Skip to main content
SpringerLink
Log in

Molecular Pathology of Cancer Metastasis: Suggestions for Future Therapy

  • Chapter
  • First Online:
Biotargets of Cancer in Current Clinical Practice

Part of the book series: Current Clinical Pathology ((CCPATH))

Abstract

Sooner or later during the progression of most types of cancer, genetically selected cells move out from the primary tumors to invade adjacent tissues and travel to distant sites, where they may establish new colonies. These distant replicas of primary tumors represent the most advanced step in the natural history of cancer. Before they are established, several discrete biological abilities must be acquired by the cancer cell in the metastatic cascade such as loss of cell adhesion, increased motogenic properties, entry and survival in blood and lymphatic circulation, extravasation in new tissues, and finally colonization of a distant site. At a mechanicistic level, metastatization is an extremely complex process, involving changes in the physical coupling of cells to their microenvironment and activation of extracellular matrix degrading proteases. At a clinical level, metastases, rather than primary tumors, are the cause of 90% of deaths from solid tumors. To prevent these deaths, improved strategies to treat metastatic disease must be absolutely devised. In this chapter, we firstly describe how a cancer cell acquires metastatic capability and then how we can engage the metastases in battle by using the most rationale and useful approaches.

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 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 279.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
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

Abbreviations

ADAMs:

A disintegrin and metalloproteinases

ADAMTS:

ADAM with thrombospondin motifs

BMPs:

Bone morphogenetic proteins

CTCs:

Circulating tumor cells

DTCs:

Disseminated tumor cells

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

EMMPRIN:

Extracellular matrix proteinase inducer

FAK:

Focal adhesion kinase

FGF:

Fibroblast growth factor

HS:

Heparan sulfate

ICAM-1:

Intercellular adhesion molecule-1

IGF-1:

Insulin-like growth factor-1

IgSF:

Immunoglobulin gene superfamily

IL:

Interleukin

LMWHs:

Low-molecular-weight heparins

MCF-1:

Macrophage chemotactic factor-1

MEI:

Metastatic efficiency index

MMP:

Metalloproteinase

MT-MMP:

Membrane-type MMP

OPG:

Osteoprotegerin

OPN:

Osteopontin

PA:

Plasminogen activation

PAR:

Protease-activated receptor

PDGF:

Platelet-derived growth factor

PECAM-1:

Platelet endothelial cell adhesion molecule-1

PSGL-1:

P-selectin glycoprotein ligand-1

RANKL:

Receptor activator of nuclear factor κB ligand

RECK:

Reversion-inducing cysteine-rich protein with Kazal motifs

RT-PCR:

Reverse-transcriptase polymerase chain reaction techniques

SLeA:

Sialyl-Lewis(A)

SLeX:

Sialyl-Lewis(X)

TEM:

Transendothelial migration

TF:

Tissue factor

TFG:

Transforming growth factor

TFPI:

Tissue factor pathway inhibitor

TIMP:

Tissue inhibitors of metalloprotease

TNF:

Tumor necrosis factor

tPA:

Tissue-type plasminogen activator

UFH:

Unfractioned heparin

uPA:

Urokinase-type plasminogen activator

VCAM-1:

Vascular cell adhesion molecule-1

VEGF:

Vascular endothelial growth factor

vWF:

von Willebrand factor

References

  1. Dorland WAN. Dorland’s illustrated medical dictionary. 25th ed. Philadelphia: Saunders; 1974.

    Google Scholar 

  2. LeDran H. Observations in surgery. 3rd ed. London: Crowther; 1758.

    Google Scholar 

  3. Travers B. Observations on the local diseases termed malignant. Med Chir Trans. 1829;15:195–262.

    PubMed  CAS  Google Scholar 

  4. Récamier J. Recherches sur le traitement du cancer. Paris: Gabon; 1829.

    Google Scholar 

  5. Weiss L. Metastasis of cancer: a conceptual history from antiquity to the 1990s. Cancer Metastasis Rev. 2000;19(3–4):I–XI, 193–383.

    Google Scholar 

  6. Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 1989;8(2):98–101.

    PubMed  CAS  Google Scholar 

  7. Virchow R. Cellular pathology. As based upon physiological and pathological histology. Lecture XVI–Atheromatous affection of arteries. 1858. Nutr Rev. 1989;47(1):23–5.

    Article  PubMed  CAS  Google Scholar 

  8. Walshe W. The nature and treatment of cancer. London: Taylor & Walton; 1846.

    Google Scholar 

  9. Smith B, Selby P, Southgate J, Pittman K, Bradley C, Blair GE. Detection of melanoma cells in peripheral blood by means of reverse transcriptase and polymerase chain reaction. Lancet. 1991;338(8777):1227–9.

    Article  PubMed  CAS  Google Scholar 

  10. Jemal A, Ward E, Hao Y, Thun M. Trends in the leading causes of death in the United States, 1970–2002. JAMA. 2005;294(10):1255–9.

    Article  PubMed  CAS  Google Scholar 

  11. Viadana E, Bross ID, Pickren JW. An autopsy study of some routes of dissemination of cancer of the breast. Br J Cancer. 1973;27(4):336–40.

    Article  PubMed  CAS  Google Scholar 

  12. Saitoh H, Hida M, Shimbo T, Nakamura K, Yamagata J, Satoh T. Metastatic patterns of prostatic cancer. Correlation between sites and number of organs involved. Cancer. 1984;54(12):3078–84.

    Article  PubMed  CAS  Google Scholar 

  13. Henneford J, Baserga R, Wartman WB. The time of appearance of metastases after surgical removal of the primary tumor. Br J Cancer. 1962;16:599–607.

    Article  PubMed  CAS  Google Scholar 

  14. Walther H. Krebsmetastasen. Basel: Schwabe; 1948.

    Google Scholar 

  15. Marwick C. Pathologists request autopsy revival. JAMA. 1995;273(24):1889, 1891.

    Google Scholar 

  16. Burton EC, Troxclair DA, Newman 3rd WP. Autopsy diagnoses of malignant neoplasms: how often are clinical diagnoses incorrect? JAMA. 1998;280(14):1245–8.

    Article  PubMed  CAS  Google Scholar 

  17. Chan CK, Wells CK, McFarlane MJ, Feinstein AR. More lung cancer but better survival. Implications of secular trends in “necropsy surprise” rates. Chest. 1989;96(2):291–6.

    Article  PubMed  CAS  Google Scholar 

  18. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin. 2005;55(1):10–30.

    Article  PubMed  Google Scholar 

  19. Del Monte U. Does the cell number 10(9) still really fit one gram of tumor tissue? Cell Cycle. 2009;8(3):505–6.

    Article  PubMed  Google Scholar 

  20. Fidler IJ, Balch CM. The biology of cancer metastasis and implications for therapy. Curr Probl Surg. 1987;24(3):129–209.

    Article  PubMed  CAS  Google Scholar 

  21. Cass AW, Million RR, Pfaff WW. Patterns of recurrence following surgery alone for adenocarcinoma of the colon and rectum. Cancer. 1976;37(6):2861–5.

    Article  PubMed  CAS  Google Scholar 

  22. Morson BC, Vaughan EG, Bussey HJ. Pelvic recurrence after excision of rectum for carcinoma. Br Med J. 1963;2(5348):13–8.

    Article  PubMed  CAS  Google Scholar 

  23. Welch JP, Donaldson GA. The clinical correlation of an autopsy study of recurrent colorectal cancer. Ann Surg. 1979;189(4):496–502.

    Article  PubMed  CAS  Google Scholar 

  24. Weiss W, Gillick JS. The metastatic spread of bronchogenic carcinoma in relation to the interval between resection and death. Chest. 1977;71(6):725–9.

    Article  PubMed  CAS  Google Scholar 

  25. Braun S, Vogl FD, Naume B, et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med. 2005;353(8):793–802.

    Article  PubMed  CAS  Google Scholar 

  26. Kraeft SK, Sutherland R, Gravelin L, et al. Detection and analysis of cancer cells in blood and bone marrow using a rare event imaging system. Clin Cancer Res. 2000;6(2):434–42.

    PubMed  CAS  Google Scholar 

  27. Weckermann D, Muller P, Wawroschek F, Harzmann R, Riethmuller G, Schlimok G. Disseminated cytokeratin positive tumor cells in the bone marrow of patients with prostate cancer: detection and prognostic value. J Urol. 2001;166(2):699–703.

    Article  PubMed  CAS  Google Scholar 

  28. Braun S, Pantel K, Muller P, et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med. 2000;342(8):525–33.

    Article  PubMed  CAS  Google Scholar 

  29. Cox JD, Yesner RA. Causes of treatment failure and death in carcinoma of the lung. Yale J Biol Med. 1981;54(3):201–7.

    PubMed  CAS  Google Scholar 

  30. Galluzzi S, Payne PM. Bronchial carcinoma: a statistical study of 741 necropsies with special reference to the distribution of blood-borne metastases. Br J Cancer. 1955;9(4):511–27.

    Article  PubMed  CAS  Google Scholar 

  31. Ochsner A, DeBakey M. Significance of metastasis in primary carcinoma of the lungs: report of 2 cases with unusual site of metastasis. J Thorac Surg. 1942;11:357–87.

    Google Scholar 

  32. Loberg RD, Bradley DA, Tomlins SA, Chinnaiyan AM, Pienta KJ. The lethal phenotype of cancer: the molecular basis of death due to malignancy. CA Cancer J Clin. 2007;57(4):225–41.

    Article  PubMed  Google Scholar 

  33. Abrams HL, Spiro R, Goldstein N. Metastases in carcinoma; analysis of 1000 autopsied cases. Cancer. 1950;3(1):74–85.

    Article  PubMed  CAS  Google Scholar 

  34. Viadana E, Cotter R, Pickren JW, Bross ID. An autopsy study of metastatic sites of breast cancer. Cancer Res. 1973;33(1):179–81.

