Summary
Metastasis is the cascade of events involved in the transition of a malignancy from a localized tumor to the establishment of a distant foci. In this review we define the known stages and the factors involved. The multiplicity of steps involved allows many opportunities for therapeutic intervention. Current research has focused on interruption of a step or a series of steps to limit the spread of cancer. With emphasis on the urologic malignancies, we outline the research thus far accomplished in the field of metastasis.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Barsky SH (1983) Loss of basement membrane components by invasive tumors but not by their benign counterparts. Lab Invest 49:140–147
Bellusci S, Moens G, Gaudino G, Comoglio P, Nakamura T, Thiery JP, Jouanneau J (1994) Creation of an hepatocyte growth factor/scatter factor autocrine loop in carcinoma cells induces invasive properties associated with increased tumorigenicity. Oncogene 9:1091–1099
Birchmeier W, Weidner KM, Hulksen J, Behrens J (1993) Molecular mechanisms leading to cell junction (cadherin) deficiency in invasive carcinomas. Semin Cancer Biol 4:231–239
Blasi F (1993) Urokinase and urokinase receptor: a paracrine/autocrine system regulating cell migration and invasiveness. Bioessays 15:105–111
Blood CH, Zetter BR (1990) Tumor interactions with the vasculature: angiogenesis and tumor metastasis. Biochim Biophys Acta 1032:89–118
Boyer B, Dufour S, Thiery JP (1992) E-cadherin expression during the acidic-FGF induced dispersion of a rat bladder carcinoma cell line. Exp Cell Res 201:347–357
Brawer MK, Deering RE, Brown M, Preston SD, Bigler SA (1994) Predictors of pathologic stage in prostate carcinoma. The role of neovascularity. Cancer 73:678–687
Brooks PC, Montogomery AM, Rosenfeld M, Reisfeld RA, Hu T, Killer G, and Cheresh DA (1994) Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79:1157–1164
Chiu JJS, Cowan K (1993) Differential effect of interleukin-6 on estrogen receptor positive and negative breast carcinoma cell lines. Proc Am Assoc Cancer Res 34:55
Coman DR, Sheldon WF (1946) The significance of hyperemia around tumor implants. Am J Pathol 22:821–826
Crowley CW, Cohen RL, Lucas BK, Liu G, Shuman MA, Levinson AD (1993) Prevention of metastasis by inhibition of the urokinase receptor. Proc Natl Acad Sci USA 90:5021–5025
deCleck YA, Yean T-D, Ratzkin BJ, Lu HS, Langley KE (1989) Purification and characterization of two related but distinct metalloproteinase inhibitors secreted by bovine aortic endothelial cells. J Biol Chem 264:17445–17453
Dedhar S (1990) Integrins and tumor invasion. Bioessays 12:583–590
Dedhar S, Saulnier R, Nagle R, Overall CM (1993) Specific alterations in the expression of alpha 3 beta 1 and alpha 6 beta 4 integrins in highly invasive and metastatic variants of human prostate carcinoma cells selected by in vitro invasion through reconstituted basement membrane. Clin Exp Metastasis 11:391–400
DeLaRosa A, Williams RL, Steeg PS (1995) Nm23/nucleoside diphosphate kinases: toward a structural and biochemical understanding of its biological functions. Bioessays 17:53–62
Dickinson AJ, Fox SB, Persad RA, Hollyer J, Sibley GN, Harris AL (1994) Quantification of angiogenesis as an independent predictor of prognosis in invasive bladder carcinomas. Br J Urol 74:762–766
Docherty AJP, Lyons A, Smith BJ, Wright EM, Stephens PE, Harris TJ, Murphy G, Reynolds JJ (1985) Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Nature 318:66–69
Dong J-T, Lamb PW, Rinker-Schaeffer CW, Vukanovic J, Ichikawa T, Isaacs JT, Barret JC (1995) KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science 268:884–886
