al. Relaxin binds to and elicits a response from cells of the human monocytic cell line, THP-1. J Biol Chem 1996; 271:27936–27941.

    Article  PubMed  CAS  Google Scholar 

  15. Zimmermann S, Steding G, Emmen JMA et al. Targeted disruption of the Insl-3 gene causes bilateral cryptorchism. Mol Endocrinol 1999; 13:681–691.

    Article  PubMed  CAS  Google Scholar 

  16. Nef S, Parada LF. Cryptorchidism in mice mutant for INSL3. Nat Genet 1999; 22:295–299.

    Article  PubMed  CAS  Google Scholar 

  17. Gorlov IP, Kamat A, Bogatcheva NV et al. Mutations of the GREAT gene cause cryptorchidism. Hum Mol Genet 2002; 11:2309–2318.

    Article  PubMed  CAS  Google Scholar 

  18. Bogatcheva NV, Truong A, Feng S et al. GREAT/LGR8 is the only receptor for insulin-like 3 peptide. Mol Endocrinol 2003; 17:2639–2646.

    Article  PubMed  CAS  Google Scholar 

  19. Ivell R. Biology of the relaxin-like factor (RLF). Rev Reprod 1997; 2:133–138.

    Article  PubMed  CAS  Google Scholar 

  20. Hsu SY, Nakabayashi K, Nishi S et al. Activation of orphan receptors by the hormone relaxin. Science 2002; 295:671–674.

    Article  PubMed  CAS  Google Scholar 

  21. Krajnc-Franken MA, Van Disseldorp AJ, Koenders JE et al. Impaired nipple development and parturition in LGR7 knockout mice. Mol Cell Biol 2004; 24:687–696.

    Article  PubMed  CAS  Google Scholar 

  22. Kawamura K, Kumagai J, Sudo S et al. Paracrine regulation of mammalian oocyte maturationand male germ cell survival. Proc Natl Acad Sci USA 2004; 101:7323–7328.

    Article  PubMed  CAS  Google Scholar 

  23. Guan K, Nayernia K, Maier LS et al. Pluripotency of spermatogonial stem cells from adult mouse testis. Nature 2006; 440:1199–1203.

    Article  PubMed  CAS  Google Scholar 

  24. Pusch W, Balvers M, Ivell R. Molecular cloning and expression of the relaxin-like factor from the mouse testis. Endocrinology 1996; 137:3009–3013.

    Article  PubMed  CAS  Google Scholar 

  25. Balvers M, Spiess AN, Domagalski R et al. Relaxin-like factor expression as a marker of differentiation in the mouse testis and ovary. Endocrinology 1998; 139:2960–2970.

    Article  PubMed  CAS  Google Scholar 

  26. Hombach-Klonisch S, Schoen J, Kehlen A et al. Seasonal expression of INSL3 and Lgr8/Insl3 receptor transcripts indicates variable differentiation of Leydig cells in the roe deer testis. Biol Reprod 2004; 71:1079–1087.

    Article  PubMed  CAS  Google Scholar 

  27. Cook JC, Klinefelter GR, Hardisty JF et al. Rodent Leydig cell tumorigenesis: a review of the physiology, pathology, mechanisms and relevance to humans. Crit Rev Toxicol 1999; 29:169–261.

    Article  PubMed  CAS  Google Scholar 

  28. Fowler KA, Gill K, Kirma N et al. Overexpression of aromatase leads to development of testicular leydig cell tumors: an in vivo model for hormone-mediated testicular cancer. Am J Pathol 2000; 156:347–353.

    PubMed  CAS  Google Scholar 

  29. Navickis RJ, Shimkin MB, Hsueh AJW. Increase in testis luteinizing hormone receptor by estrogen in mice susceptible to Leydig cell tumors. Cancer Res 1981; 41:1646–1651.

    PubMed  CAS  Google Scholar 

  30. Düe W, Dieckmann KP, Ley V et al. Immunohistological determination of oestrogen receptor, progesterone receptor and intermediate filaments in Leydig cell tumours, Leydig cell hyperplasia and normal Leydig cells of the human testis. J Pathol 1989; 157:225–234.

