Summary
Prostate cancer is one of the most commonly diagnosed cancers and is a major cause of cancer death in men. Although the majority of the diagnosed prostate cancers will remain localized and never produce clinical symptoms during the lifetime of the host, a subset of these cancers will progress to a more malignant state requiring therapeutic intervention. Acquisition of metastatic ability by prostatic cancer cells is the most lethal aspect of prostatic cancer progression. Once this has occurred, definitive therapy is required before the initially localized metastatic cells escape from the prostate. At present, metastatic prostate cancer is incurable. Therefore, there is an urgent need to develop molecular markers that can be used to predict the metastatic potential of prostate cancers. Using somatic cell hybridization, we have demonstrated that acquisition of metastatic ability requires both the loss of metastasis-suppressor function(s) and the activation of oncogenes. In further studies using micro-cell-mediated chromosomal transfer, we located genes on human chromosome, 8, 10cen-q23, 11p11.2-13, and 17pter-q23, which, when introduced into rat prostatic cancer cells, are capable of suppressing their metastatic ability without affecting their tumorigenicity or growth rate in vivo. Initially we focused upon the human chromosome 11p11.2-13 region to clone metastasis-suppressor gene(s) positionally. One such gene, termed KAI-1, encodes a membrane glycoprotein. KAI-1 has been mapped to the p11.2 region of human chromosome 11 by fluorescence in-situ hybridization analysis. Expression of KAI-1 has been detected in all normal human tissues thus far tested, including prostate tissue. When introduced into rat metastatic prostatic cancer cells, KAI-1 significantly suppressed the metastasis without affecting the tumor growth rate. KAI-1 expression is high in human normal prostate and benign prostatic hyperplasia but is dramatically lower in cancer cell lines derived from metastatic prostate tumors.
Similar content being viewed by others
References
Amiot M (1990) Identification and analysis of cDNA clones encoding CD53. A panleukocyte antigen related to membrane transport proteins. J Immunol 145:4322–4325
Atkin NB, Baker MC (1985) Chromosome study of five cancers of the prostate. Hum Genet 70:359–364
Backer JM, Mendola CE, Kovesdi I, Fairhurst JL, O'Hara B, Eddy R Jr, Shows TB, Mathew S, Murty VV, Chaganti RS (1993) Chromosomal localization and nucleoside diphosphate kinase activity of human metastasis-suppressor genes NM23–1 and NM23–2. Oncogene 8:497–502
Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, van Tuinen P, Ledbetter DH, Barker DF, Nakamura Y (1989) Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244:217–221
Bergerheim US, Kunimi K, Collins VP, Ekman P (1991) Deletion mapping of chromosomes 8, 10, and 16 in human prostatic carcinoma. Genes Chromosomes Cancer 3:215–220
Bernstein SC, Weinberg RA (1985) Expression of the metastatic phenotype in cells transfected with human metastatic tumor DNA. Proc Natl Acad Sci USA 82:1726–1730
Boucheix C, Benoit P, Frachet P, Billard M, Worthington RE, Gagnon J, Uzan G (1991) Molecular cloning of the CD9 antigen, A new family of cell surface proteins. J Biol Chem 266:117–122
Bova GS, Carter BS, Bussemakers MJ, Emi M, Fujiwara Y, Kyprianou N, Jacobs SC, Robinson JC, Epstein JI, Walsh PC, Isaacs WB (1993) Homozygous deletion and frequent allelic loss of chromosome 8q22 loci in human prostate cancer. Cancer Res 53:3869–3873
Bradley MO, Kraynak AR, Storer RD, Gibbs JB (1986) Experimental metastasis in nude mice of NIH 3T3 cells containing various ras genes. Proc Natl Acad Sci USA 83:5277–5281
Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM (1984) Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 224:1121–1124
Bussemakers MJ, Moorselaar RJ van, Giroldi LA, Ichikawa T, Isaacs JT, Takeichi M, Debruyne FM, Schalken JA (1992) Decreased expression of E-cadherin in the progression of rat prostatic cancer. Cancer Res 52:2916–2922
Classon BJ, Williams AF, Willis AC, Seed B, Stamenkovic I (1989) The primary structure of the human leukocyte antigen CD37, a species homologue of the rat MRC OX-44 antigen. J Exp Med 169:1497–1502
Dennis JW, Laferte S, Wagborne C, Brettman ML, Kerbel RS (1987) b1–6 branching of Asn-linked oligosaccharides is directly associated with metastasis. Science 236:582–585
Dong JT, Lamb PW, Rinker-Schaeffer CW, Vukanovic J, Ichikawa T, Isaacs JT, Barrett JC (1995) KA11, a metastasis suppressor gene for prostate cancer on human chromosome 11q11.2. Science 268:884–886
Drickamer K, Taylor ME (1993) Biology of animal lectins. Annu Rev Cell Biol 9:237–264
Dunning WF (1963) Prostate cancer in the rat. Monogr Natl Cancer Inst 12:351–369
Egan SE, McClarty GA, Jarolim L, Wright JA, Spiro I, Hager G, Greenberg AH (1987) Expression of H-ras correlates with metastatic potential: evidence for direct regulation of the metastatic phenotype in 10T1/2 and NIH 3T3 cells. Mol Cell Biol 7:830–837
Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A, Lochner D, Birchmeier W (1991) E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 113:173–185
Fukudome K, Furuse M, Imai T, Nishimura M, Takagi S, Hinuma Y, Yoshie O (1992) Identification of membrane antigen C33 recognized by monoclonal antibodies inhibitory to human T-cell leukemia virus type 1 (HTLV-1)-induced syncytium formation: altered glycosylation of C33 antigen in HTLV-1-positive T cells. J Virol 66:1394–1401
Gaugitsch HW, Hofer E, Huber NE, Schnabl E, Baumruker T (1992) A new superfamily of lymphoid and melanoma cell proteins with extensive homology to Schistosoma mansoni antigen Sm23. Eur J Immunol 21:377–383
Gil ML, Vita N, Lebel-Binay S, Miloux B, Chalon P, Kaghad M, Marchiol-Fournigault C, Conjeaud H, Caput D, Ferrara P, Fradelizi D, Quillet-Mary A (1992) A member of the tetra spans transmembrane protein superfamily is recognized by a monoclonal antibody raised against an HLA class I-deficient, lymphokine-activated, killer-susceptible B lymphocyte line. Cloning and preliminary functional studies. J Immunol 148:2826–2833
Greig RG, Koestler TP, Trainer DL, Corwin SP, Miles L, Kline T, Sweet R, Yokoyama S, Poste G (1985) Tumorigenic and metastatic properties of “normal” and ras-transfected NIH/3T3 cells. Proc Natl Acad Sci USA 82:3698–3701
Griffin CA, McKeon C, Israel MA, Gegonne A, Ghysdeal J, Stehelin D, Douglass EC, Green AE, Emanuel BS (1986) Comparison of constitutional and tumor-associated 11;22 translocations: nonidentical breakpoints on chromosome 11 and 22. Proc Natl Acad Sci USA 83:6122–6126
Hakomori S-I (1989) Aberrant glycosylation in tumors and tumor-associated carbohydrate antigens. Adv Cancer Res 52:257–331
Horejsi V, Vlcek C (1991) Novel structurally distinct family of leucocyte surface glycoproteins including CD9, CD37, CD53 and CD63. FEBS Lett 288:1–4
Hotta H, Ross AH, Huebner K, Isobe M, Wendeborn S, Chao MV, Ricciardi RP, Tsujimoto Y, Croce CM, Koprowski H (1988) Molecular cloning and characterization of an antigen associated with early stages of melanoma tumor progression. Cancer Res 48:2955–2962
Ichikawa T, Ichikawa Y, Isaacs JT (1991) Genetic factors and suppression of metastatic ability of prostatic cancer. Cancer Res 51:3788–3792
Ichikawa T, Schalken JA, Ichikawa Y, Steinberg GD, Isaacs JT (1991) H-ras expression, genetic instability, and acquisition of metastatic ability by rat prostatic cancer cells following v-H-ras oncogene transfection. Prostate 18:163–172
Ichikawa T, Ichikawa Y, Dong J, Hawkins AL, Griffin CA, Isaacs WB, Oshimura M, Barrett JC, Isaacs JT (1992) Localization of metastasis suppressor gene(s) for prostatic cancer to the short arm of human chromosome 11. Cancer Res 52:3486–3490
Ichikawa T, Ichikawa Y, Isaacs JT (1992) Genetic factors and suppression of metastatic ability of v-Ha-ras-transfected rat mammary cancer cells. Proc Natl Acad Sci USA 89:1607–1610
Ichikawa T, Nihei N, Suzuki H, Oshimura M, Emi M, Nakamura Y, Hayata I, Isaacs JT; Shimazaki J (1994) Suppression of metastasis of rat prostatic cancer by introducing human chromosome 8. Cancer Res 54:2299–2302
Ikeyama S, Koyama M, Yamaoko M, Sasada R, Miyake M (1993) Suppression of cell motility and metastasis by transfection with human motility-related protein (MRP-1/CD9) DNA. J Exp Med 177:1231–1237
Imai T, Fukudome K, Takagi S, Nagira M, Furuse M, Fukuhara N, Nishimura M, Hinuma Y, Yoshie O (1992) C33 antigen recognized by monoclonal antibodies inhibitory to human T cell leukemia virus type 1-induced syncytium formation is a member of a few family of transmembrane proteins including CD9, CD37, CD53, and CD63. J Immunol 149:2879–2886
Isaacs JT, Hukku B (1988) Nonrandom involvement of chromosome 4 in the progression of rat prostatic cancer. Prostate 13:165–188
Isaacs WB, Carter BS (1991) Genetic changes associated with prostate cancer in humans. Cancer Surv 11:15–24
Ishikawa M, Dennis JW, Kerbel RS (1988) Isolation and characterization of spontaneous wheat-germ-agglutinin-resistant human melanoma mutants displaying remarkable different metastatic profiles in nude mice. Cancer Res 48:655–670
Junien C, Heyningen V van (1990) Report of the Committee on the Genetic Constitution of Chromosome 11. Cytogenet Cell Genet 55:153–169
Koi M, Morita H, Yamada H, Satoh H, Barrett JC, Oshimura M (1989) Normal human chromosome 11 suppresses tumorigenicity of human cervical tumor cell line SiHa. Mol Carcinog 2:12–21
Kondoh M, Ueda M, Ichihashi M, Mishima Y (1993) Decreased expression of human melanoma-associated antigen ME491 along the progression of melanoma pre-canceroses to invasive and metastatic melanomas. Melanoma Res 3:241–245
Levy S, Nguyen VQ, Andria ML, Takahashi S (1991) Structure and membrane topology of TAPA-1. J Biol Chem 266:14597–14602
Liu E, Dollbaum C, Scott G, Rochlitz C, Benz C, Smith HS (1988) Molecular lesions involved in the progression of a human breast cancer. Oncogene 3:323–327
Lundgren R, Kristoffersson U, Heim S, Mandahl N, Mitelman F (1988) Multiple structural chromosome rearrangements, including del(7q) and del(10q), in an adenocarcinoma of the prostate. Cancer Genet Cytogenet 35:103–108
Mareel MM, Behrens J, Birchmeier W, DeBruyne GK, Vleminckx K, Hoogewijs A, Fiers WC, Van Roy FM (1991) Down-regulation of E-cadherin expression in Madin Darby canine kidney (MDCK) cells inside tumors of nude mice. Int J Cancer 47:922–928
Metzelaar MJ, Wijngaard PL, Peters PJ, Sixma JJ; Nieuwenhuis HK, Clevers HC (1991) CD63 antigen. A novel lysosomal membrane glycoprotein, cloned by a screening procedure for intracellular antigens in eukaryotic cells. J Biol Chem 266:3239–3245
Miyake M, Koyama M, Seno M, Ikeyama S (1992) Identification of the motility-related protein (MRP-1), recognized by monoclonal antibody M31–15, which inhibits cell motility. J Exp Med 174:1347–1354
Nelson DL, Ledbetter SA, Corbo L, Victoria MF, Ramirez-Solis R, Webster TD, Ledbetter DH, Caskey CT (1989) Au polymerase chain reaction: a method for rapid isolation of human-specific sequences from complex DNA sources. Proc Natl Acad Sci USA 86:6686–6690
Nihei N, Ichikawa T, Kawato Y, Kuramochi H, Kugo H, Oshimura M, Killary AM, Rinker-Schaeffer CW, Barrett JC, Isaacs JT, Shimazaki J (1995) Localization of metastasis suppressor gene(s) for rat prostatic cancer to the long arm of human chromosome 10. Genes Chromosomes Cancer 14:112–119
Oren R, Takahashi S, Doss C, Levy R, Levy S (1990) TAPA-1, the target of an antiproliferative antibody, defines a new family of transmembrane proteins. Mol Cell Biol 10:4007–4015
Oshimura M, Kogoh H, Koi M, Shimizu M, Yamada H, Satoh H, Barrett JC (1990) Transfer of a normal human chromosome 11 suppresses tumorigenicity of some but not all tumor cell lines. J Cell Biochem 42:135–142
Partin AW, Isaacs JT, Treiger B, Coffey DS (1988) Early cell motility changes associated with an increase in metastatic ability in rat prostatic cancer cells transfected with the v-Harveyras oncogene. Cancer Res 48:6050–6053
Rinker-Schaeffer CW, Partin AW, Isaacs WB, Coffey DS, Isaacs JT (1994) Molecular and cellular changes associated with the acquisition of metastatic ability by prostatic cancer cells. Prostate 25:249–265
Schalken JA, Ebeling SB, Isaacs JT, Treiger B, Bussemarkers MJ, Jong ME de, Van de Ven WJ (1988) Down modulation of fibronectin messenger RNA in metastasizing rat prostatic cancer cells revealed by differential hybridization analysis. Cancer Res 48:2042–2046
Sharon N, Lis H (1989) Lectins as cell recognition molecules. Sciences 246:227–234
Steeg PS, Bevilacqua G, Kopper L, Thorgeirsson UP, Talmadge JE, Liotta LA, Sobel ME (1988) Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst 80:200–204
Takeichi M (1988) The cadherins: cell-cell adhesion molecules controlling animal morphogenesis. Development 102:639–655
Takeichi M (1991) Cadherin cell adhesion receptors as a morphogenetic regulator. Science 251:1451–1455
Thorgeirsson UP, Turpeenniemi-Hujanen T, Williams JE, Westin EH, Heilman CA, Talmadge JE, Liotta LA (1985) NIH/3T3 cells transfected with human tumor DNA containing activated ras oncogenes express the metastatic phenotype in nude mice. Mol Cell Biol 5:259–262
Treiger B, Isaacs JT (1988) Expression of a transfected v-Harvey-ras oncogene in a Dunning rat prostate adenocarcinoma and the development of high metastatic ability. J Urol 140:1580–1586
Umbas R, Schalken JA, Aalders TW, Carter BS, Karthaus HF, Schaafsma HE, Debruyne FM, Isaacs WB (1992) Expression of the cellular adhesion molecule E-cadherin is reduced or absent in high-grade prostate cancer. Cancer Res 52:5104–5109
Umbas R, Isaacs WB, Bringuier PP, Schaafsma HE, Karthaus HF, Oosterhof GO, Debruyne FM, Schalken JA (1994) Decreased E-cadherin expression is associated with poor prognosis in patients with prostate cancer. Cancer Res 54:3929–3933
Viola MV, Fromowitz F, Oravez S, Deb S, Finkel G, Lundy J, Hand P, Thor A, Schlom J (1986) Expression of ras oncogene p21 in prostate cancer. N Engl J Med 314:133–137
Vleminckx K, Vakaet L Jr, Mareel M, Fiers W, Roy F van (1991) Genetic manipulation of E-cadherin expression by epithelial tumor cell reveals an invasion suppressor role. Cell 66:107–119
Weissman BE, Saxon PJ, Pasquale SR, Jones GR, Geiser AG, Stanbridge EJ (1987) Introduction of a normal human chromosome 11 into a Wilms' tumor cell line controls its tumorigenic expression. Science 236:175–180
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Dong, J.T., Rinker-Schaeffer, C.W., Ichikawa, T. et al. Prostate cancer — biology of metastasis and its clinical implications. World J Urol 14, 182–189 (1996). https://doi.org/10.1007/BF00186898
Issue Date:
DOI: https://doi.org/10.1007/BF00186898