Dvorak HF, Senger DR, Dvorak AM (1983) Fibrin as a component of the tumor stroma: origins and biological significance. Cancer Metastasis Rev 2:41–73
Effert PJ, Neubauer A, Walther PJ, Liu ET (1992) Alterations of the p53 gene are associated with the progression of a human prostate carcinoma. J Urol 147:789–793
Fregene TA, Khanuja PS, Noto AC, Gehani SK, Egmont EMV, Luz DA, Pienta KL (1993) Tumor-associated angiogenesis in prostate cancer. ANticancer Res 13:2377–2381
Freije JM, Diez-Itza I, Balbin M, Sanchez LM, Blasco R, Tolivia J, Lopez-Otin C (1994) Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas. J Biol Chem 269:16766–16773
Frisch SM, Francis H (1994) Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 124:619–626
Fujita S, Suzuki H, Kinoshita M, Hiroashi S (1992) Inhibition of cell attachment, invasion and metastasis of human carcinoma cell lines by anti-integrin beta 1 subunit antibody. Jpn J Cancer 83:1317–1326
Hall MC, Troncoso P, Pollack A, Zhau HY, Zagars GK, Chung LW, Eschenbach AC (1994) Significance of tumor angiogenesis in clinically localized prostate carcinoma treated with external beam radiotherapy. Urology 44:869–875
Hammersen F, Endrich B, Messmer K (1985) The fine structure of tumor blood vessels. Int J Microcircul 4:31–34
Hynes RO, Lander AD (1992) Contact and adhesive specificities in the associations, migrations, and targeting of cells and axons. Cell 63:303–322
Ichikawa T, Ichikawa Y, Dong J, Hawkins AL, Griffin CA, Isaacs WB, Oshimura M, Barrett JC, Isaacs JT (1992) Localization of metastasis suppressor gene for prostatic cancer to the short arm of human chromosome 11. Cancer Res 52:3486–3490
Ingber DE (1991) Control of capillary growth and differentiation by extracellular matrix. Use of tensegrity mechanism for signal processing. Chest 99:34S-40S
Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamaru T, Brem H, Folkman J (1990) Synthetic analogues of funagillin that inhibit angiogenesis and suppress tumor growth. Nature 348:555–557
Jain RK (1988) Determinants of tumor blood flow: a review. Cancer Res 48:2641–2658
Jain RK, Ward-Hartley KA (1987) Dynamics of cancer cell interaction with microvascular and interstitium. Biorrheology 24:117–125
Johnson RC, Zhu D, Voss HGA, Pauli BU (1993) Lung endothelial dipeptidyl peptidase IV is an adhesion molecule for lung metastatic rat breast and prostate carcinoma cells. J Cell Biol 121:1423–1432
Kantor JD, McCormick B, Steeg PS, Zetter BR (1993) Inhibition of cell motility after nm23 transfection of human and murine tumor cells. Cancer Res 53:1971–1973
Katagiri A, Watanabe R, Tomita Y (1995) E-cadherin expression in renal cell cancer and its significance in metastasis and survival. Br J Cancer 71:376–379
Leone A, Flatow U, King CR, Sandeen MA, Margulies IMK, Liotta LA, Steegs PS (1991) Reduced tumor incidence, metastatic potential, and cytokine responsiveness of nm23-transfected melanoma cells. Cell 65:25–35
Leone A, Flatow U, VanHoutte K, Steeg PS (1993) Transfection of human nm23-H1 into the human MDa-MB-435 breast carcinoma cell line: Effects on tumor metastatic potential, colonization, and enzymatic activity. Oncogene 8:2325–2333
Liotta LA, Steeg PS, Stetler-Stevenson WG (1991) Cancer metastasis and angiogenesis: an imbalance of negative and positive regulation. Cell 64:327–336
Lu C, Kerbel RS (1993) Interleukin-6 undergoes transition from paracrine growth inhibitor to autocrine stimulator during human melanoma progression. J Cell Biol 120:1281–1288
Lu C, Kerbel RS (1994) Cytokines, growth factors and the loss of negative controls in the progression of human cutaneous malignant melanoma. Curr Opin Oncol 6:212–220