    Article  PubMed  Google Scholar 

  31. Young M, Lephart ED, McPhaul MJ. Expression of aromatase cytochrome p450 in rat H540 Leydig cell tumor cells. J Steroid Biochem Mol Biol 1997; 63:37–44.

    Article  PubMed  CAS  Google Scholar 

  32. Castle WN, Richardson JR. Leydig cell tumor and metachronous Leydig cell hyperplasia: a case associated with gynecomastia and elevated urinary estrogens. J Urol 1986; 136:1307–1308.

    PubMed  CAS  Google Scholar 

  33. Emmen JM, McLuskey A, Adham IM et al. Involvement of insulin-like factor 3 (Insl3) in diethylstilbestrol-induced cryptorchidism. Endocrinology 2000; 141:846–849.

    Article  PubMed  CAS  Google Scholar 

  34. Hamdy FC. Prognostic and predictive factors in prostate cancer. Cancer Treat Rev 2001; 27:143–151.

    Article  PubMed  CAS  Google Scholar 

  35. Klonisch T, Müller-Huesmann H, Riedel M et al. INSL3 in the benign hyperplastic and neoplastic human prostate gland. Int J Oncol 2005; 27:307–315.

    PubMed  CAS  Google Scholar 

  36. Cameron DF, Corton GL, Larkin LH. Relaxin-like antigenicity in the armadillo prostate gland. Ann NY Acad Sci 1982; 380:231–240.

    Article  PubMed  CAS  Google Scholar 

  37. Samuel CS, Tian H, Zhao L et al. Realxin is a key mediator of prostate growth and male reproductive tract development. Lab Invest 2003; 83:1055–1067.

    Article  PubMed  CAS  Google Scholar 

  38. Kamat AA, Feng S, Bogatcheva NV et al. Genetic targeting of relaxin and insulin-like factor receptors in mice. Endocrinology 2004; 145:4712–4720.

    Article  PubMed  CAS  Google Scholar 

  39. Gunnersen JM, Fu P, Roche PJ et al. Expression of human relaxin genes: characterization of a novel alternatively-spliced human relaxin mRNA species. Mol Cell Endocrinol 1996; 118:85–94.

    Article  PubMed  CAS  Google Scholar 

  40. Thompson V. Relaxin is upregulated during prostate cancer progression to androgen independence and is repressed by androgens. 4th International Conference on Relaxin and Related Peptides, Abstract Book 2004:O-58.

    Google Scholar 

  41. Janßen M, Albrecht M, Möschler O et al. Cell lineage characteristics of human prostatic stromal cells cultured in vitro. Prostate 2000; 43:20–30.

    Article  PubMed  Google Scholar 

  42. Silvertown JD, Ng J, Sato T et al. H2 relaxin overexpression increases in vivo prostate xenograft tumor growth and angiogenesis. Int J Cancer 2006; 118:62–73.

    Article  PubMed  CAS  Google Scholar 

  43. Unlu A, Leake RE. The effect of EGFR-related tyrosine kinase activity inhibition on the growth and invasion mechanisms of prostate carcinoma cell lines. Int J Biol Markers 2003; 18:139–146.

    PubMed  CAS  Google Scholar 

  44. Madarame J, Higashiyama S, Kiyota H et al. Transactivation of epidermal growth factor receptor after heparin-binding epidermal growth factor-like growth factor shedding in the migration of prostate cancer cells promoted by bombysin. Prostate 2003; 57:187–195.

    Article  PubMed  CAS  Google Scholar 

  45. Jarrard DF, Blitz BF, Smith RC et al. Effect of epidermal growth factor on prostate cancer cell line PC3 growth and invasion. Prostate 1994; 24:46–53.

    Article  PubMed  CAS  Google Scholar 

  46. Zhang XK. Vitamin A and apoptosis in prostate cancer. Endocrine-related Cancer 2002; 9:87–102.

    Article  PubMed  CAS  Google Scholar 

  47. Sporn MB, Roberts AB, Goodman DS. The Retinoids, 2nd, ed. Sporn MB, Roberts AB, Goodman DS eds. New York Raven Press, 1994:319–350.