    PubMed  CAS  Google Scholar 

  35. Cho SY, Choi HY. Causes of death and metastatic patterns in patients with mammary cancer. Ten-year autopsy study. Am J Clin Pathol. 1980;73(2):232–4.

    PubMed  CAS  Google Scholar 

  36. Abrams MS, Lerner HJ. Survival of patients at Pennsylvania Hospital with hepatic metastases from carcinoma of the colon and rectum. Dis Colon Rectum. 1971;14(6):431–4.

    Article  PubMed  CAS  Google Scholar 

  37. Bacon H, Gilbert P. Sites of metastases from carcinoma of the anus, rectum and sigmoid colon. JAMA. 1938;111:219–21.

    Article  Google Scholar 

  38. Buirge R. Carcinoma of the large intestine; review of 416 autopsy records. Arch Surg. 1941;42:801–18.

    Article  Google Scholar 

  39. Cedermark BJ, Blumenson LE, Pickren JW, Elias EG. The significance of metastases to the adrenal gland from carcinoma of the stomach and esophagus. Surg Gynecol Obstet. 1977;145(1):41–8.

    PubMed  CAS  Google Scholar 

  40. Shah RB, Mehra R, Chinnaiyan AM, et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res. 2004;64(24):9209–16.

    Article  PubMed  CAS  Google Scholar 

  41. Bubendorf L, Schopfer A, Wagner U, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol. 2000;31(5):578–83.

    Article  PubMed  CAS  Google Scholar 

  42. Lee YT. Patterns of metastasis and natural courses of breast carcinoma. Cancer Metastasis Rev. 1985;4(2):153–72.

    Article  PubMed  CAS  Google Scholar 

  43. Viadana E, Au KL. Patterns of metastases in adenocarcinomas of man. An autopsy study of 4,728 cases. J Med. 1975;6(1):1–14.

    PubMed  CAS  Google Scholar 

  44. Viadana E, Bross ID, Pickren JW. The metastatic spread of cancers of the digestive system in man. Oncology. 1978;35(3):114–26.

    Article  PubMed  CAS  Google Scholar 

  45. Weiss L, Grundmann E, Torhorst J, et al. Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J Pathol. 1986;150(3):195–203.

    Article  PubMed  CAS  Google Scholar 

  46. Weiss L. Comments on hematogenous metastatic patterns in humans as revealed by autopsy. Clin Exp Metastasis. 1992;10(3):191–9.

    Article  PubMed  CAS  Google Scholar 

  47. Weiss L, Ward PM, Holmes JC. Liver-to-lung traffic of cancer cells. Int J Cancer. 1983;32(1):79–83.

    Article  PubMed  CAS  Google Scholar 

  48. Society AC. Cancer facts & figures 2010. Atlanta: American Cancer Society; 2010.

    Google Scholar 

  49. Higginson IJ, Costantini M. Dying with cancer, living well with advanced cancer. Eur J Cancer. 2008;44(10):1414–24.

    Article  PubMed  Google Scholar 

  50. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.

    Article  PubMed  CAS  Google Scholar 

  51. Inagaki J, Rodriguez V, Bodey GP. Proceedings: causes of death in cancer patients. Cancer. 1974;33(2):568–73.

    Article  PubMed  CAS  Google Scholar 

  52. Ambrus JL, Ambrus CM, Mink IB, Pickren JW. Causes of death in cancer patients. J Med. 1975;6(1):61–4.

    PubMed  CAS  Google Scholar 

  53. Dudgeon DJ, Lertzman M, Askew GR. Physiological changes and clinical correlations of dyspnea in cancer outpatients. J Pain Symptom Manage. 2001;21(5):373–9.

    Article  PubMed  CAS  Google Scholar 

  54. Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. Lancet Oncol. 2005;6(6):401–10.

    Article  PubMed  Google Scholar 

  55. Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005;293(6):715–22.

    Article  PubMed  CAS  Google Scholar 

  56. Tisdale MJ. Cachexia in cancer patients. Nat Rev Cancer. 2002;2(11):862–71.

    Article  PubMed  CAS  Google Scholar 

  57. Argiles JM, Alvarez B, Lopez-Soriano FJ. The metabolic basis of cancer cachexia. Med Res Rev. 1997;17(5):477–98.

    Article  PubMed  CAS  Google Scholar 

  58. Muscaritoli M, Bossola M, Aversa Z, Bellantone R, Rossi Fanelli F. Prevention and treatment of cancer cachexia: new insights into an old problem. Eur J Cancer. 2006;42(1):31–41.

    Article  PubMed  CAS  Google Scholar 

  59. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539–45.

    Article  PubMed  CAS  Google Scholar 

  60. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295(19):2275–85.

    Article  PubMed  CAS  Google Scholar 

  61. Pannu HK, Bristow RE, Montz FJ, Fishman EK. Multidetector CT of peritoneal carcinomatosis from ovarian cancer. Radiographics. 2003;23(3):687–701.

    Article  PubMed  Google Scholar 

  62. Zeidman I. Experimental studies on the spread of cancer in the lymphatic system. III. Tumor emboli in thoracic duct; the pathogenesis of Virchow’s node. Cancer Res. 1955;15(11):719–21.

    PubMed  CAS  Google Scholar 

  63. Zeidman I. Experimental studies on the spread of cancer in the lymphatic system. IV. Retrograde spread. Cancer Res. 1959;19:1114–7.

    PubMed  CAS  Google Scholar 

  64. Middleton RG, Smith Jr JA. Radical prostatectomy for stage B2 prostatic cancer. J Urol. 1982;127(4):702–3.

    PubMed  CAS  Google Scholar 

  65. Passlick B, Kubuschok B, Izbicki JR, Thetter O, Pantel K. Isolated tumor cells in bone marrow predict reduced survival in node-negative non-small cell lung cancer. Ann Thorac Surg. 1999;68(6):2053–8.

    Article  PubMed  CAS  Google Scholar 

  66. Pantel K, Cote RJ, Fodstad O. Detection and clinical importance of micrometastatic disease. J Natl Cancer Inst. 1999;91(13):1113–24.

    Article  PubMed  CAS  Google Scholar 

  67. Veronesi U, Banfi A, Salvadori B, et al. Breast conservation is the treatment of choice in small breast cancer: long-term results of a randomized trial. Eur J Cancer. 1990;26(6):668–70.

    Article  PubMed  CAS  Google Scholar 

  68. Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet. 2009;373(9658):125–36.

    Article  PubMed  CAS  Google Scholar 

  69. Halsted WS. I. The results of radical operations for the cure of carcinoma of the breast. Ann Surg. 1907;46(1):1–19.

    Article  PubMed  CAS  Google Scholar 

  70. Fisher B. Laboratory and clinical research in breast cancer–a personal adventure: the David A. Karnofsky memorial lecture. Cancer Res. 1980;40(11):3863–74.

    PubMed  CAS  Google Scholar 

  71. Kawada K, Taketo MM. Significance and mechanism of lymph node metastasis in cancer progression. Cancer Res. 2011;71(4):1214–8.

    Article  PubMed  CAS  Google Scholar 

  72. Burns FJ, Pfaff Jr J. Vascular invasion in carcinoma of the colon and rectum. Am J Surg. 1956;92(5):704–9.

    Article  PubMed  CAS  Google Scholar 

  73. Vider M, Maruyama Y, Narvaez R. Significance of the vertebral venous (Batson’s) plexus in metastatic spread in colorectal carcinoma. Cancer. 1977;40(1):67–71.

    Article  PubMed  CAS  Google Scholar 

  74. Poste G, Fidler IJ. The pathogenesis of cancer ­metastasis. Nature. 1980;283(5743):139–46.

    Article  PubMed  CAS  Google Scholar 

  75. Price JE, Aukerman SL, Fidler IJ. Evidence that the process of murine melanoma metastasis is sequential and selective and contains stochastic elements. Cancer Res. 1986;46(10):5172–8.

    PubMed  CAS  Google Scholar 

  76. Perl AK, Wilgenbus P, Dahl U, Semb H, Christofori G. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature. 1998;392(6672):190–3.

    Article  PubMed  CAS  Google Scholar 

  77. Qi J, Chen N, Wang J, Siu CH. Transendothelial migration of melanoma cells involves N-cadherin-mediated adhesion and activation of the beta-catenin signaling pathway. Mol Biol Cell. 2005;16(9):4386–97.

    Article  PubMed  CAS  Google Scholar 

  78. Hazan RB, Kang L, Whooley BP, Borgen PI. N-cadherin promotes adhesion between invasive breast cancer cells and the stroma. Cell Adhes Commun. 1997;4(6):399–411.

    Article  PubMed  CAS  Google Scholar 

  79. Tomita K, van Bokhoven A, van Leenders GJ, et al. Cadherin switching in human prostate cancer progression. Cancer Res. 2000;60(13):3650–4.

    PubMed  CAS  Google Scholar 

  80. Chu K, Cheng CJ, Ye X, et al. Cadherin-11 promotes the metastasis of prostate cancer cells to bone. Mol Cancer Res. 2008;6(8):1259–67.

    Article  PubMed  CAS  Google Scholar 

  81. Perotti A, Sessa C, Mancuso A, et al. Clinical and pharmacological phase I evaluation of Exherin (ADH-1), a selective anti-N-cadherin peptide in patients with N-cadherin-expressing solid tumours. Ann Oncol. 2009;20(4):741–5.

    Article  PubMed  CAS  Google Scholar 

  82. Butler TP, Grantham FH, Gullino PM. Bulk transfer of fluid in the interstitial compartment of mammary tumors. Cancer Res. 1975;35(11 Pt 1):3084–8.

    PubMed  CAS  Google Scholar 

  83. Roma AA, Magi-Galluzzi C, Kral MA, Jin TT, Klein EA, Zhou M. Peritumoral lymphatic invasion is associated with regional lymph node metastases in prostate adenocarcinoma. Mod Pathol. 2006;19(3):392–8.

    Article  PubMed  Google Scholar 

  84. Dadras SS, Lange-Asschenfeldt B, Velasco P, et al. Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes. Mod Pathol. 2005;18(9):1232–42.

    Article  PubMed  Google Scholar 

  85. Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med. 2005;201(7):1089–99.

    Article  PubMed  CAS  Google Scholar 

  86. Ji RC. Lymphatic endothelial cells, tumor lymphangiogenesis and metastasis: new insights into intratumoral and peritumoral lymphatics. Cancer Metastasis Rev. 2006;25(4):677–94.

    Article  PubMed  Google Scholar 

  87. Tsakraklides V, Olson P, Kersey JH, Good RA. Prognostic significance of the regional lymph node histology in cancer of the breast. Cancer. 1974;34(4):1259–67.

    Article  PubMed  CAS  Google Scholar 

  88. Pickren JW. Significance of occult metastases. A study of breast cancer. Cancer. 1961;14:1266–71.

    Article  PubMed  CAS  Google Scholar 

  89. Fidler IJ. Metastasis: quantitative analysis of distribution and fate of tumor embolilabeled with 125 I-5-iodo-2′-deoxyuridine. J Natl Cancer Inst. 1970;45(4):773–82.

    PubMed  CAS  Google Scholar 

  90. Glinsky VV. Intravascular cell-to-cell adhesive interactions and bone metastasis. Cancer Metastasis Rev. 2006;25(4):531–40.

    Article  PubMed  Google Scholar 

  91. Nieswandt B, Hafner M, Echtenacher B, Mannel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res. 1999;59(6):1295–300.

    PubMed  CAS  Google Scholar 

  92. Im JH, Fu W, Wang H, et al. Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Res. 2004;64(23):8613–9.

    Article  PubMed  CAS  Google Scholar 

  93. Glinskii OV, Huxley VH, Glinsky GV, Pienta KJ, Raz A, Glinsky VV. Mechanical entrapment is insufficient and intercellular adhesion is essential for metastatic cell arrest in distant organs. Neoplasia. 2005;7(5):522–7.

    Article  PubMed  CAS  Google Scholar 

  94. Honn KV, Tang DG. Adhesion molecules and tumor cell interaction with endothelium and subendothelial matrix. Cancer Metastasis Rev. 1992;11(3–4):353–75.

    Article  PubMed  CAS  Google Scholar 

  95. Lehr JE, Pienta KJ. Preferential adhesion of prostate cancer cells to a human bone marrow endothelial cell line. J Natl Cancer Inst. 1998;90(2):118–23.

    Article  PubMed  CAS  Google Scholar 

  96. Khatib AM, Kontogiannea M, Fallavollita L, Jamison B, Meterissian S, Brodt P. Rapid induction of cytokine and E-selectin expression in the liver in response to metastatic tumor cells. Cancer Res. 1999;59(6):1356–61.

    PubMed  CAS  Google Scholar 

  97. Vidal-Vanaclocha F, Fantuzzi G, Mendoza L, et al. IL-18 regulates IL-1beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1. Proc Natl Acad Sci USA. 2000;97(2):734–9.

    Article  PubMed  CAS  Google Scholar 

  98. Voura EB, Sandig M, Kalnins VI, Siu C. Cell shape changes and cytoskeleton reorganization during transendothelial migration of human melanoma cells. Cell Tissue Res. 1998;293(3):375–87.

    Article  PubMed  CAS  Google Scholar 

  99. Naumov GN, Wilson SM, MacDonald IC, et al. Cellular expression of green fluorescent protein, coupled with high-resolution in vivo videomicroscopy, to monitor steps in tumor metastasis. J Cell Sci. 1999;112(Pt 12):1835–42.

    PubMed  CAS  Google Scholar 

  100. Paku S, Dome B, Toth R, Timar J. Organ-specificity of the extravasation process: an ultrastructural study. Clin Exp Metastasis. 2000;18(6):481–92.

    Article  PubMed  CAS  Google Scholar 

  101. Nicolson GL. Organ specificity of tumor metastasis: role of preferential adhesion, invasion and growth of malignant cells at specific secondary sites. Cancer Metastasis Rev. 1988;7(2):143–88.

    Article  PubMed  CAS  Google Scholar 

  102. van der Bij GJ, Oosterling SJ, Bogels M, et al. Blocking alpha2 integrins on rat CC531s colon carcinoma cells prevents operation-induced augmentation of liver metastases outgrowth. Hepatology. 2008;47(2):532–43.

    PubMed  Google Scholar 

  103. Fidler IJ. Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res. 1990;50(19):6130–8.

    PubMed  CAS  Google Scholar 

  104. Campbell PJ, Yachida S, Mudie LJ, et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 2010;467(7319):1109–13.

    Article  PubMed  CAS  Google Scholar 

  105. Talmadge JE, Fidler IJ. Enhanced metastatic potential of tumor cells harvested from spontaneous metastases of heterogeneous murine tumors. J Natl Cancer Inst. 1982;69(4):975–80.

    PubMed  CAS  Google Scholar 

  106. Fidler IJ, Talmadge JE. Evidence that intravenously derived murine pulmonary melanoma metastases can originate from the expansion of a single tumor cell. Cancer Res. 1986;46(10):5167–71.

    PubMed  CAS  Google Scholar 

  107. Demicheli R. Tumour dormancy: findings and hypotheses from clinical research on breast cancer. Semin Cancer Biol. 2001;11(4):297–306.

    Article  PubMed  CAS  Google Scholar 

  108. Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer. 2007;7(11):834–46.

    Article  PubMed  CAS  Google Scholar 

  109. Bross ID, Viadana E, Pickren J. Do generalized metastases occur directly from the primary? J Chronic Dis. 1975;28(3):149–59.

    Article  PubMed  CAS  Google Scholar 

  110. Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005;438(7069):820–7.

    Article  PubMed  CAS  Google Scholar 

  111. Yan HH, Pickup M, Pang Y, et al. Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung. Cancer Res. 2010;70(15):6139–49.

    Article  PubMed  CAS  Google Scholar 

  112. Fidler IJ. Biological behavior of malignant melanoma cells correlated to their survival in vivo. Cancer Res. 1975;35(1):218–24.

    PubMed  CAS  Google Scholar 

  113. Sugarbaker ED. The organ selectivity of experimentally induced metastases in rats. Cancer. 1952;5(3):606–12.

    Article  PubMed  CAS  Google Scholar 

  114. Kinsey DL. An experimental study of preferential metastasis. Cancer. 1960;13:674–6.

    Article  PubMed  CAS  Google Scholar 

  115. Ewing J. Neoplastic diseases: a treatise on tumors. 3rd ed. Philadelphia: Saunders; 1919.

    Google Scholar 

  116. Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer. 2009;9(4):302–12.

    Article  PubMed  CAS  Google Scholar 

  117. McCarter MD, Fong Y. Metastatic liver tumors. Semin Surg Oncol. 2000;19(2):177–88.

    Article  PubMed  CAS  Google Scholar 

  118. Karrison TG, Ferguson DJ, Meier P. Dormancy of mammary carcinoma after mastectomy. J Natl Cancer Inst. 1999;91(1):80–5.

    Article  PubMed  CAS  Google Scholar 

  119. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467(7319):1114–7.

    Article  PubMed  CAS  Google Scholar 

  120. Jones S, Chen WD, Parmigiani G, et al. Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci USA. 2008;105(11):4283–8.

    Article  PubMed  CAS  Google Scholar 

  121. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194(4260):23–8.

    Article  PubMed  CAS  Google Scholar 

  122. Fidler IJ, Kripke ML. Metastasis results from preexisting variant cells within a malignant tumor. Science. 1977;197(4306):893–5.

    Article  PubMed  CAS  Google Scholar 

  123. Nicolson GL, Brunson KW, Fidler IJ. Specificity of arrest, survival, and growth of selected metastatic variant cell lines. Cancer Res. 1978;38(11 Pt 2):4105–11.

    PubMed  CAS  Google Scholar 

  124. Kozlowski JM, Hart IR, Fidler IJ, Hanna N. A human melanoma line heterogeneous with respect to metastatic capacity in athymic nude mice. J Natl Cancer Inst. 1984;72(4):913–7.

    PubMed  CAS  Google Scholar 

  125. Waghorne C, Thomas M, Lagarde A, Kerbel RS, Breitman ML. Genetic evidence for progressive selection and overgrowth of primary tumors by metastatic cell subpopulations. Cancer Res. 1988;48(21):6109–14.

    PubMed  CAS  Google Scholar 

  126. Kuukasjarvi T, Karhu R, Tanner M, et al. Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer. Cancer Res. 1997;57(8):1597–604.

    PubMed  CAS  Google Scholar 

  127. Fidler IJ. The organ microenvironment and cancer metastasis. Differentiation. 2002;70(9–10):498–505.

    Article  PubMed  Google Scholar 

  128. Cifone MA, Fidler IJ. Increasing metastatic potential is associated with increasing genetic instability of clones isolated from murine neoplasms. Proc Natl Acad Sci USA. 1981;78(11):6949–52.

    Article  PubMed  CAS  Google Scholar 

  129. Welch DR, Tomasovic SP. Implications of tumor progression on clinical oncology. Clin Exp Metastasis. 1985;3(3):151–88.

    Article  PubMed  CAS  Google Scholar 

  130. Talmadge JE, Fidler IJ. AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res. 2010;70(14):5649–69.

    Article  PubMed  CAS  Google Scholar 

  131. Kang Y, Siegel PM, Shu W, et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003;3(6):537–49.

    Article  PubMed  CAS  Google Scholar 

  132. Minn AJ, Gupta GP, Siegel PM, et al. Genes that mediate breast cancer metastasis to lung. Nature. 2005;436(7050):518–24.

    Article  PubMed  CAS  Google Scholar 

  133. Wang Y, Klijn JG, Zhang Y, et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet. 2005;365(9460):671–9.

    PubMed  CAS  Google Scholar 

  134. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA. 2003;100(14):8418–23.

    Article  PubMed  CAS  Google Scholar 

  135. van de Vijver MJ, He YD, Van’t Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347(25):1999–2009.

    Article  PubMed  Google Scholar 

  136. Suzuki M, Tarin D. Gene expression profiling of human lymph node metastases and matched primary breast carcinomas: clinical implications. Mol Oncol. 2007;1(2):172–80.

    Article  PubMed  Google Scholar 

  137. Gancberg D, Di Leo A, Cardoso F, et al. Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites. Ann Oncol. 2002;13(7):1036–43.

    Article  PubMed  CAS  Google Scholar 

  138. Hynes RO. Cell adhesion: old and new questions. Trends Cell Biol. 1999;9(12):M33–7.

    Article  PubMed  CAS  Google Scholar 

  139. Plow EF, Haas TA, Zhang L, Loftus J, Smith JW. Ligand binding to integrins. J Biol Chem. 2000;275(29):21785–8.

    Article  PubMed  CAS  Google Scholar 

  140. Komoriya A, Green LJ, Mervic M, Yamada SS, Yamada KM, Humphries MJ. The minimal essential sequence for a major cell type-specific adhesion site (CS1) within the alternatively spliced type III connecting segment domain of fibronectin is leucine-aspartic acid-valine. J Biol Chem. 1991;266(23):15075–9.

    PubMed  CAS  Google Scholar 

  141. Jin H, Varner J. Integrins: roles in cancer development and as treatment targets. Br J Cancer. 2004;90(3):561–5.

    Article  PubMed  CAS  Google Scholar 

  142. Angelucci A, Bologna M. Targeting vascular cell migration as a strategy for blocking angiogenesis: the central role of focal adhesion protein tyrosine kinase family. Curr Pharm Des. 2007;13(21):2129–45.

    Article  PubMed  CAS  Google Scholar 

  143. Schlaepfer DD, Jones KC, Hunter T. Multiple Grb2-mediated integrin-stimulated signaling pathways to ERK2/mitogen-activated protein kinase: summation of both c-Src- and focal adhesion kinase-initiated tyrosine phosphorylation events. Mol Cell Biol. 1998;18(5):2571–85.

    PubMed  CAS  Google Scholar 

  144. Luo BH, Carman CV, Springer TA. Structural basis of integrin regulation and signaling. Annu Rev Immunol. 2007;25:619–47.

    Article  PubMed  CAS  Google Scholar 

  145. Varner JA, Cheresh DA. Integrins and cancer. Curr Opin Cell Biol. 1996;8(5):724–30.

    Article  PubMed  CAS  Google Scholar 

  146. Lukashev ME, Werb Z. ECM signalling: orchestrating cell behaviour and misbehaviour. Trends Cell Biol. 1998;8(11):437–41.

    Article  PubMed  CAS  Google Scholar 

  147. Folgiero V, Bachelder RE, Bon G, Sacchi A, Falcioni R, Mercurio AM. The alpha6beta4 integrin can regulate ErbB-3 expression: implications for alpha6beta4 signaling and function. Cancer Res. 2007;67(4):1645–52.

    Article  PubMed  CAS  Google Scholar 

  148. Stewart DA, Cooper CR, Sikes RA. Changes in extracellular matrix (ECM) and ECM-associated proteins in the metastatic progression of prostate cancer. Reprod Biol Endocrinol. 2004;2:2.

    Article  PubMed  Google Scholar 

  149. Heino J, Ignotz RA, Hemler ME, Crouse C, Massague J. Regulation of cell adhesion receptors by transforming growth factor-beta. Concomitant regulation of integrins that share a common beta 1 subunit. J Biol Chem. 1989;264(1):380–8.

    PubMed  CAS  Google Scholar 

  150. Conti JA, Kendall TJ, Bateman A, et al. The desmoplastic reaction surrounding hepatic colorectal adenocarcinoma metastases aids tumor growth and survival via alphav integrin ligation. Clin Cancer Res. 2008;14(20):6405–13.

    Article  PubMed  CAS  Google Scholar 

  151. Wang J, Zhang Z, Xu K, et al. Suppression of integrin alphaupsilonbeta6 by RNA interference in colon cancer cells inhibits extracellular matrix degradation through the MAPK pathway. Int J Cancer. 2008;123(6):1311–7.

    Article  PubMed  CAS  Google Scholar 

  152. Friedlander M, Theesfeld CL, Sugita M, et al. Involvement of integrins alpha v beta 3 and alpha v beta 5 in ocular neovascular diseases. Proc Natl Acad Sci USA. 1996;93(18):9764–9.

    Article  PubMed  CAS  Google Scholar 

  153. Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 1994;264(5158):569–71.

    Article  PubMed  CAS  Google Scholar 

  154. Hong YK, Lange-Asschenfeldt B, Velasco P, et al. VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins. FASEB J. 2004;18(10):1111–3.

    PubMed  CAS  Google Scholar 

  155. Avraamides CJ, Garmy-Susini B, Varner JA. Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer. 2008;8(8):604–17.

    Article  PubMed  CAS  Google Scholar 

  156. Shannon KE, Keene JL, Settle SL, et al. Anti-metastatic properties of RGD-peptidomimetic agents S137 and S247. Clin Exp Metastasis. 2004;21(2):129–38.

    Article  PubMed  CAS  Google Scholar 

  157. Reinmuth N, Liu W, Ahmad SA, et al. Alphavbeta3 integrin antagonist S247 decreases colon cancer metastasis and angiogenesis and improves survival in mice. Cancer Res. 2003;63(9):2079–87.

    PubMed  CAS  Google Scholar 

  158. Reynolds AR, Hart IR, Watson AR, et al. Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat Med. 2009;15(4):392–400.

    Article  PubMed  CAS  Google Scholar 

  159. Reynolds AR. Potential relevance of bell-shaped and u-shaped dose-responses for the therapeutic targeting of angiogenesis in cancer. Dose Response. 2009;8(3):253–84.

    Article  CAS  Google Scholar 

  160. Moschos SJ, Sander CA, Wang W, et al. Pharmacodynamic (phase 0) study using etaracizumab in advanced melanoma. J Immunother. 2010;33(3):316–25.

    Article  PubMed  CAS  Google Scholar 

  161. Zhang D, Pier T, McNeel DG, Wilding G, Friedl A. Effects of a monoclonal anti-alphavbeta3 integrin antibody on blood vessels - a pharmacodynamic study. Invest New Drugs. 2007;25(1):49–55.

    Article  PubMed  CAS  Google Scholar 

  162. Hersey P, Sosman J, O’Day S, et al. A randomized phase 2 study of etaracizumab, a monoclonal antibody against integrin alpha(v)beta(3), + or - dacarbazine in patients with stage IV metastatic melanoma. Cancer. 2010;116(6):1526–34.

    Article  PubMed  CAS  Google Scholar 

  163. Gramoun A, Shorey S, Bashutski JD, et al. Effects of Vitaxin, a novel therapeutic in trial for metastatic bone tumors, on osteoclast functions in vitro. J Cell Biochem. 2007;102(2):341–52.

    Article  PubMed  CAS  Google Scholar 

  164. Nabors LB, Mikkelsen T, Rosenfeld SS, et al. Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol. 2007;25(13):1651–7.

    Article  PubMed  CAS  Google Scholar 

  165. Stoeltzing O, Liu W, Reinmuth N, et al. Inhibition of integrin alpha5beta1 function with a small peptide (ATN-161) plus continuous 5-FU infusion reduces colorectal liver metastases and improves survival in mice. Int J Cancer. 2003;104(4):496–503.

    Article  PubMed  CAS  Google Scholar 

  166. Khalili P, Arakelian A, Chen G, et al. A non-RGD-based integrin binding peptide (ATN-161) blocks breast cancer growth and metastasis in vivo. Mol Cancer Ther. 2006;5(9):2271–80.

    Article  PubMed  CAS  Google Scholar 

  167. Karpatkin S, Pearlstein E, Ambrogio C, Coller BS. Role of adhesive proteins in platelet tumor interaction in vitro and metastasis formation in vivo. J Clin Invest. 1988;81(4):1012–9.

    Article  PubMed  CAS  Google Scholar 

  168. Biggerstaff JP, Seth N, Amirkhosravi A, et al. Soluble fibrin augments platelet/tumor cell adherence in vitro and in vivo, and enhances experimental metastasis. Clin Exp Metastasis. 1999;17(8):723–30.

    Article  PubMed  CAS  Google Scholar 

  169. Amirkhosravi A, Amaya M, Siddiqui F, Biggerstaff JP, Meyer TV, Francis JL. Blockade of GpIIb/IIIa inhibits the release of vascular endothelial growth factor (VEGF) from tumor cell-activated platelets and experimental metastasis. Platelets. 1999;10(5):285–92.

    Article  PubMed  CAS  Google Scholar 

  170. Terraube V, Marx I, Denis CV. Role of von Willebrand factor in tumor metastasis. Thromb Res. 2007;120 Suppl 2:S64–70.

    Article  PubMed  Google Scholar 

  171. Gomes N, Legrand C, Fauvel-Lafeve F. Shear stress induced release of von Willebrand factor and thrombospondin-1 in HUVEC extracellular matrix enhances breast tumour cell adhesion. Clin Exp Metastasis. 2005;22(3):215–23.

    Article  PubMed  CAS  Google Scholar 

  172. Al-Mehdi AB, Tozawa K, Fisher AB, Shientag L, Lee A, Muschel RJ. Intravascular origin of ­metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat Med. 2000;6(1):100–2.

    Article  PubMed  CAS  Google Scholar 

  173. Glinsky VV, Glinsky GV, Glinskii OV, et al. Intravascular metastatic cancer cell homotypic aggregation at the sites of primary attachment to the endothelium. Cancer Res. 2003;63(13):3805–11.

    PubMed  CAS  Google Scholar 

  174. Rao LV, Pendurthi UR. Tissue factor-factor VIIa ­signaling. Arterioscler Thromb Vasc Biol. 2005;25(1):47–56.

    PubMed  CAS  Google Scholar 

  175. Versteeg HH, Ruf W. Emerging insights in tissue factor-dependent signaling events. Semin Thromb Hemost. 2006;32(1):24–32.

    Article  PubMed  CAS  Google Scholar 

  176. Seto S, Onodera H, Kaido T, et al. Tissue factor expression in human colorectal carcinoma: correlation with hepatic metastasis and impact on prognosis. Cancer. 2000;88(2):295–301.

    Article  PubMed  CAS  Google Scholar 

  177. Lwaleed BA, Bass PS. Tissue factor pathway inhibitor: structure, biology and involvement in disease. J Pathol. 2006;208(3):327–39.

    Article  PubMed  CAS  Google Scholar 

  178. Contrino J, Hair G, Kreutzer DL, Rickles FR. In situ detection of tissue factor in vascular endothelial cells: correlation with the malignant phenotype of human breast disease. Nat Med. 1996;2(2):209–15.

    Article  PubMed  CAS  Google Scholar 

  179. Bounameaux H. The novel anticoagulants: entering a new era. Swiss Med Wkly. 2009;139(5–6):60–4.

    PubMed  CAS  Google Scholar 

  180. Lever R, Page CP. Novel drug development opportunities for heparin. Nat Rev Drug Discov. 2002;1(2):140–8.

    Article  PubMed  CAS  Google Scholar 

  181. Niers TM, Klerk CP, DiNisio M, et al. Mechanisms of heparin induced anti-cancer activity in experimental cancer models. Crit Rev Oncol Hematol. 2007;61(3):195–207.

    Article  PubMed  CAS  Google Scholar 

  182. Smorenburg SM, Van Noorden CJ. The complex effects of heparins on cancer progression and metastasis in experimental studies. Pharmacol Rev. 2001;53(1):93–105.

    PubMed  CAS  Google Scholar 

  183. Harvey JR, Mellor P, Eldaly H, Lennard TW, Kirby JA, Ali S. Inhibition of CXCR4-mediated breast cancer metastasis: a potential role for heparinoids? Clin Cancer Res. 2007;13(5):1562–70.

    Article  PubMed  CAS  Google Scholar 

  184. Stevenson JL, Choi SH, Varki A. Differential metastasis inhibition by clinically relevant levels of heparins–correlation with selectin inhibition, not antithrombotic activity. Clin Cancer Res. 2005;11(19 Pt 1):7003–11.

    Article  PubMed  CAS  Google Scholar 

  185. Amirkhosravi A, Mousa SA, Amaya M, Francis JL. Antimetastatic effect of tinzaparin, a low-molecular-weight heparin. J Thromb Haemost. 2003;1(9):1972–6.

    Article  PubMed  CAS  Google Scholar 

  186. Bereczky B, Gilly R, Raso E, Vago A, Timar J, Tovari J. Selective antimetastatic effect of heparins in preclinical human melanoma models is based on inhibition of migration and microvascular arrest. Clin Exp Metastasis. 2005;22(1):69–76.

    Article  PubMed  CAS  Google Scholar 

  187. Hettiarachchi RJ, Smorenburg SM, Ginsberg J, Levine M, Prins MH, Buller HR. Do heparins do more than just treat thrombosis? The influence of heparins on cancer spread. Thromb Haemost. 1999;82(2):947–52.

    PubMed  CAS  Google Scholar 

  188. Kakkar AK, Levine MN, Kadziola Z, et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol. 2004;22(10):1944–8.

    Article  PubMed  CAS  Google Scholar 

  189. Schlesinger M, Simonis D, Schmitz P, Fritzsche J, Bendas G. Binding between heparin and the integrin VLA-4. Thromb Haemost. 2009;102(5):816–22.

    PubMed  CAS  Google Scholar 

  190. Borsig L, Wong R, Feramisco J, Nadeau DR, Varki NM, Varki A. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc Natl Acad Sci USA. 2001;98(6):3352–7.

    Article  PubMed  CAS  Google Scholar 

  191. Okada T, Okuno H, Mitsui Y. A novel in vitro assay system for transendothelial tumor cell invasion: significance of E-selectin and alpha 3 integrin in the transendothelial invasion by HT1080 fibrosarcoma cells. Clin Exp Metastasis. 1994;12(4):305–14.

    Article  PubMed  CAS  Google Scholar 

  192. Lafrenie RM, Gallo S, Podor TJ, Buchanan MR, Orr FW. The relative roles of vitronectin receptor, E-selectin and alpha 4 beta 1 in cancer cell adhesion to interleukin-1-treated endothelial cells. Eur J Cancer. 1994;30A(14):2151–8.

    Article  PubMed  CAS  Google Scholar 

  193. Sheski FD, Natarajan V, Pottratz ST. Tumor necrosis factor-alpha stimulates attachment of small cell lung carcinoma to endothelial cells. J Lab Clin Med. 1999;133(3):265–73.

    Article  PubMed  CAS  Google Scholar 

  194. Liang S, Slattery MJ, Dong C. Shear stress and shear rate differentially affect the multi-step process of leukocyte-facilitated melanoma adhesion. Exp Cell Res. 2005;310(2):282–92.

    Article  PubMed  CAS  Google Scholar 

  195. Khatib AM, Auguste P, Fallavollita L, et al. Characterization of the host proinflammatory response to tumor cells during the initial stages of liver metastasis. Am J Pathol. 2005;167(3):749–59.

    Article  PubMed  CAS  Google Scholar 

  196. Kansas GS. Selectins and their ligands: current concepts and controversies. Blood. 1996;88(9):3259–87.

    PubMed  CAS  Google Scholar 

  197. Mannori G, Crottet P, Cecconi O, et al. Differential colon cancer cell adhesion to E-, P-, and L-selectin: role of mucin-type glycoproteins. Cancer Res. 1995;55(19):4425–31.

    PubMed  CAS  Google Scholar 

  198. Barthel SR, Wiese GK, Cho J, et al. Alpha 1,3 fucosyltransferases are master regulators of prostate cancer cell trafficking. Proc Natl Acad Sci USA. 2009;106(46):19491–6.

    Article  PubMed  CAS  Google Scholar 

  199. Crockett-Torabi E. Selectins and mechanisms of signal transduction. J Leukoc Biol. 1998;63(1):1–14.

    PubMed  CAS  Google Scholar 

  200. Biancone L, Araki M, Araki K, Vassalli P, Stamenkovic I. Redirection of tumor metastasis by expression of E-selectin in vivo. J Exp Med. 1996;183(2):581–7.

    Article  PubMed  CAS  Google Scholar 

  201. Krause T, Turner GA. Are selectins involved in metastasis? Clin Exp Metastasis. 1999;17(3):183–92.

    Article  PubMed  CAS  Google Scholar 

  202. Borsig L, Wong R, Hynes RO, Varki NM, Varki A. Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proc Natl Acad Sci USA. 2002;99(4):2193–8.

    Article  PubMed  CAS  Google Scholar 

  203. Laubli H, Borsig L. Selectins promote tumor metastasis. Semin Cancer Biol. 2010;20(3):169–77.

    Article  PubMed  CAS  Google Scholar 

  204. Glinskii OV, Turk JR, Pienta KJ, Huxley VH, Glinsky VV. Evidence of porcine and human endothelium activation by cancer-associated carbohydrates expressed on glycoproteins and tumour cells. J Physiol. 2004;554(Pt 1):89–99.

    Article  PubMed  CAS  Google Scholar 

  205. Yu LG, Andrews N, Zhao Q, et al. Galectin-3 interaction with Thomsen-Friedenreich disaccharide on cancer-associated MUC1 causes increased cancer cell endothelial adhesion. J Biol Chem. 2007;282(1):773–81.

    Article  PubMed  CAS  Google Scholar 

  206. Kaltner H, Stierstorfer B. Animal lectins as cell adhesion molecules. Acta Anat (Basel). 1998;161(1–4):162–79.

    Article  CAS  Google Scholar 

  207. Bresalier RS, Mazurek N, Sternberg LR, et al. Metastasis of human colon cancer is altered by modifying expression of the beta-galactoside-binding protein galectin 3. Gastroenterology. 1998;115(2):287–96.

    Article  PubMed  CAS  Google Scholar 

  208. Khaldoyanidi SK, Glinsky VV, Sikora L, et al. MDA-MB-435 human breast carcinoma cell homo- and heterotypic adhesion under flow conditions is mediated in part by Thomsen-Friedenreich antigen-galectin-3 interactions. J Biol Chem. 2003;278(6):4127–34.

    Article  PubMed  CAS  Google Scholar 

  209. Kobayashi K, Matsumoto S, Morishima T, Kawabe T, Okamoto T. Cimetidine inhibits cancer cell adhesion to endothelial cells and prevents metastasis by blocking E-selectin expression. Cancer Res. 2000;60(14):3978–84.

    PubMed  CAS  Google Scholar 

  210. Hollingsworth MA, Swanson BJ. Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 2004;4(1):45–60.

    Article  PubMed  CAS  Google Scholar 

  211. Satoh M, Numahata K, Kawamura S, Saito S, Orikasa S. Lack of selectin-dependent adhesion in prostate cancer cells expressing sialyl Le(x). Int J Urol. 1998;5(1):86–91.

    Article  PubMed  CAS  Google Scholar 

  212. Ley K. The role of selectins in inflammation and ­disease. Trends Mol Med. 2003;9(6):263–8.

    Article  PubMed  CAS  Google Scholar 

  213. Fuster MM, Brown JR, Wang L, Esko JD. A disaccharide precursor of sialyl Lewis X inhibits metastatic potential of tumor cells. Cancer Res. 2003;63(11):2775–81.

    PubMed  CAS  Google Scholar 

  214. Brown JR, Fuster MM, Li R, Varki N, Glass CA, Esko JD. A disaccharide-based inhibitor of glycosylation attenuates metastatic tumor cell dissemination. Clin Cancer Res. 2006;12(9):2894–901.