Lu C, Rak J, Kobayashi H, Kerbel R (1993) Increased resistance to oncostatin M-induced growth inhibition of human melanoma cell lines derived from advanced-stage lesions. Cancer Res 53:2708–2711
Madri JA, Williams SK (1983) Capillary endothelial cell cultures: phenotypic modulation by matrix components. J Cell Biol 97:153–165
McCormick BA, Zetter BR (1992) Adhesive interactions in angiogenesis and metastasis. Pharmacol Ther 53:239–260
Miyamoto H, Kubota Y, Shuin T, Torigoe S, Hosaka M, Iwasaki Y, Danenberg K, Danenberg PV (1993) Analyses of p53 gene mutations in primary human bladder cancer. Oncol Res 5:245–249
Morita T, Shinohara N, Tikue A (1994) Antitumor effect of a synthetic analogue of fumagillin on murine renal carcinoma. Br J Urol 74:416–421
Nguyen NM, Lehr JE, Pienta KJ (1993) Pentostatin inhibits angiogenesis in vitro and suppresses prostate tumor growth in vivo. Anticancer Res 13:2143–2147
Nguyen M, Watanabe H, Budson AE, Richie JP, Hayes DF, Folkman J (1994) Elevated levels of angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers. J Natl Cancer Inst 86:356–361
O'Brien T, Cranston D, Fuggle S, Bcknell R, Harris AL (1995) Different angiogenic pathways characterize superficial and invasive bladder cancer. Cancer Res 55:510–513
O'Reilly MS, Holmgrem L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastasis by a Lewis lung carcinoma. Cell 79:315–328
Ossowski L, Russo-Payne H, Wilson EL (1991) Inhibition of urokinase-type plasminogen activator by antibodies: the effect on dissemination of a human tumor in the nude mouse model. Cancer Res 51:274–281
Otto T, Birchmeier W, Schmidt U, Hinke A, Schipper J, Rubben H, Raz A (1994) Inverse relation of E-cadherin and autocrine motility factor receptor expression as a prognostic factor in patients with bladder carcinomas. Cancer Res 54:3120–3123
Parhar RS, Shi Y, Zou M, Farid NR, Ernst P, Al-Sedairy S (1995) Effects of cytokine mediated modulation of Nm23 expression on the invasion and metastatic behavior of B16F10 melanoma cells. Int J Cancer 60:204–210
Pienta KJ, Naik H, Akhtar A, Yamazaki K, Replogle TS, Lehr J, Donat TL, Tait L, Hogan V, Raz A (1995) Inhibition of spontaneous metastasis in a rat prostate cancer model by administration of modified citrus pectin. J Natl Cancer Inst 87:348–353
Ries LAG, Miller BA, Hankey BF, Kosary CL, Harras, Edwards BK (1994) Cancer statistics review 1973–1991: Tables and graphs. NIH publication 94–2789. National Cancer Institute, Bethesda, Maryland
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
Rinker-Schaeffer CW, Hawkins AL, Ru N, Dong J, Stoica G, Griffin CA, Ichikawa T, Barrett JC, Isaacs JT (1994) Differential suppression of mammary and prostate cancer metastatis by human chromosomes 17 and 11. Cancer Res 54:6249–6256
Roberts A, Sporn M (1988) Transforming growth factor beta. Adv Cancer Res 51:107–145
Rouslahti E (1991) Integrins. J Clin Invest 87:1–5
Rouslahti E, Pierschbacher MD (1987) New perspectives in cell adhesion: RGD and integrins. Science 238:491–497
Sato K, Terada K, Sugiyama T, Takahashi S, Saito M, Moriyama M, Kakinuma H, Suzuki Y, Kato M, Kato T (1994) Frequent overexpression of vascular endothelial growth factor gene in human renal cell carcinoma. Tohoku J Exp Med 173:355–360
Shi I-M, Herlyn M (1993) Role of growth factors and their receptors in the development and progression of melanoma. J Invest Dermatol 100:196S-203S
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 Nat Cancer Inst 80:200–204
Steiner MS, Zhou ZZ, Tonb DC, Barrack ER (1994) Expression of transforming growth factor-beta 1 in prostate cancer. Endocrinology 135:2240–2247
Stetler-Stevenson WG, Krutzsch HC, Liotta LA (1989) TIMP-2, a new member of the metalloproteinase inhibitor family. J Biol Chem 264:17374–17378
Stetler-Stevenson W, Liotta L, Kleiner DE Jr (1993) Extracellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis. FASEB J 7:1434–1441
Sugarbaker EV, Thornwaite J, Ketcham AS (1977) Inhibitory effect of a primary tumor on metastasis. In: Day 58 (ed) Progress in cancer research and therapy. Raven, New York, pp 227–240
Takahashi A, Sasaki H, Kim SJ, Tobisu K, Kakizoe T, Tsukamoto T, Kumamoto Y, Sugimura T, Tereda M (1994) Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res 54:4233–4237
Thompson TC, Park SH, Timme TL, Ren C, Eastham JA, Donehower LA, Bradley A, Kamon D, Yang G (1995) Loss of p53 function leads to metastasis in ras+myc-initiated mouse prostate cancer. Oncogene 10:869–879
Tomita Y, Saito T, Saito K, Oite T, Shimizu F, Sato S (1995) Possible significance of VLA-4 (alpha 4 beta 1) for hematogenous metastasis of renal cell cancer. Int J Cancer 60:753–758
Trousseau A (1865) Phlegmasia alba dolens. Clin Med Hotel Dieu Paris 3:654–655
Umbas R, Schalken JA, Aalders TW, Carter BS, Karthaus HFM, Schaafsma EW, Debruyne FMJ, Isaacs WB (1992) Expression of cellular adhesion molecule E-cadherin is reduced or absent in high-grade prostate cancer. Cancer Res 52:5104–5109
Uria JA, Ferrando AE, Velasco G, Freije JMP, Lopez-Otin C (1994) Structure expression in breast tumors of human TIMP-3, a new member of the metalloproteinase inhibitor family. Cancer Res 54:2091–2094
Vleminckx K, Vakaet L, Mareel M, Fiers W, Roy FV (1991) Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66:107–119
Vukanovic J, Isaacs JT (1995) Linomide inhibits angiogenesis, growth, metastasis, and macrophage infiltration within rat prostatic cancers. Cancer Res 55:1499–1504
Warren BA (1979) The vascular morphology of tumors. Tumor blood circulation. CRC, Boca Raton, Florida
Warren BA, Shubik P, Feldman R (1978) Metastasis via the bloodstream: the method of intravasation of tumor cell in a transplantable melanoma of the hamster. Cancer Lett 4:245–251
Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis correlation in invasive breast carcinoma. New Engl J Med 324:1–8
Weidner N, Carroll P, Flax J, Blumenfeld W, Folkman J (1993) Tumor aniogenesis correlates with metastasis in invasive prostate cancer. Am J Pathol 143:401–409
Weinstat-Saslow D, Steeg P (1994) Angiogenesis and colonization in the tumor metastatic process: basic and applied advances. FASEB J 8:401–408
Weinstat-Saslow D, Zabrenetzky V, VanHoutte K, Frazier W, Roberts D, Steeg P (1994) Transfection of thrombospondin-1 cDNA into a human breast carcinoma cell line reduces primary tumor growth, metastatic potential and angiogenesis. Cancer Res 54:6504–6511
Witkowski CM, Rabinovitz I, Nagle RB, Affinito KS, Cress AE (1993) Characterization of integrin subunits, cellular adhesion and tumorgenicity of four human prostate cell lines. J Cancer Res Clin Oncol 119:637–644
Witty JP, Lempka T, Coffey RJ, Matrisian LM (1995) Decreased tumor formation in 7,12-dimethylbenzanthracenetreated stromelysin-1 transgenic mice is associated with alterations in mammary epithelial cell apoptosis. Cancer Res 55:1401–1406
Yanase T, Tamura M, Fujita K, Kodama S, Tanaka K (1993) Inhibitory effect of angiogenesis inhibitor TNP-470 on tumor growth and metastasis of human cell lines in vitro and in vivo. Cancer Res 53:2566–2570
Zocchi MR, Ferrero E, Toninelli E, Castellani P, Poggi A, Rugarli C (1994) Expression of N-CAM by human renal cell carcinomas correlates with growth rate and adhesive properties. Exp Cell Res 214:499–509
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lawrence, J.A., Steeg, P.S. Mechanisms of tumor invasion and metastasis. World J Urol 14, 124–130 (1996). https://doi.org/10.1007/BF00186891
Issue Date:
DOI: https://doi.org/10.1007/BF00186891