    Google Scholar 

  48. Thompson JN, Howell J, Pitt GAJ. Vitamin A and reproduction in rats. Proc Royal Soc 1964; 159:510–535.

    Article  CAS  Google Scholar 

  49. Pasquali D, Thaller C, Eichele G. Abnormal level of retinoic acid in prostate cancer tissues. J Clin Endocrinol Metab 1996; 81:2186–2191.

    Article  PubMed  CAS  Google Scholar 

  50. Gyftopoulos K, Perimenis P, Sotiropoulou-Bonikou G et al. Immunohistochemical detection of retinoic acid receptor-alpha in prostate carcinoma: correlation with proliferative activity and tumor grade. Int Urol Nephrol 2000; 32:263–269.

    Article  PubMed  CAS  Google Scholar 

  51. Richter F, Huang HF, Li MT et al. Retinoid and androgen regulation of cell growth, epidermal growth factor and retinoid acid receptors in normal and carcinoma rat prostate cells. Mol Cell Endocrinol 1999; 153:29–38.

    Article  PubMed  CAS  Google Scholar 

  52. Gunnersen JM, Roche PJ, Tregear GW et al. Characterization of human relaxin gene regulation in the relaxin-expressing human prostate adenocarcinoma cell line LNCaP.FGC. J Mol Endocrinol 1995; 15:153–166.

    Article  PubMed  CAS  Google Scholar 

  53. Garibay-Tupas JL, Okazaki KJ, Tashima LS et al. Regulation of the human relaxin genes H1 and H2 by steroid hormones. Mol Cell Endocrinol 2004; 219:115–125.

    Article  PubMed  CAS  Google Scholar 

  54. Bonkhoff H, Fixemer T, Hunsicker I et al. Progesterone receptor expression in human prostate cancer: correlation with tumor progression. Prostate 2001; 48:285–291.

    Article  PubMed  CAS  Google Scholar 

  55. Mohler LJ, Chen Y, Hamil K et al. Androgen and glucocorticoid receptors in the stroma and epithelium of prostate hyperplasia and carcinoma. Clin Cancer Res 1996; 2:889–895.

    PubMed  CAS  Google Scholar 

  56. Vinall R, Tepper CG, Shi XB et al. The R273H p53 mutation can facilitate the androgen-independent growth of LNCaP by a mechanism that involves H2 relaxin and its cognate receptor LGR7. Oncogene 2006; 25:2082–2093.

    Article  PubMed  CAS  Google Scholar 

  57. Dinjens WN, van der Weiden MM, Schroeder FH et al. Frequency and characterization of p53 mutations in primary and metastatic human prostate cancer. Int J Cancer 1994; 56:630–633.

    Article  PubMed  CAS  Google Scholar 

  58. Dschietzig T, Bartsch C, Stangl V et al. Identification of the pregnancy hormone relaxin as glucocorticoid receptor agonist. FASEB J 2004; 18:1536–1548.

    PubMed  CAS  Google Scholar 

  59. Dschietzig T, Bartsch C, Greinwald M et al. The pregnancy hormone relaxin binds to and activates the human glucocorticoid receptor. Ann NY Acad Sci 2005; 1041:256–271.

    Article  PubMed  CAS  Google Scholar 

  60. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA 2006; 295:2164–2167.

    Article  PubMed  CAS  Google Scholar 

  61. Monson JP. The epidemiology of endocrine tumours. Endocrine-related Cancer 2000; 7:29–36.

    Article  PubMed  CAS  Google Scholar 

  62. Plunkett ER, Squires BP, Richardson SJ. The effect of relaxin on thyroid weights in laboratory animals. J Endocrinol 1960; 21:241–246.

    Article  PubMed  CAS  Google Scholar 

  63. Plunkett ER, Squires BP, Heagy FC. Effect of relaxin on thyroid function in the rat. J Endocrinol 1963; 26:331–338.

    Article  PubMed  CAS  Google Scholar 

  64. Braverman LE, Ingbar SH. Effects of preparations containing relaxin on thyroid function in the female rat. Endocrinology 1963; 72:337–341.

    PubMed  CAS  Google Scholar 

  65. Hombach-Klonisch S, Bialek J, Trojanowicz B et al. Relaxin enhances the oncogenic potential of human thyroid carcinoma cells. Am J Pathol 2006; 169:617–32.

    Article  PubMed  CAS  Google Scholar 

  66. Silvertown JD, Geddes BJ, Summerlee AJS. Adenovirus-mediated expression of human prorelaxin promotes the invasive potential of canine mammary cancer cells. Endocrinology 2003; 144:1683–1691.

    Article  CAS  Google Scholar 

  67. Zarreh-Hoshyari-Khah R, Bartsch O, Einspanier A et al. Bioactivity of recombinant prorelaxin from the marmoset monkey. Regul Pept 2001; 97:139–146.

    Article  PubMed  CAS  Google Scholar 

  68. Vu AL, Green CB, Roby KF et al. Recombinant porcine prorelaxin produced in Chinese hamster ovary cells is biologically active. Life Science 1993; 52:1055–1061.

    Article  CAS  Google Scholar 

  69. Klonisch T, Mustafa T, Bialek, J et al. Human medullary thyroid carcinoma. A source and potential target for relaxin-like hormones. Ann NY Acad Sci 2005; 1041:449–461.

    Article  PubMed  CAS  Google Scholar 

  70. Kamat AA, Feng S, Agoulnik IU et al. The role of relaxin in endometrial cancer. Cancer Biol Ther 2006; 5:71–77.

    Article  PubMed  CAS  Google Scholar 

  71. Binder C, Hagemann T, Husen B et al. Relaxin enhances in vitro invasiveness of breast cancer cell lines by up-regulation of matrix-metalloproteinases. Mol Hum Reprod 2002; 8:789–796.

    Article  PubMed  CAS  Google Scholar 

  72. Wyatt TA, Sisson JH, Forget MA et al. Relaxin stimulates bronchial epithelial cell PKA activation, migration and ciliary beating. Exp Biol Med 2002; 227:1047–1053.

    CAS  Google Scholar 

  73. Unemori EN, Lewis M, Constant J et al. Relaxin induces vascular endothelial growth factor expression and angiogenesis selectively at wound sites. Wound Repair Regen 2000; 8:361–370.

    Article  PubMed  CAS  Google Scholar 

  74. Khasigov PZ, Podobed OV, Gracheva TS et al. Role of matrix metalloproteinases and their inhibitors in tumor invasion and metastasis. Biochemistry 2003; 68:711–717.

    PubMed  CAS  Google Scholar 

  75. Jiang Y, Goldberg ID, Shi YE. Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene 2002; 21:2245–2252.

    Article  PubMed  CAS  Google Scholar 

  76. Kraiem Z, Korem S. Matrix metalloproteinases and the thyroid. Thyroid 2000; 10:1061–1069.

    PubMed  CAS  Google Scholar 

  77. Lennon-Dumenil AM, Bakker AH, Wolf-Bryant P et al. A closer look at proteolysis and MHC-class-II-restricted antigen presentation. Curr Opin Immunol 2002; 14:15–21.

    Article  PubMed  CAS  Google Scholar 

  78. Lauritzen E, Moller S, Leerhoy J. Leucocyte migration inhibition in vitro with inhibitors of aspartic and sulphhydryl proteinases. Acta Pathol Microbiol Immunol Scand [C] 1984; 92:107–112.

    CAS  Google Scholar 

  79. Cataldo AM, Nixon RA. Enzymatically active lysosomal proteases are associated with amyloid deposits in Alzheimer brain. Proc Natl Acad Sci USA 1990; 87:3861–3865.

    Article  PubMed  CAS  Google Scholar 

  80. Adamec E, Mohan PS, Cataldo AM et al. Up-regulation of the lysosomal system in experimental models of neuronal injury: implications for Alzheimer’s disease. Neuroscience 2000; 100:663–675.

    Article  PubMed  CAS  Google Scholar 

  81. Leto G, Tumminello FM, Crescimanno M et al. Cathepsin D expression levels in nongynecological solid tumors: clinical and therapeutic implications. Clin Exp Metastasis 2004; 21:91–106.

    Article  PubMed  CAS  Google Scholar 

  82. Leto G, Gcbbia N, Rausa L et al. Cathepsin D in the malignant progression of neoplastic diseases (review). Anticancer Res 1992;12:235–240.

    PubMed  CAS  Google Scholar 

  83. Metaye T, Kraimps JL, Goujon JM et al. Expression, Localisation and Thyrotropin Regulation of Cathepsin D in Human Thyroid Tissues. J Clin Endocrinol Metab 1997;82:3383–3388.

    Article  PubMed  CAS  Google Scholar 

  84. Metaye T, Millet C, Kraimps JL et al. Estrogen receptors and cathepsin D in human thyroid tissue. Cancer 1993;72:1991–1996.

    Article  PubMed  CAS  Google Scholar 

  85. Kraimps JL, Metaye T, Millet C et al. Cathepsin D in normal and neoplastic thyroid tissues. Surgery 1995;118:1036–1040.

    Article  PubMed  CAS  Google Scholar 

  86. Krueger S, Kellner U, Buehling F et al. Cathepsin L antisense oligonucleotides in a human osteosarcoma cell line: effects on the invasive phenotype. Cancer Gene Ther 2001;8:522–528.

    Article  PubMed  CAS  Google Scholar 

  87. Kirschke H, Eerola R, Hopsu-Havu VK et al. Antisense RNA inhibaition of cathepsin L expression reduces tumorigenicity of malignant cells. Eur J Cancer 2000;36:787–795.

    Article  PubMed  CAS  Google Scholar 

  88. Dohchin A, Suzuki JI, Seki H et al. Immunostained cathepsins B and L correlate with depth of invasion and different metastatic pathways in early stage gastric carcinoma. Cancer 2000;89:482–487.

    Article  PubMed  CAS  Google Scholar 

  89. Urbich C, Heeschen C, Aicher A et al. Cathepsin L is required for endothelial progenitor cell-induced neovascularization. Nat Med 2005;11:206–213.

    Article  PubMed  CAS  Google Scholar 

  90. Von Figura K, Hasilik A. Lysosomal enzymes and their receptors. Annu Rev Biochem 1986;55:167–193.

    Article  Google Scholar 

  91. Laurant-Matha V, Maruani-Herrmann S, Prebois C et al. Catalytically inactive human cathepsin D triggers fibroblast invasive growth. J Cell Biol 2005;168:489–499.

    Article  CAS  Google Scholar 

  92. Koike M, Shibata M, Ohsawa Y et al. Involvement of two different cell death pathways in retinal atrophy of cathepsin D-deficient mice. Mol Cell Neurosci 2003;22:146–161.

    Article  PubMed  CAS  Google Scholar 

  93. Nakanishi H, Zhang J, Koike M et al. Involvement of nitric oxide released from microglia-macrophages in pathological changes of cathepsin D-deficient mice. J Neurosci 2001;21:7526–7533.

    PubMed  CAS  Google Scholar 

  94. Saftig P, Hetman M, Schmahl W et al. Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. EMBO J 1995;14:3599–3608.

    PubMed  CAS  Google Scholar 

  95. American Cancer Society, Cancer Facts and Figures, 2005. Available at http://www.cancer.org/downloads/STT/CAFF2005f4PWSecured.pdf.

  96. Nardi E, Bigazzi M, Agrimonti F et al. In: Biology of relaxin and its role in the human, eds. Bigazzi, Greenwood, Gasparri; Excerpta Medica: Amsterdam 1983:417.

    Google Scholar 

  97. Kuenzi MJ, Sherwood OD. Monoclonal antibodies specific for rat relaxin. VII. Passive immunization with monoclonal antibodies throughout the second half of pregnancy prevents development of normal mammary nipple morphology and function in rats. Endocrinology 1992;131:1841–1847.

    Article  PubMed  CAS  Google Scholar 

  98. Peaker M, Taylor E, Tashima L et al. Relaxin detected by immunocytochemistry and northern analysis in the mammary gland of the guinea pig. Endocrinology 1989;125:693–698.

    PubMed  CAS  Google Scholar 

  99. Hurley WL, Doane RM, O’Day-Bowman MB et al. Effect of relaxin on mammary development in ovariectomized pregnant gilts. Endocrinology 1991;128:1285–1290.

    PubMed  CAS  Google Scholar 

  100. Min G, Sherwood OD. Identification of specific relaxin-binding cells in the cervix, mammary glands, nipples, small intestine and skin of pregnant pigs. Biol Reprod 1996:55:1243–1252.

    Article  PubMed  CAS  Google Scholar 

  101. Winn RJ, Baker MD, Merle CA et al. Individual and combined effects of relaxin, estrogen and progesterone in ovariectomized gilts. II. Effects on mammary development. Endocrinology 1994;35:1250–1255.

    Article  Google Scholar 

  102. Hwang JJ, Lee AB, Fields PA et al. Monoclonal antibodies specific for rat relaxin. V. Passive immunization with monoclonal antibodies throughout the second half of pregnancy disrupts development of the mammary apparatus and, hence, lactational performance in rats. Endocrinology 1991;129:3034–3042.

    PubMed  CAS  Google Scholar 

  103. Kuenzi MJ, Connolly BA, Sherwood OD. Relaxin acts directly on rat mammary nipples to stimulate their growth. Endocrinology 1995;136:2943–2947.

    Article  PubMed  CAS  Google Scholar 

  104. Zhao L, Roche PJ, Gunnerson JM et al. Mice without a functional relaxin gene are unable to deliver milk to their pups. Endocrinology 1999;140:445–453.

    Article  PubMed  CAS  Google Scholar 

  105. Kohsaka T, Min G, Lukas G et al. Identification of specific relaxin-binding cells in the human female. Biol Reprod 1998;59:991–999.

    Article  PubMed  CAS  Google Scholar 

  106. Ivell R, Balvers M, Pohnke Y et al. Immunoexpression of the relaxin receptor LGR7 in breast and uterine tissues of humans and primates. Reprod Biol Endocrinol 2003;1:114–127.

    Article  PubMed  Google Scholar 

  107. Steinetz BG, Sherwood OD, Lasano S et al. Immuno-neutralization of circulating relaxin does not alter the breast cancer-protective action of parity in MNU-treated rats. J Exp Ther Oncol 2004;4:59–68.

    PubMed  CAS  Google Scholar 

  108. Radestock Y, Hoang-Vu C, Hombach-Klonisch S. Relaxin downregulates the calcium binding protein S100A4 in MDA-MB-231 human breast cancer cells. Ann N Y Acad Sci 2005;1041:462–469.

    Article  PubMed  CAS  Google Scholar 

  109. Bigazzi M, Brandi ML, Bani G et al. Relaxin influences the growth of MCF-7 breast cancer cells. Mitogenic and antimitogenic action depends on peptide concentration. Cancer 1992;70:639–643.

    Article  PubMed  CAS  Google Scholar 

  110. Sacchi TB, Bani D, Brandi ML et al. Relaxin influences growth, differentiation and cell-cell adhesion of human breast-cancer cells in culture. Int J Cancer 1994;57:129–134.

    Article  PubMed  CAS  Google Scholar 

  111. Bani D, Riva A, Bigazzi M et al. Differentiation of breast cancer cells in vitro is promoted by the concurrent influence of myoepithelial cells and relaxin. Br J Cancer 1994;70:900–904.

    PubMed  CAS  Google Scholar 

  112. Bani D. Relaxin and breast cancer. Bull Cancer 1997;84:179–182.

    PubMed  CAS  Google Scholar 

  113. Bani D, Flagiello D, Poupon MF et al. Relaxin promotes differentiation of human breast cancer cells MCF-7 transplanted into nude mice. Virchows Arch 1999;435:509–519.

    Article  PubMed  CAS  Google Scholar 

  114. Hovey RC, Trott JF. Morphogenesis of mammary gland development. Adv Exp Med Biol 2004;554:219–228.

    PubMed  CAS  Google Scholar 

  115. Pillai SB, Rockwell C, Sherwood OD et al. Relaxin stimulates uterine edema via activation of estrogen receptors: blockade of its effects using ICI 182,780, a specific estrogen receptor antagonist. Endocrinology 1999;14:2426–2429.

    Article  Google Scholar 

  116. Pillai SB, Jones JM, Koos RD. Treatment of rats with 17beta-estradiol or relaxin rapidly inhibits uterine estrogen receptor beta1 and beta2 messenger ribonucleic acid levels. Biol Reprod 2000;67:1919–1926.

    Article  CAS  Google Scholar 

  117. Clayton H, Titley I, Vivanco MM. Growth and differentiation of progenitor/stem cells derived from the human mammary gland. Exp Cell Res 2004;297:444–460.

    Article  PubMed  CAS  Google Scholar 

  118. Bryant-Greenwood GD. Relaxin as a new hormone. Endocr Rev 1982;3:62–90.

    PubMed  CAS  Google Scholar 

  119. Sherwood OD. Relaxin’s physiological roles and other diverse actions. Endocr Rev 2004;25:205–234.

    Article  PubMed  CAS  Google Scholar 

  120. Binder C, Simon A, Binder L et al. Elevated concentrations of serum relaxin are associated with metastatic disease in breast cancer patients. Breast Cancer Res Treat 2004;87:157–166.

    Article  PubMed  CAS  Google Scholar 

  121. Balduyck M, Zerimech F, Gouyer V et al. Specific expression of matrix metalloproteinases 1, 3, 9 and 13 associated with invasiveness of breast cancer cells in vitro. Clin Exp Metastasis 2000;18:171–178.

    Article  PubMed  CAS  Google Scholar 

  122. Ramos-DeSimone N, Hahn-Dantona E, Sipley J et al. Activation of matrix metalloproteinase-9 (MMP-9) via a converging plasmin/stromelysin-1 cascade enhances tumor cell invasion. J Biol Chem 1999;274:13066–13076.

    Article  PubMed  CAS  Google Scholar 

  123. Lloyd BH, Platt-Higgins A, Rudland PS et al. Human S100A4 (p9Ka) induces the metastatic phenotype upon benign tumour cells. Oncogene 1998;17:465–473.

    Article  PubMed  CAS  Google Scholar 

  124. Schmidt-Hansen B, Ornas D, Grigorian M et al. Extracellular S100A4(mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity. Oncogene 2004;23:5487–5495.

    Article  PubMed  CAS  Google Scholar 

  125. Sherbet GV, Lakshmi MS. S100A4 (MTS1) calcium binding protein in cancer growth, invasion and metastasis. Anticancer Res 1998;18:2415–2421.

    PubMed  CAS  Google Scholar 

  126. Jenkinson SR, Barraclough R, West CR et al. S100A4 regulates cell motility and invasion in an in vitro model for breast cancer metastasis. Brit J Cancer 2004;90:253–262.

    Article  PubMed  CAS  Google Scholar 

  127. Lee WY, Su WC, Lin PW et al. Expression of S100A4 and Met: potential predictors for metastasis and survival in early-stage breast cancer. Oncology 2004;66:429–438.

    Article  PubMed  CAS  Google Scholar 

  128. Grigorian M, Andresen S, Tulchinsky E et al. Tumor suppressor p53 protein is a new target for the metastasis-associated Mtsl/S100A4 protein: functional consequences of their interaction. J Biol Chem 2001;276:22699–22708.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, 130 Basic Medical Science Bldg., 730 William Avenue, Winnipeg, Manitoba, Canada, R3E 0W3

    Thomas Klonisch & Sabine Hombach-Klonisch

  2. Universitätsklinik und Poliklinik für Allgemein Viszeral- und Gefäßchirurgie, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany

    Joanna Bialek, Yvonne Radestock & Cuong Hoang-Vu

Authors
  1. Thomas Klonisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joanna Bialek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yvonne Radestock
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cuong Hoang-Vu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sabine Hombach-Klonisch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Klonisch .

Editor information

Editors and Affiliations

  1. Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA

    Alexander I. Agoulnik Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Klonisch, T., Bialek, J., Radestock, Y., Hoang-Vu, C., Hombach-Klonisch, S. (2007). Relaxin-Like Ligand-Receptor Systems Are Autocrine/Paracrine Effectors in Tumor Cells and Modulate Cancer Progression and Tissue Invasiveness. In: Agoulnik, A.I. (eds) Relaxin and Related Peptides. Advances in Experimental Medicine and Biology, vol 612. Springer, New York, NY. https://doi.org/10.1007/978-0-387-74672-2_8

Download citation

  • DOI: https://doi.org/10.1007/978-0-387-74672-2_8

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-0-387-74670-8

  • Online ISBN: 978-0-387-74672-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation