Skip to main content
SpringerLink
Log in

Molecular pathology of tumor metastasis III

Target array and combinatorial therapies

  • Seminar
  • Published:
Pathology Oncology Research

Abstract

Therapy of tumor progression and the metastatic disease is the biggest challenge of clinical oncology. Discovery of the diverse molecular pathways behind this complex disease outlined an approach to better treatment strategies. The development of combined cytotoxic treatment protocols has produced promising results but no breakthrough in the clinical management of metastatic disease. The multiple-specific and non-specific pathways and cellular targets of tumor progression are outlined in this review. Such an approach, individually designed for various cancer types, may have a better chance to treat or even cure cancer patients with progressive disease.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Tímár J, Csuka O, Orosz Zs, et al: Molecular pathology of tumor metastasis. I. Predictive Pathology. Pathol Oncol Res 7: 217–230, 2001.

    PubMed  Google Scholar 

  2. Tímár J, Csuka O, Orosz Zs, et al: Molecular pathology of tumor metastasis. II. Molecular staging and differential diagnosis. Pathol Oncol Res 8: 204–219, 2002.

    Article  PubMed  Google Scholar 

  3. Thierry JP: Epithelial mesenchymal transitions in tumor progression. Nature Rev Cancer 2: 442–454, 2002.

    Article  CAS  Google Scholar 

  4. Chambers AF, Groom AC, MacDonald IC: Dissemination and growth of cancer cells in metastatic sites. Nature Rev Cancer 2: 563–572, 2002.

    Article  CAS  Google Scholar 

  5. Ramaswamy S, Ross KN, Golub TR: A molecular signature of metastasis in primary tumors. Nature Genetics 33: 1–6, 2003.

    Article  CAS  Google Scholar 

  6. Fidler IJ andKripke ML: Metastasis results from pre-existing variant cells within a malignant tumor. Science 197:893–895, 1977.

    Article  PubMed  CAS  Google Scholar 

  7. Liotta A andKohn EC: The microenvironment of the tumor-host interface. Nature 411:375–379, 2001.

    Article  PubMed  CAS  Google Scholar 

  8. Braun, et al: Cytokeratin positive cells in the bone marrow and survival of patiens with stage I, II, or III breast cancer. N England J Med 329:257–263, 2000.

    Google Scholar 

  9. Hood JD andCheresh DA: Role of integrins in cell invasion and migration. Nature Rev Cancer 2: 91–100, 2002.

    Article  Google Scholar 

  10. Yamamoto Y, Tsutsumi Y, Mayumi T: Molecular design of bioconjugated cell adhesion peptide with a water-soluble polymeric modifier for enhancement of antimetastatic effect. Curr Drug Targets 3:123–130, 2002.

    Article  PubMed  CAS  Google Scholar 

  11. Buerkle MA, Pahernik SA, Sutter A, et al: Inhibition of the alpha-nu integrins with a cyclic RGD peptide impairs angiogenesis, growth and metastasis of solid tumours in vivo. Br J Cancer 86: 788–795, 2002.

    Article  PubMed  CAS  Google Scholar 

  12. Yi M andRuoslahti E: A fibronectin fragment inhibits tumor growth, angiogenesis, and metastasis. PNAS 98: 620–624, 2001.

    Article  PubMed  CAS  Google Scholar 

  13. Trikha M, De Clerck YA, Markland FS: Contortrostatin, a snake venom disintegrin, inhibits beta 1 integrin-mediated human metastatic melanoma cell adhesion and blocks experimental metastasis. Cancer Res 54: 4993–4998, 1994.

    PubMed  CAS  Google Scholar 

  14. Zhou Q, Sherwin RP, Parrish C, et al: Contortrostatin, a dimeric disintegrin from Agkistrodon contortrix inhibits breast cancer progression. Breast Cancer Res Treat 61: 249–260, 2000.

    Article  PubMed  CAS  Google Scholar 

  15. Correa MC Jr, Maria DA, Moura-da-Silva AM, et al: Inhibition of melanoma cells tumorigenicity by the snake venom toxin jararhagin. Toxicon 40: 739–748, 2002.

    Article  PubMed  CAS  Google Scholar 

  16. Ritter MR, Zhou Q, Markland FS Jr: Contortrostatin, a homodimeric disintegrin, actively disrupts focal adhesion and cytoskeletal structure and inhibits cell motility through a novel mechanism. Cell Commun Adhes 8: 71–86, 2001.

    Article  PubMed  CAS  Google Scholar 

  17. Gutheil JC, Campbell TN, Pierce PR, et al: Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3. Clin Cancer Res 30: 3056–3061, 2000.

    Google Scholar 

  18. Cohen SA, Trikha M, Mascelli MA: Potential future clinical applications for the GPIIb/IIIa antagonist, abciximab in thrombosis, vascular and oncological indications. Pathol Oncol Res 6: 163–174, 2000.

    Article  PubMed  CAS  Google Scholar 

  19. Trikha M, Zhou Z, Tímár J, et al: Multiple roles for platelet GPIIb/IIIa and αvβ3 integrins in tumor growth, angiogenesis, and metastasis. Cancer Res 62: 2824–2833, 2002.

    PubMed  CAS  Google Scholar 

  20. Chen YO, Trikha M, Gao X, et al.: Ectopic expression of platelet integrin αIIibβ3 in tumor cells from various species and histological origin. Int J Cancer 72: 642–648, 1997.

    Article  PubMed  CAS  Google Scholar 

  21. Damiano JS: Integrins ad novel drug targets for overcoming innate drug resistance. Current Cancer Drug Targets 2: 37–43, 2002.

    Article  PubMed  CAS  Google Scholar 

  22. Favoni RE, de Cupis A: The role of polypeptide growth factors in human carcinomas: New targets for a novel pharmacological approach. Pharmacol Rev 52: 179–206, 2000.

    PubMed  CAS  Google Scholar 

  23. Zugmaier G, Lippman ME, Wellstein A: Inhibition by pentosan polysulfate (PRS) of heparin-binding growth factors relased from tumor cells and blockage by PRS of tumor growth in animals. J Natl Cancer Res 84: 1716–1724, 1992.

    Article  CAS  Google Scholar 

  24. Tímár J, Döme B, Fazekas K, et al: Angiogenesis-dependent diseases and angiogenesis therapy. Pathol Oncol Res 7: 85–94, 2001.

    PubMed  Google Scholar 

  25. Baselga J: Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist 7: 2–8, 2002.

    Article  PubMed  CAS  Google Scholar 

  26. Shak S andthe Herceptin Multinational Investigator Study Group: Overview of the trastuzumab (Herceptin) anti-HER2 monoclonal antibody clinical program in HER2-overexpressing metastatic breast cancer. Semin Oncol 26: 71–77, 1999.

    PubMed  CAS  Google Scholar 

  27. Sliwkowski MX, Lofgren JA, Lewis GD, et al: Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol 26(Suppl 12): 60–70, 1999.

    PubMed  CAS  Google Scholar 

  28. Herbst RS, Hong WK: IMC-C225, an anti-epidermal growth factor receptor monoclonal antibody for treatment of head and neck cancer. Semin Oncol 29(Suppl 14): 18–30, 2002.

    Article  PubMed  CAS  Google Scholar 

  29. Huang SM, Li J, Harari PM: Molecular inhibition of angiogenesis and metastatic potential in human squamous cell carcinomas after epidermal growth factor receptor blockade. Mol Cancer Ther 1: 507–514, 2002.

    PubMed  CAS  Google Scholar 

  30. Fazekas K, Csuka O, Köves I, et al: Experimental and clinicopathologic studies on the function of the HGF receptor in human colon cancer metastasis. Clin Exp Metast 18: 639–649, 2001.

    Article  Google Scholar 

  31. Maehara N, Nagai E, Mizumoto K, et al: Gene transduction of NK4, HGF antagonist, inhibits in vitro invasion and in vivo growth of human pancreatic cancer. Clin Exp Metast 19: 417–426, 2002.

    Article  CAS  Google Scholar 

  32. Saimura M, Nagai E, Mizumoto K, et al: Tumor suppression through angiogenesis inhibition by SUIT-2 pancreatic cancer cells genetically engineered to secrete NK4. Clin Cancer Res 8: 3243–3249, 2002.

    PubMed  CAS  Google Scholar 

  33. Fazekas K, Rásó E, Zarándi M, et al.: Basic HGF-like peptides inhibit generation of liver metastases in murine and human tumor models. Anticancer Res 22:2575–2580, 2002.

    PubMed  CAS  Google Scholar 

  34. Fazekas K, Janovics A, Döme B, et al: Effect of HGF-like basic hexapeptides on angiogenesis. Microvasc Res 62: 440–444, 2001.

    Article  PubMed  CAS  Google Scholar 

  35. Webb CP, Hose CD, Koochekpour S, et al: The geldanamycins are poteint inhibitors of the hepatocyte growth factor/scatter factor-met-urokinase plasminogen activator-plasmin proteolytic network. Cancer Res 60: 342–349, 2000.

    PubMed  CAS  Google Scholar 

  36. Tímár J, Lapis K, Dudás J, et al: Proteoglycans and tumor progression: Janus-faced molecules with contradictory functions in cancer. Semin Cancer Biol 12: 173–186, 2002.

    Article  PubMed  CAS  Google Scholar 

  37. Sasisekharan R, Shriver Z, Venkataraman G, Narayanasami U: Roles of heparan-sulphate glycosaminoglycans in cancer. Nature Rev Cancer 2: 521–528, 2002.

    Article  CAS  Google Scholar 

  38. Tímár J, Tóvári J, Pogány G, et al: The antimetabolite tiazofurin (TR) inhibits glycoconjugate biosynthesis and invasiveness of tumour cells. Eur J Cancer 32A: 152–159, 1996.

    Article  PubMed  Google Scholar 

  39. Jeney A, Tímár J, Pogány G, et al: Glycosaminoglycans as novel target in antitumor therapy. Tokai J Exp Clin Med 15:167–177, 1990.

    PubMed  CAS  Google Scholar 

  40. Jeney A, Kopper L, Hidvégi E, et al: Pharmacobiochemical properties of 5-alkyl-2′ deoxyuridine on tumor growth and glycoconjugate synthesis. Int J Exp Clin Chemother 4: 32–39, 1991.

    Google Scholar 

  41. Tímár J, Diczházi Cs, Bartha I, et al: Modulation of heparansulphate/chondroitin-sulphate ratio by glycosaminoglycan biosynthesis inhibitors affects liver metastatic potential of tumor cells. Int J Cancer 62: 755–761, 1995.

    Article  PubMed  Google Scholar 

  42. Pumphrey CY, Theus AM, Li S, et al: Neoglycans, carbodiimide-modified glycosamino-glycans: A new class of anticancer agents that inhibit cancer cell proliferation and induce apoptosis. Cancer Res 62: 3722–3728, 2002.

    PubMed  CAS  Google Scholar 

  43. Guilford P: E-cadherin downregulation in cancer. Fuel on fire. Mol Med Today 5: 172–177, 1999.

    Article  PubMed  CAS  Google Scholar 

  44. Mbalaviele G, Dunstan CR, Sasaki A, et al: E-cadherin expression in human breast cancer cells suppresses the development of osteolytic metastasis in an experimental metastasis model. Cancer Res 56: 4063–4070. 1996.

    PubMed  CAS  Google Scholar 

  45. Vleminckx KL, Deman JJ, Bruyneel EA, Vandenbossche GM: Enlarged cell associated proteoglycans abolish E-cadherin functionality in invasive tumor cells, Cancer Res 54: 873–877, 1994.

    PubMed  CAS  Google Scholar 

  46. Steeg PS: Metastasis suppressors alter the signal transduction of cancer cells. Nature Rev 3: 55–63, 2003.

    Article  CAS  Google Scholar 

  47. Ranson M: ZD 1839 (Iressa): for more than just non-small cell lung cancer. Oncologist 7: 16–24, 2002.

    Article  PubMed  CAS  Google Scholar 

  48. Boyer SJ: Small molecule inhibitors of KDR (VEGFR-2) kinase: an overview of structure activity relationships. Curr Top Med Chem 2: 973–1000, 2002.

    Article  PubMed  CAS  Google Scholar 

  49. O’Dwyer ME, Druker BJ: The role of the tyrosine kinase inhibitor STI571 in the treatment of cancer. Curr Cancer Drug Targets 1:49–57, 2001.

    Article  PubMed  CAS  Google Scholar 

  50. Favoni RE, de CulpisA: The role of polypeptide growth factors in human carcinoma: New targets for a novel pharmacological approach. Pharmacol Rev 2000, 53: 179–205.

    Google Scholar 

  51. Downward J: Targeting ras signaling pathways in cancer therapy. Nature Rev Cancer 3: 11–22, 2002.

    Article  CAS  Google Scholar 

  52. Aplin AE, Howe A, Alahari SK, Juliano RL: Signal transduction and signal modulation by cell adhesion receptors: The role of integrins, cadherins, immunoglobulin-cell adhesion molecules and selectins. Pharmacol Rev 50:197–263, 1998.

    PubMed  CAS  Google Scholar 

  53. Nam JS, Ino Y, Sakamoto M, Hirohashi S: Src family kinase inhibitor PP2 restores the E-cadherin/catenin cell adhesion system in human cancer cells and reduces cancer metastasis. Clin Cancer Res 8: 2430–2430, 2002.

    PubMed  CAS  Google Scholar 

  54. Tokumura A, Majima E, Kariya Y, et al: Identification of human plasma lysophospholipase D, lysophosphatidic acidproducing enzyme, as autotaxin, a multifunctional phosphodiesterase. J Biol Chem 277: 39436–39442, 2002.

    Article  PubMed  CAS  Google Scholar 

  55. Umezu-Goto M, Kishi Y, Taira A, et al: Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J Cell Biol 158: 227–233, 2002.

    Article  PubMed  CAS  Google Scholar 

  56. Shimizu K, Tani M, Watanabe H, et al: The autocrine motility factor receptor gene encodes a novel type of seven transmembrane protein. FEBS 456: 295–300, 1999.

    Article  CAS  Google Scholar 

  57. Kohn EC, Liotta LA: Invasion and metastasis: New approaches to an old problem. Oncology 7: 47–52, 1993.

    PubMed  CAS  Google Scholar 

  58. Otto T, Lümmen G, Bex A, et al: Tumor cell motility as a novel target in cancer — experimental and clinical results. Onkologie 25: 172–177, 2002.

    Article  PubMed  CAS  Google Scholar 

  59. Murata K, Kameyama M, Fukui F, et al: Phosphodiesterase type III inhibitor, cilostazol, inhibits colon cancer cell motility. Clin Exp Metast 17: 525–530, 1999.

    Article  CAS  Google Scholar 

  60. Jansen B, Schlagbauer-Wadl H, Kahr H, et al: Novel Ras antagonist blocks human melanoma growth. Proc Natl Acad Sci USA 96: 14019–14024, 1999.

    Article  PubMed  CAS  Google Scholar 

  61. Nam JS, Ino Y, Sakamoto M, Hirohashi S: Ras farnesylation inhibitor FTI-277 restores the E-cadherin/catenin cell adhesion system in human cancer cells and reduces cancer metastasis. JPN J Cancer Res 93: 1020–1028, 2002.

    PubMed  CAS  Google Scholar 

  62. Zhang B, Prendergast GC, Fenton RG: Farnesyltransferase inhibitors reverse Ras-mediated inhibition of Fas gene expression. Cancer Res 62: 450–458, 2002.

    PubMed  CAS  Google Scholar 

  63. Davies H, Bignell GR, Cox C, et al: Mutation of the BRAF gene in human cancer. Nature 417: 949–954, 2002.

    Article  PubMed  CAS  Google Scholar 

  64. Honn KV, Tang DG, Gao X, et al: 12-lipoxygenases and 12(S)-HETE: role in cancer metastasis. Cancer Metast Rev 13: 365–396, 1994.

    Article  CAS  Google Scholar 

  65. Rásó E, Tóvári J, Tóth K, et al: Ectopic αIIbβ3 integrin signaling involves 12-lipoxygenase- and PKC-mediated serine phosphorylation events in melanoma cells. Thromb Haemost 85: 1037–1042, 2001.

    PubMed  Google Scholar 

  66. Pidgeon GP, Kandouz M, Meram A, Honn KV: Mechanisms controlling cell cycle arrest and induction of apoptosis after 12-lipoxygenase inhibition in prostate cancer cells. Cancer Res 62: 2721–2727, 2002.

    PubMed  CAS  Google Scholar 

  67. Tímár J, Rásó E, Fazakas Zs, et al: Multiple use of a signal transduction pathway in tumor cell invasion. Anticancer Res 16: 3299–3306, 1996.

    PubMed  Google Scholar 

  68. Tímár J, Tóth Sz, Tóvári J, et al: Autocrine motility factor induces cell movement through 12-lipoxygenase-dependent tyrosine phosphorylation and serine dephosphorylation events. Clin Exp Metast 17: 809–816, 1999.

    Article  Google Scholar 

  69. Tang DG, Li L, Zhu Z, et al. BMD188, a novel hydroxamic acid compound, demonstrates potent anti-prostate cancer effects in vitro and in vivo by inducing apoptosis: requirements for mitochondria, reactive oxygen species and proteases. Pathol Oncol Res 4: 179–190, 1998.

    Article  PubMed  CAS  Google Scholar 

  70. Tímár J, Rásó E, Döme B, et al: Expression, subcellular localization and putative function of platelet-type 12-lipoxygenase in human prostate cancer cell lines of different metastatic potential. Int J Cancer 87: 37–43, 2000.

    Article  PubMed  Google Scholar 

  71. Tímár J, Döme B, Fazekas K, et al: Angiogenesis-dependent diseases and angiogenesis therapy. Pathol Oncol Res 7: 85–95, 2001.

    PubMed  Google Scholar 

  72. Chen WS, Wei SJ, Liu JM, et al: Tumor invasiveness and liver metastasis of colon cancer cell correlated with cyclooxygenase-2 (COX-2) expression and inhibited by a COX-2-selective inhibitor, etodolac. Int J Cancer 91: 894–899, 2001.

    Article  PubMed  CAS  Google Scholar 

  73. Nagatsuka I, Yamada N, Shimizu S, et al: Inhibitory effect of a selective cyclooxygenase-2 inhibitor on liver metastasis of colon cancer. Int J Cancer 100: 515–519, 2002.

    Article  PubMed  CAS  Google Scholar 

  74. Bedikian AX Plager C, Stewart JR, et al: Phase II evaluation of bryostatin-1 in metastatic melanoma. Melanoma Res 11: 183–188, 2001.

    Article  PubMed  CAS  Google Scholar 

  75. Zonder JA, Shields AF, Zalupski M, et al: A phase II trial of bryostatin 1 in the treatment of metastatic colorectal cancer. Clin Cancer Res 7: 38–42, 2001.

    PubMed  CAS  Google Scholar 

  76. Gopalakrishna R, Gundimeda U: Protein kinase C as a molecular target for cancer prevention by selenocompounds. Nutr Cancer 40: 55–63, 2001.

    Article  PubMed  CAS  Google Scholar 

  77. Carafoli E: Calcium signaling: A tale for all seasons. PNAS 99: 1115–1122, 2002.

    Article  PubMed  CAS  Google Scholar 

  78. Cullen PJ, Lockeyer PJ: Integration of calcium and Ras signaling. Nat Rev Mol Cell Biol 3: 339–348, 2002.

    Article  PubMed  CAS  Google Scholar 

  79. Alessandro R, Masiero L, Liotta LA, Kohn EC: The role of calcium in the regulation of invasion and angiogenesis. In Vivo 10: 153–160, 1996.

    PubMed  CAS  Google Scholar 

  80. Onoda JM, Nelson KK, Taylor JD, Honn KV: In vivo characterization of combination antitumor chemotherapy with calcium channel blockers and cis-diaminedichloroplatinum (II). Cancer Res 49:2844–2850, 1989.

    PubMed  CAS  Google Scholar 

  81. Tímár J, Chopra H, Rong X, et al: Calcium channel blocker treatment of tumor cells induces alterations in the cytoskeleton, mobility of the integrin αIIbβ3 and tumor cell-induced platelet aggregation. J Cancer Res Clin Oncol 118: 425–434 1992.

    Article  PubMed  Google Scholar 

  82. Kohn EC, Figg WD, Sarosy GA, et al: Phase I trial of micronized formulation carboxyamidotriazole in patients with refractory solid tumors: pharmacokinetics, clinical outcome, and comparison of formulations. J Clin Oncol 15: 1985–1993, 1997.

    PubMed  CAS  Google Scholar 

  83. Wu Y, Palad AJ, Wasilenko WJ, et al: Inhibition of head and neck squamous cell carcinoma growth and invasion by the calcium influx inhibitor carboxyamido-triazole. Clin Cancer Res 3: 1915–1921, 1997.

    PubMed  CAS  Google Scholar 

  84. Kohn EC, Reed E, Sarosy GA, et al: A phase I trial of carbvoxyamido-triazole and paclitaxel for relapsed solid tumors: potential efficacy of the combination and demonstration of pharmacokinetic interaction. Clin Cancer Res 7: 1600–1609, 2001.

    PubMed  CAS  Google Scholar 

  85. Egeblad M, Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nature Rev Cancer 2: 161–172, 2002.

    Article  CAS  Google Scholar 

  86. Coussens LM, Fingleton B, Matrisian LM: Matrix metalloproteinase inhibitors and cancer: Trials and tribulations. Science 295: 2387–2392, 2002.

    Article  PubMed  CAS  Google Scholar 

  87. Jeney A, Kovalszky I, Kopper L, et al: Anticollagenase oligodeoxynucleotid (CRIC-2) modifies microinvasiveness and drug sensitivity of malignant cells. Ann Oncol 7: 72, 1996.

    Google Scholar 

  88. Ötvös L, Sági J, Sági Gy, et al: Enzymatic hydrolysis and biological activity of oligonucleotides containing 5-substitutesd pyrimidine bases. Nucleosides and Nucleotides 18: 1655–1666, 1999.

    Article  Google Scholar 

  89. Elkin M, Reich R, Nagler A, et al: Inhibition of matrix metalloproteinase-2 expression and bladder carcinoma metastasis by halofuginone. Clin Cancer Res 5: 1982–1988, 1999.

    PubMed  CAS  Google Scholar 

  90. Falardeau P, Champagne P, Poyet P, et al: Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol 28: 620–625, 2001.

    Article  PubMed  CAS  Google Scholar 

  91. Garbisa S, Biggin S, Cavallarin N, et al: Tumor invasion: molecular shears blunted by green tea. Nat Med 5: 1216, 1999.

    Article  PubMed  CAS  Google Scholar 

  92. Tímár F, Botyánszky J, Süli-Vargha H, et al: The antiproliferative action of melphalan hexapeptide with collagenase cleavable site. Cancer Chemother Pharmacol 41: 292–298, 1998.

    Article  PubMed  Google Scholar 

  93. Kos J, Werle B, Lah T, Brunner N: Cysteine proteinases and their inhibitors in extracellular fluids: markers for diagnosis and prognosis in cancer. Int J Biol Markers 15: 84–89, 2000.

    PubMed  CAS  Google Scholar 

  94. Rochefort H, Liaudet-Coopman E: Cathepsin D in cancer metastasis: a protease and a ligand. APMIS 107: 86–95, 1999.

    Article  PubMed  CAS  Google Scholar 

  95. Montaser M, Lalmanach G andMach L: CA-074, but not its methyl ester CA-074Me, is a selective inhibitor of cathepsin B within living cells. Biol Chem 383: 1305–1308, 2002.

    Article  PubMed  CAS  Google Scholar 

  96. Bromme D, Kaleta J: Thiol-dependent cathepsins: pathophysiological implication and recent advances in inhibitor design. Curr Pharm Des 8: 1639–1658, 2002.

    Article  PubMed  CAS  Google Scholar 

  97. Del Rosso M, Fibbi G, Pucci M, et al: Multiple pathways of cell invasion are regulated by multiple families of serine proteases. Clin Exp Metast 19: 193–207, 2002.

    Article  Google Scholar 

  98. Scotton CJ, Wilson JL, Scott K, et al: Multiple actions of chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Res 62: 5930–5938, 2002.

    PubMed  CAS  Google Scholar 

  99. Martin TJ: Manipulating the environment of cancer cells in bone: a novel therapeutic approach. J Clin Invest 110: 1399–1401, 2002.

    PubMed  CAS  Google Scholar 

  100. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nature Rev Cancer 2: 584–593, 2002.

    Article  CAS  Google Scholar 

  101. Guise TA, Yin JJ, Taylor SD, et al: Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest 98: 1544–1549, 1996.

    Article  PubMed  CAS  Google Scholar 

  102. Yin JJ, Selander K, Chirgwin JM, et al: TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest 103: 197–206, 1999.

    Article  PubMed  CAS  Google Scholar 

  103. Lindemann RK, Ballschmieter P, Nordheim A, Dittmer J: Transforming growth factor regulates parathyroid hormonerelated protein expression in MDA-MB-231 breast cancer cells through a novel Smad/Ets synergism. J Biol Chem 276: 46661–46670, 2001.

    Article  PubMed  CAS  Google Scholar 

  104. Henderson MA, Danks J, Moseley J, et al: Parathyroid hormone-related protein production by breast cancers, improved survival, and reduced bone metastases. J Natl Cancer Inst 93: 234–237, 2001.

    Article  PubMed  CAS  Google Scholar 

  105. Neville-Webbe HL, Holen I, Coleman RE: The anti-tumour activity of bishophonates. Cancer Treat Rev 28: 305–319, 2002.

    Article  PubMed  CAS  Google Scholar 

  106. Paterson AH: Adjuvant bisphosphonate therapy: the future. Semin Oncol 28: 81–85, 2001.

    Article  PubMed  CAS  Google Scholar 

  107. El Abdaimi KE, Dion N, Papavasiliou V, et al: The vitamin D analogue EB 1089 prevents skeletal metastasis and prolongs survival time in nude mice transplanted with human breast cancer cells. Cancr Res 60: 4412–4418, 2000.

    Google Scholar 

  108. Gallwitz WE, Guise TA, Mundy GR: Guanosine nucleotides inhibit different syndromes of PTHrP excess caused by human cancer in vivo. J Clin Invest 110: 1559–1572, 2002.

    PubMed  CAS  Google Scholar 

  109. Griepp P, et al: A single subcutaneous dose of an osteoprotegerin (OPG) construct (AMGN-0007) causes a profound and sustained decrease of bone resorption comparable to standard intravenous bisphosphonate in patient with multiple myeloma. Blood 92(Suppl. 1): A3227, 1998.

    Google Scholar 

  110. Oyajobi BO, Anderson DM, Traianedes K, et al: Therapeutic efficacy of a soluble receptor activator of nuclear factor kappaB-IgG Fc fusion protein in suppressing bone resorption and hypercalcemia in a model of humoral hypercalcemia of malignancy. Cancer Res 61: 2572–2578, 2001.

    PubMed  CAS  Google Scholar 

  111. Kakkar AK andWilliamson RCN: Antithrombotic therapy in cancer. BMJ 318: 1571–1572, 1999.

    PubMed  CAS  Google Scholar 

  112. Letai A andKuter DJ: Cancer, coagulation, and anticoagulation. Oncologist 4: 443–449, 1999.

    PubMed  CAS  Google Scholar 

  113. Loreto MF, De Martinis M, Corsi MP, et al: Coagulation and cancer: Implications for diagnosis and management. Pathol Oncol Res 6: 301–312, 2000.

    Article  PubMed  CAS  Google Scholar 

  114. Nash GF, Walsh DC, Kakkar AK: The role of the coagulation system in tumour angiogenesis. Lancet Oncol 2: 608–613, 2001.

    Article  PubMed  CAS  Google Scholar 

  115. Hejna M, Raderer M, Zielinsky ChC: Inhibition of metastases by anticoagulants J Natl Cancer Inst 91: 22–36, 1999.

    Article  PubMed  CAS  Google Scholar 

  116. Cosgrove RH, Zacharski LR, Racine E, Andersen JC: Improved cancer mortality with low-molecular weight heparin treatment: a review of the evidence. Semin Thromb Haemost 28: 79–87, 2002.

    Article  CAS  Google Scholar 

  117. von Tempelhoff GF, Harenberg J, Niemann F, et al: Effect of low molecular weight heparin (Certoparin) versus unfractionated heparin on cancer survival following breast and pelvic cancer surgery: A prospective randomized double-blind trial. Int J Oncol 16: 815–824, 2000.

    Google Scholar 

  118. Borsing L, Wong R, Feramisco J, et al: Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. PNAS 98: 3352–3357, 2001.

    Article  Google Scholar 

  119. Smorenburg SM, von Noorden CJF: The complex effects of heparins on cancer progression and metastasis in experimental studies. Pharmacol Rev 53: 93–105, 2001.

    PubMed  CAS  Google Scholar 

  120. Varki A, Varki NM: P-selectin, carcinoma metastasis and heparin: novel mechanistic connections with therapeutic implications. Braz J Med Biol Res 34: 711–717, 2001.

    Article  PubMed  CAS  Google Scholar 

  121. De Larco JE, Wuertz BRK, Manivel JC, et al: Dissemination and growth of cancer cells in metastatic sites. Nature Rev Cancer 2: 563–572, 2002.

    Article  CAS  Google Scholar 

  122. Trikha M, Nakada MT: Platelets and cancer: Implications for antiangiogenic therapy. Semin Thromb Haemost 28: 39–44, 2002.

    Article  CAS  Google Scholar 

  123. Cohen SA, Trikha M, Mascelli MA: Potential future clinical applications for the GPIIb/IIIa antagonist, abciximab in thrombosis, vascular and oncological indications. Pathol Oncol Res 6: 163–174, 2000.

    Article  PubMed  CAS  Google Scholar 

  124. Steinert BW, Tang DG, Grossi IM, et al: Studies on the role of platelet eicosanoid metabolism and integrin αIIbβ3 in tumor-cell-induced platelet aggregation. Int J Cancer 54: 92–101, 1993.

    Article  PubMed  CAS  Google Scholar 

  125. Schneider MR, Tang DG, Schirner M, Honn KV: Prostacyclin and its analogues: antimetastatic effects and mechanism of action. Cancer Metast Rev 13: 349–364, 1994.

    Article  CAS  Google Scholar 

  126. Jeney A, Lapis K, Kopper L et al: Tumor progression and prostaglandins. In: Hemostasis and Cancer (Ed: Muszbek L) CRC Press, 1987, pp.207–214.

  127. Moller P, Koretz K, Leithauser F, et al: Expression of APO-1 (CD95), a member of the NGF/TNF receptor superfamily, in normal and neoplastic colon epithelium. Int J Cancer 57: 371–377, 1994.

    Article  PubMed  CAS  Google Scholar 

  128. MullerM, Wilder S, Bannasch D, et al: p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J Exp Med 188: 2033–2045, 1998.

    Article  PubMed  CAS  Google Scholar 

  129. Lowin B, Hahne M, Mattmann C andTschopp J: Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature 370: 650–652, 1994.

    Article  PubMed  CAS  Google Scholar 

  130. Harwood FG, Kasibhatla S, Petak I, et al: Regulation of FasL by NF-kappaB and AP-1 in Fas-dependent thymineless death of human colon carcinoma cells. J Biol Chem 275: 10023–10029, 2000.

    Article  PubMed  CAS  Google Scholar 

  131. Petak I, Tillman DM andHoughton, JA: p53 dependence of Fas induction and acute apoptosis in response to 5-fluorouracil-leucovorin in human colon carcinoma cell lines. Clin Cancer Res 6: 4432–4441, 2000.

    PubMed  CAS  Google Scholar 

  132. Tillman DM, Petak I andHoughton JA: A Fas-dependent component in 5-fluorouracil/leucovorin-induced cytotoxicity in colon carcinoma cells. Clin Cancer Res 5: 425–430, 1999.

    PubMed  CAS  Google Scholar 

  133. Schwartzberg LS, Petak I, Stewart C, et al: Modulation of the Fas signaling pathway by IFN-gamma in therapy of colon cancer: phase I trial and correlative studies of IFN-gamma, 5-fluorouracil, and leucovorin. Clin Cancer Res 8: 2488–2498, 2002.

    PubMed  CAS  Google Scholar 

  134. Kettelhut IC, Fiers W, andGoldberg AL: The toxic effects of tumor necrosis factor in vivo and their prevention by cyclooxygenase inhibitors. Proc Natl Acad Sci USA 84: 4273–4277, 1987.

    Article  PubMed  CAS  Google Scholar 

  135. Ogasawara J, Watanabe-Fukunaga R, Adachi M, et al: Lethal effect of the anti-Fas antibody in mice. Nature, 364: 806–809, 1993.

    Article  PubMed  CAS  Google Scholar 

  136. Ashkenazi A, Pai RC, Fong S, et al: Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 104: 155–162, 1999.

    Article  PubMed  CAS  Google Scholar 

  137. Marsters SA, Pitti RA, Sheridan JP andAshkenazi A: Control of apoptosis signaling by Apo2 ligand. Recent Prog Horm Res 54:225–234, 1999.

    PubMed  CAS  Google Scholar 

  138. Pollack IF, Erff M andAshkenazi, A: Direct stimulation of apoptotic signaling by soluble apo2l/tumor necrosis factor-related apoptosis-inducing ligand leads to selective killing of glioma cells. Clin Cancer Res 7: 1362–1369, 2001.

    PubMed  CAS  Google Scholar 

  139. Keane MM, Ettenberg SA, Nau MM, et al: Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. Cancer Res 59: 734–741, 1999.

    PubMed  CAS  Google Scholar 

  140. Jo M, Kim TH, Seol DW, et al: Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat Med 6: 564–567, 2000

    Article  PubMed  CAS  Google Scholar 

  141. Lawrence D, Shahrokh Z, Marsters S, et al: Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med 7: 383–385, 2001.

    Article  PubMed  CAS  Google Scholar 

  142. Tai YT, Strobel T, Kufe D andCannistra SA: In vivo cytotoxicity of ovarian cancer cells through tumor-selective expression of the BAX gene. Cancer Res 59: 2121–2126, 1999.

    PubMed  CAS  Google Scholar 

  143. Teitz T, Wei T, Valentine MB, et al: Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med 6: 529–535, 2000.

    Article  PubMed  CAS  Google Scholar 

  144. Petak I, Douglas L, Tillman DM, et al: Pediatric rhabdomyosarcoma cell lines are resistant to Fas-induced apoptosis and highly sensitive to TRAIL-induced apoptosis. Clin Cancer Res 6: 4119–4127, 2000.

    PubMed  CAS  Google Scholar 

  145. Mazumder S. andAlmasan A: Is caspase-8 a neuroendocrine lung tumor suppressor? Cancer Biol Ther 1: 70–71, 2002.

    PubMed  Google Scholar 

  146. Shivapurkar N, Toyooka S, Eby MT, et al: Differential inactivation of caspase-8 in lung cancers. Cancer Biol Ther 1: 65–69, 2002.

    PubMed  CAS  Google Scholar 

  147. Fulda S, Kufer MU, Meyer E, et al: Sensitization for death receptoror drug-induced apoptosis by re-expression of cas-pase-8 through demethylation or gene transfer. Oncogene 20: 5865–5877, 2001.

    Article  PubMed  CAS  Google Scholar 

  148. Yanagisawa J, Takahashi M, Kanki H, et al: The molecular interaction of Fas and FAP-1. A tripeptide blocker of human Fas interaction with FAP-1 promotes Fas-induced apoptosis. J Biol Chem 272: 8539–8545, 1997.

    Article  PubMed  CAS  Google Scholar 

  149. Li Y, Kanki H, Hachiya T, et al: Negative regulation of Fasmediated apoptosis by FAP-1 in human cancer cells. Int J Cancer 87: 473–479, 2000.

    Article  PubMed  CAS  Google Scholar 

  150. Tschopp J, Irmler M andThome M: Inhibition of fas death signals by FLIPs. Curr Opin Immunol 10: 552–558, 1998.

    Article  PubMed  CAS  Google Scholar 

  151. Que FG, Phan VA, Phan VH, et al: Cholangiocarcinomas express Fas ligand and disable the Fas receptor. Hepatology 30: 1398–1404, 1999.

    Article  PubMed  CAS  Google Scholar 

  152. Banerjee D: Genasense (Genta Inc). Curr Opin Invest Drugs 2: 574–580, 2001.

    CAS  Google Scholar 

  153. Olie RA andZangemeister-Wittke U: Targeting tumor cell resistance to apoptosis induction with antisense oligonucleotides: progress and therapeutic potential. Drug Resist Updat 4: 9–15, 2001.

    Article  PubMed  CAS  Google Scholar 

  154. Yamamoto T andTanigawa N: The role of survivin as a new target of diagnosis and treatment in human cancer. Med Electron Microsc 34: 207–212, 2001.

    Article  PubMed  CAS  Google Scholar 

  155. Khwaja A: Akt is more than just a Bad kinase. Nature 401: 33–34, 1999.

    Article  PubMed  CAS  Google Scholar 

  156. Capdeville R, Buchdunger E, Zimmermann J, et al: Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Perspectives on the development of a molecularly targeted agent. Nat Rev Drug Discov 1: 493–502, 2002.

    Article  PubMed  CAS  Google Scholar 

  157. Fox SB, Gasparini G andHarris AL: Angiogenesis: pathological, prognostic, and growth-factor pathways and their link to tiral design and anticancer drugs. Lancer Oncol 2: 278–289, 2001

    Article  CAS  Google Scholar 

  158. Stopeck A, Sheldon M, Vahedian M, et al: Results of a phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies. Clin Cancer Res 8: 2798–1805, 2002.

    PubMed  CAS  Google Scholar 

  159. Holmgren L, Reilly MSO, Folkman J: Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1: 149–153, 1995.

    Article  PubMed  CAS  Google Scholar 

  160. Liao F, Doddy JF, Overholser J, et al: Selective targeting of angiogenic tumor vasculature by vascular endothelial-cadherin antibody inhibits tumor growth without affecting vascular permeability. Cancer Res 62: 2567–2575, 2002.

    PubMed  CAS  Google Scholar 

  161. Thorpe PE, Ran S: Tumor infarction by targeting tissue factor to tumor vasculature. Cancer J 6 (Suppl 3): S237–244, 2000.

    PubMed  Google Scholar 

  162. Weenendaal LM, Jin H, Ran S, et al: In vitro and in vivo studies of a VEGF121/rGelonin chimeric fusion toxin targeting the neovasculature of solid tumors. PNAS 99:7866–7871, 2002.

    Article  Google Scholar 

  163. Burke PA, De Nardo SJ, Miers LA, et al: Cilengitide targeting of alpha(v)beta(3) integrin receptor synergizes with radioimmunotherapy to increase efficacy and apoptosis in breast cancer xenografts. Cancer Res 62: 4263–4272, 2002.

    PubMed  CAS  Google Scholar 

  164. Schraa AJ, Kok RJ, Moorlag HE, et al: Targeting of RGD-modified proteins to tumor vasculature: pharmacokinetic and cellular distribution study. Int J Cancer 102: 469–475, 2002.

    Article  PubMed  CAS  Google Scholar 

  165. Semenza GL: HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol 13: 167–171, 2001.

    Article  PubMed  CAS  Google Scholar 

  166. Harris AL: Hypoxia — A key regulatory factor in tumour growth. Nature Rev Cancer 2: 38–47, 2001.

    Article  CAS  Google Scholar 

  167. Fyles AW, Milosevic M, Wong R, et al: Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol 48: 149–156, 1998.

    Article  PubMed  CAS  Google Scholar 

  168. Kung AL, Wang S, Klco JM, et al: Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nat Med 6: 1335–1340, 2000.

    Article  PubMed  CAS  Google Scholar 

  169. Dunst J: Hemoglobin level and anemia in radiation oncology: prognostic impact and therapeutic implications. Semin Oncol 27: 4–8, 2000.

    PubMed  CAS  Google Scholar 

  170. Girinski T, Pejovic-Lenfant MH, Bourhis J, et al: Prognostic value of hemoglobin concentrations and blood transfusions in advanced carcinoma of the cervix treated by radiation therapy: results of a retrospective study of 386 patients. Int J Radiat Oncol Biol Phys 16: 37–42, 1989.

    PubMed  CAS  Google Scholar 

  171. Grogan M, Thomas GM, Melamed I, et al: The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. Cancer 86: 1528–1536, 1999.

    Article  PubMed  CAS  Google Scholar 

  172. Obermair A, Handisurya A, Kaider A, et al: The relationship of pretreatment serum hemoglobin level to the survival of epithelial ovarian carcinoma patients. Cancer 83: 726–731, 1998.

    Article  PubMed  CAS  Google Scholar 

  173. Clark O, Adams JR, Bennett CL, Djulbegovic B: Erythropoetin, uncertainty principle and cancer related anaemia. BMC Cancer 2: 23–31, 2002.

    Article  PubMed  Google Scholar 

  174. Chews O, Koenig R, Kelleher DK, et al: Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia. Br J Cancer 78: 752–756, 1998.

    Google Scholar 

  175. Tisdale MJ: Cachexia in cancer patients. Nature Rev Cancer 2: 862–871, 2002.

    Article  CAS  Google Scholar 

  176. Cabrero A, Alegret M, Sanchez RM, et al: Down-regulation of uncoupling protein-3 and H-2 by thiazolidinediones in C2C12 myotubes. FEBS Lett 484: 37–42, 2000.

    Article  PubMed  CAS  Google Scholar 

  177. Hasselgren PO, Fischer JE: Muscle cachexia: current concepts of intracellular mechanisms and molecular regulation. Ann Surg 232: 9–17, 2001.

    Article  Google Scholar 

  178. Guttridge DC, Mayo MV, Madrid LV, et al: NF-KB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science 289: 2363–2366, 2000.

    Article  PubMed  CAS  Google Scholar 

  179. Zimmers TA, Davies MV, Koniaris LG, et al: Induction of cachexia in mice by systemically administered myostatin. Science 296: 1486–1488, 2002.

    Article  PubMed  CAS  Google Scholar 

  180. Lorite MJ, Smith HJ, Arnold JA, et al: Activation of ATP-ubiquitin-dependent proteolysis in skeletal muscle in vivo and murine myoblasts in vitro by a proteolysis-inducing factor (PIF). Br J Cancer 85: 297–302, 2001.

    Article  PubMed  CAS  Google Scholar 

  181. Wigmore SJ, Barber MD, Ross JA, et al: Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer 36: 177–184, 2000.

    Article  PubMed  CAS  Google Scholar 

  182. Smith HJ, Lorite MJ, Tisdale MJ: Effect of a cancer cachectic factor on protein synthesis/degradation in murine C2C12 myoblasts: modulation by eicosapentaenoic acid. Cancer Res 59:5507–5513, 1999.

    PubMed  CAS  Google Scholar 

  183. Tan C andWaldmann TA: Proteasome inhibitor PS-341, a potential therapeutic agent for adult T-cell leukaemia. Cancer Res 62: 1083–1086, 2002.

    PubMed  CAS  Google Scholar 

  184. Russell ST, Hirai K andTisdale MJ: Role of β-adrenergic receptors in the action of a tumour lipid mobilizing factor. Br J Cancer 86: 424–428, 2002.

    Article  PubMed  CAS  Google Scholar 

  185. Marincola FM, Jaffee EM, Hicklin DJ, et al: Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 74:181–273, 2000.

    Article  PubMed  CAS  Google Scholar 

  186. Brandau S, Böhle A: Therapy of bladder cancer with BCG: the mechanism behind a successful immunotherapy. Mod Asp Immunobiol 2:37–41, 2001.

    Google Scholar 

  187. Nathan PD, Eisen TG: The biological treatment of renal-cell carcinoma and melanoma. Lancet Oncol 3:89–96, 2002.

    Article  PubMed  CAS  Google Scholar 

  188. Rosenberg SA, Yang JC, White DE, et al: Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2. Ann Surg 228:307–319, 1998.

    Article  PubMed  CAS  Google Scholar 

  189. Panelli MC, Wang E, Phan G, et al: Gene-expression profiling of the response of peripheral blood mononuclear cells and melanoma metastases to systemic IL-2 administration. Genome Biol 3:research0035.1–0035.17.

  190. Berd D: Autologous, hapten-modified vaccine as a treatment for human cancers. Vaccine 19:2565–2570, 2001.

    Article  PubMed  CAS  Google Scholar 

  191. Soiffer R, Lynch T, Mihm M, et al: Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma. Proc Natl Acad Sci USA 95:13141–13146, 1998.

    Article  PubMed  CAS  Google Scholar 

  192. Nelson WG, Simons JW, Mikhak B, et al: Cancer cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer as vaccines for the treatment of genitourinary malignancies. Cancer Chemother Pharmacol 46(Suppl):S67-S72, 2000.

    Article  PubMed  CAS  Google Scholar 

  193. Chan AD, Morton DL: Active immunotherapy with allogeneic tumor cell vaccines: present status. Semin Oncol 25:611–622, 1998.

    PubMed  CAS  Google Scholar 

  194. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al: Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4:321–327, 1998.

    Article  PubMed  CAS  Google Scholar 

  195. Marchand M, van Baren N, Weynants P, et al: Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1. Int J Cancer 80:219–230, 1999.

    Article  PubMed  CAS  Google Scholar 

  196. Jäger E, Ringhoffer M, Altmannsberger M, et al: Immunoselection in vivo: independent loss of MHC class I and melanocyte differentiation antigen expression in metastatic melanoma. Int J Cancer 71:142–147, 1997.

    Article  PubMed  Google Scholar 

  197. Riker A, Cormier J, Panelli M, et al: Immune selection after antigen-specific immunotherapy of melanoma. Surgery 126:112–120, 1999.

    PubMed  CAS  Google Scholar 

  198. Rosenberg SA, Zhai X Yang JC, et al: Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens. J Natl Cancer Inst 90:1894–1900, 1998.

    Article  PubMed  CAS  Google Scholar 

  199. Marshall JL, Hawkins MJ, Tsang KY, et al: Phase I study in cancer patients of a replication-defective recombinant vaccine that expresses human carcinoembryonic antigen. J Clin Oncol 17:332–337, 1999.

    PubMed  CAS  Google Scholar 

  200. Nestle FO, Alijagic S, Gilliet M, et al: Vaccination of melanoma patients with peptideor tumor pulsed dendritic cells. Nat Med 4:328–332, 1998.

    Article  PubMed  CAS  Google Scholar 

  201. Thurner B, Haendle I, Röder C, et al: Vaccination with Mage-3A1 peptide-pulsed mature monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med 190:1669–1678, 1999.

    Article  PubMed  CAS  Google Scholar 

  202. Höltl L, Zelle-Rieser C, Gander H, et al: Immunotherapy of metastatic renal cell carcinoma with tumor lysate-pulsed autologous dendritic cells. Clin Cancer Res 8:3369–3376, 2002.

    PubMed  Google Scholar 

  203. Jefford M, Maraskovsky E, Cebon J, et al: The use of dendritic cells in cancer therapy. Lancet Oncol 2:343–353, 2001.

    Article  PubMed  CAS  Google Scholar 

  204. Murphy GP, Tjoa BA, Simmons SJ, et al: Infusion of dendritic cells pulsed with HLA-A2-specific prostate-specific membrane antigen peptides: a phase II prostate cancer vaccine trial involving patients with hormone-refractory metastatic disease. Prostate 38:73–78, 1999.

    Article  PubMed  CAS  Google Scholar 

  205. Kugler A, Stuhler G, Walden P, et al: Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids. Nat Med 6:332–336, 2000.

    Article  PubMed  CAS  Google Scholar 

  206. Rosenberg SA, Yannelli JR, Yang JC, et al: Treatment of patients with metastatic melanoma with autologous tumorinfiltrating lymphocytes and interleukin 2. J Natl Cancer Inst 86:1159–1166, 1994.

    Article  PubMed  CAS  Google Scholar 

  207. Figlin RA, Pierce WC, Kaboo R, et al: Treatment of metastatic renal cell carcinoma with nephrectomy, interleukin-2 and cytokine-primed or CD8+ selected tumor-infiltrating lymphocytes from primary tumor. J Urol 158:740–745, 1997.

    Article  PubMed  CAS  Google Scholar 

  208. Figlin RA, Thompson JA, Bukowski RM, et al: Multicenter, randomized, phase III trial of CD8+ tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol 17:2521–2529, 1999.

    PubMed  CAS  Google Scholar 

  209. Dudley ME, Wunderlich JR, Robbins PF, et al: Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850–854, 2002.

    Article  PubMed  CAS  Google Scholar 

  210. Yee C, Thompson JA, Byrd D, et al: Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: In vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 99:16168–16173, 2002.

    Article  PubMed  CAS  Google Scholar 

  211. Lee K-H, Wang E, Nielsen M-B, et al: Increased vaccine-specific T cell frequency after peptide-based vaccination correlates with increased susceptibility to in vitro stimulation but does not lead to tumor regression. J Immunol 163:6292–6300, 1999.

    PubMed  CAS  Google Scholar 

  212. Clay TM, Hobeika AC, Mosca PJ, et al: Assays for monitoring cellular immune responses to active immunotherapy of cancer. Clin Cancer Res 7:1127–1135, 2001.

    PubMed  CAS  Google Scholar 

  213. Keilholz U, Weber J, Finke JH, et al: Immunologic monitoring of cancer vaccine therapy: results of a workshop sponsored by the Society for Biological Therapy. J Immunother 25:97–138, 2002.

    Article  PubMed  Google Scholar 

  214. Lapis K, Tímár J, Pápay J, et al: Experimental metastasis inhibition by the pretreatment of the host. Arch Geschwulstforsch 60: 97–102, 1990.

    PubMed  CAS  Google Scholar 

  215. Gately S andKerbel R: Antiangiogenic scheduling of lower dose cancer chemotherapy. Cancer J 7: 427–436, 2001.

    PubMed  CAS  Google Scholar 

  216. Fidler IJ, Ellis LM: Chemotherapeutic drugs: more really is not better. Nat Med 6: 500–502, 2000.

    Article  PubMed  CAS  Google Scholar 

  217. Browden T, Butterfield CE, Kraling BM, et al: Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60: 1878–1886, 2000.

    Google Scholar 

  218. Gasparini G: Metronomic scheduling: the future of chemotherapy? Lancet Oncol 2: 733–740, 2001.

    Article  PubMed  CAS  Google Scholar 

  219. Sun LM, Yeh SA, Wang CJ, et al: Postoperative radiation therapy for medulloblastoma high recurrence rate in the subfrontal region. J Neurooncol 58: 77–85, 2002.

    Article  PubMed  Google Scholar 

  220. Crane CH, Macdonald KO, Vauthey JN, et al: Limitations of conventional doses of chemoradiation for unresectable biliary cancer. Int J Radiat Oncol Biol Phys 53: 969–974, 2002.

    PubMed  Google Scholar 

  221. Bhattathiri VN: Cumulative interfraction interval analysis of influence of time and interruptions on radiotherapy result in oral cancers. Int J Radiat Oncol Biol Phys 52: 1251–1256, 2002.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. National Institute of Oncology, Semmelweis University, Budapest, Hungary

    József Tímár & Andrea Ladányi

  2. 1st Institute of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary

    József Tímár, István Peták, András Jeney & László Kopper

Authors
  1. József Tímár
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrea Ladányi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. István Peták
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. András Jeney
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. László Kopper
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to József Tímár.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tímár, J., Ladányi, A., Peták, I. et al. Molecular pathology of tumor metastasis III. Pathol. Oncol. Res. 9, 49–72 (2003). https://doi.org/10.1007/BF03033715

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03033715

Keywords

Search

Navigation