    Article  PubMed  CAS  Google Scholar 

  215. Garofalo A, Chirivi RG, Foglieni C, et al. Involvement of the very late antigen 4 integrin on melanoma in interleukin 1-augmented experimental metastases. Cancer Res. 1995;55(2):414–9.

    PubMed  CAS  Google Scholar 

  216. Takahashi M, Furihata M, Akimitsu N, et al. A highly bone marrow metastatic murine breast cancer model established through in vivo selection exhibits enhanced anchorage-independent growth and cell migration mediated by ICAM-1. Clin Exp Metastasis. 2008;25(5):517–29.

    Article  PubMed  CAS  Google Scholar 

  217. Flavin T, Ivens K, Rothlein R, et al. Monoclonal antibodies against intercellular adhesion molecule 1 prolong cardiac allograft survival in cynomolgus monkeys. Transplant Proc. 1991;23(1 Pt 1):533–4.

    PubMed  CAS  Google Scholar 

  218. Haug CE, Colvin RB, Delmonico FL, et al. A phase I trial of immunosuppression with anti-ICAM-1 (CD54) mAb in renal allograft recipients. Transplantation. 1993;55(4):766–72. discussion 772–763.

    Article  PubMed  CAS  Google Scholar 

  219. del Zoppo GJ. Acute anti-inflammatory approaches to ischemic stroke. Ann NY Acad Sci. 2010;1207: 143–8.

    Article  PubMed  CAS  Google Scholar 

  220. Dunon D, Piali L, Imhof BA. To stick or not to stick: the new leukocyte homing paradigm. Curr Opin Cell Biol. 1996;8(5):714–23.

    Article  PubMed  CAS  Google Scholar 

  221. Rosenblum WI, Nelson GH, Wormley B, Werner P, Wang J, Shih CC. Role of platelet-endothelial cell adhesion molecule (PECAM) in platelet adhesion/aggregation over injured but not denuded endothelium in vivo and ex vivo. Stroke. 1996;27(4):709–11.

    Article  PubMed  CAS  Google Scholar 

  222. DeLisser H, Liu Y, Desprez PY, et al. Vascular endothelial platelet endothelial cell adhesion molecule 1 (PECAM-1) regulates advanced metastatic progression. Proc Natl Acad Sci USA. 2010;107(43):18616–21.

    Article  PubMed  CAS  Google Scholar 

  223. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000;12(2):121–7.

    Article  PubMed  CAS  Google Scholar 

  224. Bieche I, Chavey C, Andrieu C, et al. CXC chemokines located in the 4q21 region are up-regulated in breast cancer. Endocr Relat Cancer. 2007;14(4):1039–52.

    Article  PubMed  CAS  Google Scholar 

  225. Miles FL, Pruitt FL, van Golen KL, Cooper CR. Stepping out of the flow: capillary extravasation in cancer metastasis. Clin Exp Metastasis. 2008;25(4):305–24.

    Article  PubMed  CAS  Google Scholar 

  226. Marchesi F, Piemonti L, Fedele G, et al. The chemokine receptor CX3CR1 is involved in the neural tropism and malignant behavior of pancreatic ductal adenocarcinoma. Cancer Res. 2008;68(21):9060–9.

    Article  PubMed  CAS  Google Scholar 

  227. Kato M, Kitayama J, Kazama S, Nagawa H. Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma. Breast Cancer Res. 2003;5(5):R144–50.

    Article  PubMed  CAS  Google Scholar 

  228. Helbig G, Christopherson 2nd KW, Bhat-Nakshatri P, et al. NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem. 2003;278(24):21631–8.

    Article  PubMed  CAS  Google Scholar 

  229. Andre F, Cabioglu N, Assi H, et al. Expression of chemokine receptors predicts the site of metastatic relapse in patients with axillary node positive primary breast cancer. Ann Oncol. 2006;17(6):945–51.

    Article  PubMed  CAS  Google Scholar 

  230. Allinen M, Beroukhim R, Cai L, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004;6(1):17–32.

    Article  PubMed  CAS  Google Scholar 

  231. Miao Z, Luker KE, Summers BC, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci USA. 2007;104(40):15735–40.

    Article  PubMed  CAS  Google Scholar 

  232. Gunther K, Leier J, Henning G, et al. Prediction of lymph node metastasis in colorectal carcinoma by expression of chemokine receptor CCR7. Int J Cancer. 2005;116(5):726–33.

    Article  PubMed  CAS  Google Scholar 

  233. Shields JD, Fleury ME, Yong C, Tomei AA, Randolph GJ, Swartz MA. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell. 2007;11(6):526–38.

    Article  PubMed  CAS  Google Scholar 

  234. Smith MC, Luker KE, Garbow JR, et al. CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Res. 2004;64(23):8604–12.

    Article  PubMed  CAS  Google Scholar 

  235. Liang Z, Wu T, Lou H, et al. Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4. Cancer Res. 2004;64(12):4302–8.

    Article  PubMed  CAS  Google Scholar 

  236. Fricker SP, Anastassov V, Cox J, et al. Characterization of the molecular pharmacology of AMD3100: a specific antagonist of the G-protein coupled chemokine receptor, CXCR4. Biochem Pharmacol. 2006;72(5):588–96.

    Article  PubMed  CAS  Google Scholar 

  237. Takenaga M, Tamamura H, Hiramatsu K, et al. A single treatment with microcapsules containing a CXCR4 antagonist suppresses pulmonary metastasis of murine melanoma. Biochem Biophys Res Commun. 2004;320(1):226–32.

    Article  PubMed  CAS  Google Scholar 

  238. Mason SD, Joyce JA. Proteolytic networks in cancer. Trends Cell Biol. 2011;21(4):228–37.

    Article  PubMed  CAS  Google Scholar 

  239. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69(3):562–73.

    Article  PubMed  CAS  Google Scholar 

  240. Westermarck J, Kahari VM. Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J. 1999;13(8):781–92.

    PubMed  CAS  Google Scholar 

  241. Kostoulas G, Lang A, Nagase H, Baici A. Stimulation of angiogenesis through cathepsin B inactivation of the tissue inhibitors of matrix metalloproteinases. FEBS Lett. 1999;455(3):286–90.

    Article  PubMed  CAS  Google Scholar 

  242. Vincenti MP. The matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) genes. Transcriptional and posttranscriptional regulation, signal transduction and cell-type-specific expression. Methods Mol Biol. 2001;151:121–48.

    PubMed  CAS  Google Scholar 

  243. Biswas C, Zhang Y, DeCastro R, et al. The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily. Cancer Res. 1995;55(2):434–9.

    PubMed  CAS  Google Scholar 

  244. Bauer TW, Liu W, Fan F, et al. Targeting of ­urokinase plasminogen activator receptor in human pancreatic carcinoma cells inhibits c-Met- and insulin-like growth factor-I receptor-mediated migration and invasion and orthotopic tumor growth in mice. Cancer Res. 2005;65(17):7775–81.

    PubMed  CAS  Google Scholar 

  245. Reimers N, Zafrakas K, Assmann V, et al. Expression of extracellular matrix metalloproteases inducer on micrometastatic and primary mammary carcinoma cells. Clin Cancer Res. 2004;10(10):3422–8.

    Article  PubMed  CAS  Google Scholar 

  246. Sun J, Hemler ME. Regulation of MMP-1 and MMP-2 production through CD147/extracellular matrix metalloproteinase inducer interactions. Cancer Res. 2001;61(5):2276–81.

    PubMed  CAS  Google Scholar 

  247. Tang Y, Nakada MT, Kesavan P, et al. Extracellular matrix metalloproteinase inducer stimulates tumor angiogenesis by elevating vascular endothelial cell growth factor and matrix metalloproteinases. Cancer Res. 2005;65(8):3193–9.

    Article  PubMed  CAS  Google Scholar 

  248. Welgus HG, Stricklin GP. Human skin fibroblast collagenase inhibitor. Comparative studies in human connective tissues, serum, and amniotic fluid. J Biol Chem. 1983;258(20):12259–64.

    PubMed  CAS  Google Scholar 

  249. Muraguchi T, Takegami Y, Ohtsuka T, et al. RECK modulates Notch signaling during cortical neurogenesis by regulating ADAM10 activity. Nat Neurosci. 2007;10(7):838–45.

    Article  PubMed  CAS  Google Scholar 

  250. Zeng ZS, Guillem JG. Distinct pattern of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 mRNA expression in human colorectal cancer and liver metastases. Br J Cancer. 1995;72(3):575–82.

    Article  PubMed  CAS  Google Scholar 

  251. Arkona C, Wiederanders B. Expression, subcellular distribution and plasma membrane binding of cathepsin B and gelatinases in bone metastatic tissue. Biol Chem. 1996;377(11):695–702.

    PubMed  CAS  Google Scholar 

  252. Nemeth JA, Yousif R, Herzog M, et al. Matrix metalloproteinase activity, bone matrix turnover, and tumor cell proliferation in prostate cancer bone metastasis. J Natl Cancer Inst. 2002;94(1):17–25.

    Article  PubMed  CAS  Google Scholar 

  253. Yoshida S, Takahashi H. Expression of extracellular matrix molecules in brain metastasis. J Surg Oncol. 2009;100(1):65–8.

    Article  PubMed  CAS  Google Scholar 

  254. Klein A, Olendrowitz C, Schmutzler R, et al. Identification of brain- and bone-specific breast cancer metastasis genes. Cancer Lett. 2009;276(2):212–20.

    Article  PubMed  CAS  Google Scholar 

  255. Wilson TJ, Nannuru KC, Futakuchi M, Sadanandam A, Singh RK. Cathepsin G enhances mammary tumor-induced osteolysis by generating soluble receptor activator of nuclear factor-kappaB ligand. Cancer Res. 2008;68(14):5803–11.

    Article  PubMed  CAS  Google Scholar 

  256. Nannuru KC, Futakuchi M, Varney ML, Vincent TM, Marcusson EG, Singh RK. Matrix metalloproteinase (MMP)-13 regulates mammary tumor-induced osteolysis by activating MMP9 and transforming growth factor-beta signaling at the tumor-bone interface. Cancer Res. 2010;70(9):3494–504.

    Article  PubMed  CAS  Google Scholar 

  257. Fizazi K, Bosserman L, Gao G, Skacel T, Markus R. Denosumab treatment of prostate cancer with bone metastases and increased urine N-telopeptide levels after therapy with intravenous bisphosphonates: results of a randomized phase II trial. J Urol. 2009;182(2):509–15. discussion 515–506.

    Article  PubMed  CAS  Google Scholar 

  258. Musso O, Theret N, Campion JP, et al. In situ detection of matrix metalloproteinase-2 (MMP2) and the metalloproteinase inhibitor TIMP2 transcripts in human primary hepatocellular carcinoma and in liver metastasis. J Hepatol. 1997;26(3):593–605.

    Article  PubMed  CAS  Google Scholar 

  259. Itoh T, Tanioka M, Yoshida H, Yoshioka T, Nishimoto H, Itohara S. Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res. 1998;58(5):1048–51.

    PubMed  CAS  Google Scholar 

  260. Itoh T, Tanioka M, Matsuda H, et al. Experimental metastasis is suppressed in MMP-9-deficient mice. Clin Exp Metastasis. 1999;17(2):177–81.

    Article  PubMed  CAS  Google Scholar 

  261. Ohishi K, Fujita N, Morinaga Y, Tsuruo T. H-31 human breast cancer cells stimulate type I collagenase production in osteoblast-like cells and induce bone resorption. Clin Exp Metastasis. 1995;13(4):287–95.

    Article  PubMed  CAS  Google Scholar 

  262. Overall CM, Kleifeld O. Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006;6(3):227–39.

    Article  PubMed  CAS  Google Scholar 

  263. Martin MD, Matrisian LM. The other side of MMPs: protective roles in tumor progression. Cancer Metastasis Rev. 2007;26(3–4):717–24.

    Article  PubMed  CAS  Google Scholar 

  264. Morgan H, Hill PA. Human breast cancer cell-­mediated bone collagen degradation requires plasminogen activation and matrix metalloproteinase activity. Cancer Cell Inst. 2005;5(1):1.

    Article  CAS  Google Scholar 

  265. Roth D, Piekarek M, Paulsson M, et al. Plasmin modulates vascular endothelial growth factor-A-mediated angiogenesis during wound repair. Am J Pathol. 2006;168(2):670–84.

    Article  PubMed  CAS  Google Scholar 

  266. Kim MH. Flavonoids inhibit VEGF/bFGF-induced angiogenesis in vitro by inhibiting the matrix-degrading proteases. J Cell Biochem. 2003;89(3):529–38.

    Article  PubMed  CAS  Google Scholar 

  267. Dano K, Romer J, Nielsen BS, et al. Cancer invasion and tissue remodeling–cooperation of protease systems and cell types. APMIS. 1999;107(1):120–7.

    Article  PubMed  CAS  Google Scholar 

  268. Roldan AL, Cubellis MV, Masucci MT, et al. Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule in cell surface, plasmin dependent proteolysis. EMBO J. 1990;9(2):467–74.

    PubMed  CAS  Google Scholar 

  269. Mazar AP. Urokinase plasminogen activator receptor choreographs multiple ligand interactions: implications for tumor progression and therapy. Clin Cancer Res. 2008;14(18):5649–55.

    Article  PubMed  CAS  Google Scholar 

  270. Wang Y. The role and regulation of urokinase-type plasminogen activator receptor gene expression in cancer invasion and metastasis. Med Res Rev. 2001;21(2):146–70.

    Article  PubMed  Google Scholar 

  271. Suzuki S, Hayashi Y, Wang Y, et al. Urokinase type plasminogen activator receptor expression in colorectal neoplasms. Gut. 1998;43(6):798–805.

    Article  PubMed  CAS  Google Scholar 

  272. Van Buren G, Gray MJ, Dallas NA, et al. Targeting the urokinase plasminogen activator receptor with a monoclonal antibody impairs the growth of human colorectal cancer in the liver. Cancer. 2009;115(14):3360–8.

    Article  PubMed  CAS  Google Scholar 

  273. Rabbani SA, Ateeq B, Arakelian A, et al. An anti-urokinase plasminogen activator receptor antibody (ATN-658) blocks prostate cancer invasion, ­migration, growth, and experimental skeletal metastasis in vitro and in vivo. Neoplasia. 2010;12(10):778–88.

    PubMed  CAS  Google Scholar 

  274. Ossowski L, Reich E. Antibodies to plasminogen activator inhibit human tumor metastasis. Cell. 1983;35(3 Pt 2):611–9.

    Article  PubMed  CAS  Google Scholar 

  275. Margheri F, D’Alessio S, Serrati S, et al. Effects of blocking urokinase receptor signaling by antisense oligonucleotides in a mouse model of experimental prostate cancer bone metastases. Gene Ther. 2005;12(8):702–14.

    Article  PubMed  CAS  Google Scholar 

  276. Schuster V, Mingers AM, Seidenspinner S, Nussgens Z, Pukrop T, Kreth HW. Homozygous mutations in the plasminogen gene of two unrelated girls with ­ligneous conjunctivitis. Blood. 1997;90(3):958–66.

    PubMed  CAS  Google Scholar 

  277. Berkenblit A, Matulonis UA, Kroener JF, et al. A6, a urokinase plasminogen activator (uPA)-derived peptide in patients with advanced gynecologic cancer: a phase I trial. Gynecol Oncol. 2005;99(1):50–7.

    Article  PubMed  CAS  Google Scholar 

  278. Fridman JS, Caulder E, Hansbury M, et al. Selective inhibition of ADAM metalloproteases as a novel approach for modulating ErbB pathways in cancer. Clin Cancer Res. 2007;13(6):1892–902.

    Article  PubMed  CAS  Google Scholar 

  279. Kenny PA, Bissell MJ. Targeting TACE-dependent EGFR ligand shedding in breast cancer. J Clin Invest. 2007;117(2):337–45.

    Article  PubMed  CAS  Google Scholar 

  280. Mazzocca A, Coppari R, De Franco R, et al. A secreted form of ADAM9 promotes carcinoma invasion through tumor-stromal interactions. Cancer Res. 2005;65(11):4728–38.

    Article  PubMed  CAS  Google Scholar 

  281. Tortorella M, Pratta M, Liu RQ, et al. The thrombospondin motif of aggrecanase-1 (ADAMTS-4) is critical for aggrecan substrate recognition and cleavage. J Biol Chem. 2000;275(33):25791–7.

    Article  PubMed  CAS  Google Scholar 

  282. Levy GG, Nichols WC, Lian EC, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413(6855):488–94.

    Article  PubMed  CAS  Google Scholar 

  283. Murphy G. The ADAMs: signalling scissors in the tumour microenvironment. Nat Rev Cancer. 2008;8(12):929–41.

    Article  PubMed  CAS  Google Scholar 

  284. Sahin U, Weskamp G, Kelly K, et al. Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands. J Cell Biol. 2004;164(5):769–79.

    Article  PubMed  CAS  Google Scholar 

  285. Liu PC, Liu X, Li Y, et al. Identification of ADAM10 as a major source of HER2 ectodomain sheddase activity in HER2 overexpressing breast cancer cells. Cancer Biol Ther. 2006;5(6):657–64.

    Article  PubMed  CAS  Google Scholar 

  286. Cruz-Munoz W, Kim I, Khokha R. TIMP-3 deficiency in the host, but not in the tumor, enhances tumor growth and angiogenesis. Oncogene. 2006;25(4):650–5.

    Article  PubMed  CAS  Google Scholar 

  287. Gocheva V, Joyce JA. Cysteine cathepsins and the cutting edge of cancer invasion. Cell Cycle. 2007;6(1):60–4.

    Article  PubMed  CAS  Google Scholar 

  288. Joyce JA, Baruch A, Chehade K, et al. Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. Cancer Cell. 2004;5(5):443–53.

    Article  PubMed  CAS  Google Scholar 

  289. Reiser J, Adair B, Reinheckel T. Specialized roles for cysteine cathepsins in health and disease. J Clin Invest. 2010;120(10):3421–31.

    Article  PubMed  CAS  Google Scholar 

  290. Calkins CC, Sloane BF. Mammalian cysteine protease inhibitors: biochemical properties and possible roles in tumor progression. Biol Chem Hoppe Seyler. 1995;376(2):71–80.

    PubMed  CAS  Google Scholar 

  291. Hazen LG, Bleeker FE, Lauritzen B, et al. Comparative localization of cathepsin B protein and activity in colorectal cancer. J Histochem Cytochem. 2000;48(10):1421–30.

    Article  PubMed  CAS  Google Scholar 

  292. Rofstad EK, Mathiesen B, Kindem K, Galappathi K. Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice. Cancer Res. 2006;66(13):6699–707.

    Article  PubMed  CAS  Google Scholar 

  293. Navab R, Pedraza C, Fallavollita L, et al. Loss of responsiveness to IGF-I in cells with reduced ­cathepsin L expression levels. Oncogene. 2008;27(37):4973–85.

    Article  PubMed  CAS  Google Scholar 

  294. Katunuma N, Tsuge H, Nukatsuka M, Fukushima M. Structure-based development of cathepsin L inhibitors and therapeutic applications for prevention of cancer metastasis and cancer-induced osteoporosis. Adv Enzyme Regul. 2002;42:159–72.

    Article  PubMed  CAS  Google Scholar 

  295. Le Gall C, Bellahcene A, Bonnelye E, et al. A cathepsin K inhibitor reduces breast cancer induced osteolysis and skeletal tumor burden. Cancer Res. 2007;67(20):9894–902.

    Article  PubMed  CAS  Google Scholar 

  296. Jensen AB, Wynne C, Ramirez G, et al. The cathepsin K inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: results of a 4-week, double-blind, randomized, controlled trial. Clin Breast Cancer. 2010;10(6):452–8.

    Article  PubMed  CAS  Google Scholar 

  297. Bone HG, McClung MR, Roux C, et al. Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J Bone Miner Res. 2010;25(5):937–47.

    PubMed  Google Scholar 

  298. Naggi A, Casu B, Perez M, et al. Modulation of the heparanase-inhibiting activity of heparin through selective desulfation, graded N-acetylation, and glycol splitting. J Biol Chem. 2005;280(13):12103–13.

    Article  PubMed  CAS  Google Scholar 

  299. Vlodavsky I, Friedmann Y. Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis. J Clin Invest. 2001;108(3):341–7.

    PubMed  CAS  Google Scholar 

  300. Hulett MD, Freeman C, Hamdorf BJ, Baker RT, Harris MJ, Parish CR. Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis. Nat Med. 1999;5(7):803–9.

    Article  PubMed  CAS  Google Scholar 

  301. Friedmann Y, Vlodavsky I, Aingorn H, et al. Expression of heparanase in normal, dysplastic, and neoplastic human colonic mucosa and stroma. Evidence for its role in colonic tumorigenesis. Am J Pathol. 2000;157(4):1167–75.

    Article  PubMed  CAS  Google Scholar 

  302. Vlodavsky I, Friedmann Y, Elkin M, et al. Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis. Nat Med. 1999;5(7):793–802.

    Article  PubMed  CAS  Google Scholar 

  303. Parish CR, Freeman C, Brown KJ, Francis DJ, Cowden WB. Identification of sulfated ­oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity. Cancer Res. 1999;59(14):3433–41.

    PubMed  CAS  Google Scholar 

  304. Ilan N, Elkin M, Vlodavsky I. Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis. Int J Biochem Cell Biol. 2006;38(12):2018–39.

    Article  PubMed  CAS  Google Scholar 

  305. Khasraw M, Pavlakis N, McCowatt S, et al. Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer. Ann Oncol. 2010;21(6):1302–7.

    Article  PubMed  CAS  Google Scholar 

  306. Liu CJ, Lee PH, Lin DY, et al. Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase II trial for safety and optimal dosage. J Hepatol. 2009;50(5):958–68.

    Article  PubMed  CAS  Google Scholar 

  307. Long L, Nip J, Brodt P. Paracrine growth stimulation by hepatocyte-derived insulin-like growth factor-1: a regulatory mechanism for carcinoma cells metastatic to the liver. Cancer Res. 1994;54(14):3732–7.

    PubMed  CAS  Google Scholar 

  308. Aguirre Ghiso JA, Kovalski K, Ossowski L. Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. J Cell Biol. 1999;147(1):89–104.

    Article  PubMed  CAS  Google Scholar 

  309. Angelucci A, Gravina GL, Rucci N, et al. Suppression of EGF-R signaling reduces the incidence of prostate cancer metastasis in nude mice. Endocr Relat Cancer. 2006;13(1):197–210.

    Article  PubMed  CAS  Google Scholar 

  310. Heiss MM, Allgayer H, Gruetzner KU, et al. Individual development and uPA-receptor expression of disseminated tumour cells in bone marrow: a reference to early systemic disease in solid cancer. Nat Med. 1995;1(10):1035–9.

    Article  PubMed  CAS  Google Scholar 

  311. Barkan D, Green JE, Chambers AF. Extracellular matrix: a gatekeeper in the transition from dormancy to metastatic growth. Eur J Cancer. 2010;46(7):1181–8.

    Article  PubMed  CAS  Google Scholar 

  312. Hasebe T, Sasaki S, Imoto S, Mukai K, Yokose T, Ochiai A. Prognostic significance of fibrotic focus in invasive ductal carcinoma of the breast: a prospective observational study. Mod Pathol. 2002;15(5):502–16.

    Article  PubMed  Google Scholar 

  313. Fedarko NS, Jain A, Karadag A, Van Eman MR, Fisher LW. Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer. Clin Cancer Res. 2001;7(12):4060–6.

    PubMed  CAS  Google Scholar 

  314. Bellahcene A, Castronovo V, Ogbureke KU, Fisher LW, Fedarko NS. Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional proteins in cancer. Nat Rev Cancer. 2008;8(3):212–26.

    Article  PubMed  CAS  Google Scholar 

  315. Ye QH, Qin LX, Forgues M, et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 2003;9(4):416–23.

    Article  PubMed  CAS  Google Scholar 

  316. Hendrix MJ, Seftor EA, Seftor RE, Kasemeier-Kulesa J, Kulesa PM, Postovit LM. Reprogramming metastatic tumour cells with embryonic microenvironments. Nat Rev Cancer. 2007;7(4):246–55.

    Article  PubMed  CAS  Google Scholar 

  317. Stark AM, Anuszkiewicz B, Mentlein R, Yoneda T, Mehdorn HM, Held-Feindt J. Differential expression of matrix metalloproteinases in brain- and bone-seeking clones of metastatic MDA-MB-231 breast cancer cells. J Neurooncol. 2007;81(1):39–48.

    Article  PubMed  CAS  Google Scholar 

  318. Guise TA, Kozlow WM, Heras-Herzig A, Padalecki SS, Yin JJ, Chirgwin JM. Molecular mechanisms of breast cancer metastases to bone. Clin Breast Cancer. 2005;5 Suppl(2):S46–53.

    Article  PubMed  Google Scholar 

  319. Hauschka PV, Mavrakos AE, Iafrati MD, Doleman SE, Klagsbrun M. Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin-Sepharose. J Biol Chem. 1986;261(27):12665–74.

    PubMed  CAS  Google Scholar 

  320. Mastro AM, Gay CV, Welch DR, et al. Breast cancer cells induce osteoblast apoptosis: a possible contributor to bone degradation. J Cell Biochem. 2004;91(2):265–76.

    Article  PubMed  CAS  Google Scholar 

  321. Bendre MS, Gaddy-Kurten D, Mon-Foote T, et al. Expression of interleukin 8 and not parathyroid hormone-related protein by human breast cancer cells correlates with bone metastasis in vivo. Cancer Res. 2002;62(19):5571–9.

    PubMed  CAS  Google Scholar 

  322. Kundu N, Yang Q, Dorsey R, Fulton AM. Increased cyclooxygenase-2 (cox-2) expression and activity in a murine model of metastatic breast cancer. Int J Cancer. 2001;93(5):681–6.

    Article  PubMed  CAS  Google Scholar 

  323. Nakamura I, le Duong T, Rodan SB, Rodan GA. Involvement of alpha(v)beta3 integrins in osteoclast function. J Bone Miner Metab. 2007;25(6):337–44.

    Article  PubMed  CAS  Google Scholar 

  324. Zheng Y, Zhou H, Fong-Yee C, Modzelewski JR, Seibel MJ, Dunstan CR. Bone resorption increases tumour growth in a mouse model of osteosclerotic breast cancer metastasis. Clin Exp Metastasis. 2008;25(5):559–67.

    Article  PubMed  Google Scholar 

  325. Nelson JB, Hedican SP, George DJ, et al. Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med. 1995;1(9):944–9.

    Article  PubMed  CAS  Google Scholar 

  326. Carducci MA, Saad F, Abrahamsson PA, et al. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer. 2007;110(9):1959–66.

    Article  PubMed  CAS  Google Scholar 

  327. Schelman WR, Liu G, Wilding G, Morris T, Phung D, Dreicer R. A phase I study of zibotentan (ZD4054) in patients with metastatic, castrate-resistant prostate cancer. Invest New Drugs. 2011;29(1):118–25.

    Article  PubMed  CAS  Google Scholar 

  328. Maes C, Goossens S, Bartunkova S, et al. Increased skeletal VEGF enhances beta-catenin activity and results in excessively ossified bones. EMBO J. 2010;29(2):424–41.

    Article  PubMed  CAS  Google Scholar 

  329. Koeneman KS, Yeung F, Chung LW. Osteomimetic properties of prostate cancer cells: a hypothesis ­supporting the predilection of prostate cancer metastasis and growth in the bone environment. Prostate. 1999;39(4):246–61.

    Article  PubMed  CAS  Google Scholar 

  330. Angelucci A, Festuccia C, D’Andrea G, Teti A, Bologna M. Osteopontin modulates prostate carcinoma invasive capacity through RGD-dependent upregulation of plasminogen activators. Biol Chem. 2002;383(1):229–34.

    PubMed  CAS  Google Scholar 

  331. Jacob K, Webber M, Benayahu D, Kleinman HK. Osteonectin promotes prostate cancer cell migration and invasion: a possible mechanism for metastasis to bone. Cancer Res. 1999;59(17):4453–7.

    PubMed  CAS  Google Scholar 

  332. Tuck AB, Chambers AF, Allan AL. Osteopontin overexpression in breast cancer: knowledge gained and possible implications for clinical management. J Cell Biochem. 2007;102(4):859–68.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Experimental Medicine, University of L’Aquila, Via Vetoio, Coppito 2, L’Aquila, 67100, Italy

    Adriano Angelucci Ph.D. & Edoardo Alesse M.D., Ph.D.

Authors
  1. Adriano Angelucci Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edoardo Alesse M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Adriano Angelucci Ph.D. .

Editor information

Editors and Affiliations

  1. Chair of General Pathology, Department of Experimental Medicine, University of L’Aquila, Via Vetoio, Coppito-2, L'Aquila, 67100, Italy

    Mauro Bologna

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Angelucci, A., Alesse, E. (2012). Molecular Pathology of Cancer Metastasis: Suggestions for Future Therapy. In: Bologna, M. (eds) Biotargets of Cancer in Current Clinical Practice. Current Clinical Pathology. Humana Press. https://doi.org/10.1007/978-1-61779-615-9_18

Download citation

  • DOI: https://doi.org/10.1007/978-1-61779-615-9_18

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-61779-614-2

  • Online ISBN: 978-1-61779-615-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation