Vasculogenic mimicry and tumour-cell plasticity: Lessons from melanoma

Nature Reviews Cancer

Volumn 3, Issue 6, 2003, Pages 411-421

  Hendrix, Mary J C ^a   Seftor, Elisabeth A ^a   Hess, Angela R ^a   Seftor, Richard E B ^a  

^a UNIVERSITY OF IOWA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVATED LEUKOCYTE CELL ADHESION MOLECULE; CADHERIN; CD34 ANTIGEN; CELL ADHESION MOLECULE; COLLAGEN TYPE 4; ENDOGLIN; ENDOTHELIAL LEUKOCYTE ADHESION MOLECULE 1; FIBRILLIN; FIBRONECTIN; HYPOXIA INDUCIBLE FACTOR 1; KALININ; MELAN A; MEMBRANE METALLOENDOPEPTIDASE; MONOPHENOL MONOOXYGENASE; NEUROPILIN; NOTCH RECEPTOR; NUCLEOTIDASE; PLASMINOGEN ACTIVATOR INHIBITOR 1; TISSUE FACTOR PATHWAY INHIBITOR; TRANSCRIPTION FACTOR; TYROSINE KINASE RECEPTOR; VASCULOTROPIN C;

ANGIOGENESIS; CELL DIFFERENTIATION; ENDOTHELIUM CELL; EXTRACELLULAR MATRIX; GENE EXPRESSION REGULATION; HEMATOPOIETIC CELL; HUMAN; HUMAN CELL; MELANOMA; MOLECULAR MIMICRY; NEOVASCULARIZATION (PATHOLOGY); PHENOTYPE; PLASTICITY; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; STEM CELL; TUMOR CELL; UVEA MELANOMA; ANIMAL; PATHOLOGY; SKIN TUMOR; UVEA TUMOR; VASCULAR ENDOTHELIUM; VASCULARIZATION;

ANIMALS; ENDOTHELIUM, VASCULAR; HUMANS; MELANOMA; NEOVASCULARIZATION, PATHOLOGIC; SKIN NEOPLASMS; UVEAL NEOPLASMS;

EID: 0038143145     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc1092     Document Type: Review

References (119)

1. Bittner, M. et al. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature 406, 536-540 (2000). This study reports the discovery of previously unrecognized subtypes of cutaneous melanoma, identified by mathematical analysis of differential gene-expression profiles.
2. Seftor, E. A. et al. Molecular determinants of human uveal melanoma invasion and metastasis. Clin. Exp. Metastasis 19, 233-246 (2002).
3. Seftor, E. A. et al. Expression of multiple molecular phenotypes by aggressive melanoma tumor cells: role in vasculogenic mimicry. Crit. Rev. Oncol. Hematol. 44, 17-27 (2002).
4. Risau, W. Mechanisms of angiogenesis. Nature 386, 671-674 (1997).
5. Carmeliet, P. Mechanisms of angiogenesis and arteriogenesis. Nature Med. 6, 389-395 (2000).
6. Assembly of the Vasculature and Its Regulation (ed. Tomanek, R. J.) (Birkhauser, Boston, 2002).
7. Folkman, J. Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N. Engl. J. Med. 333, 1757-1763 (1995). This paper describes the rationale and promise of targeting angiogenesis as a strategy for inhibiting tumour growth.
8. Rak, J. & Kerbel, R. S. Treating cancer by inhibiting angiogenesis: new hopes and potential pitfalls. Cancer Metastasis Rev. 15, 231-236 (1996).
9. Kumar, R. & Fidler, I. J. Angiogenic molecules and cancer metastasis. In Vivo 12, 27-34 (1998).
10. Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249-257 (2000). An excellent review of pathological angiogenesis in cancer and various ischaemic and inflammatory diseases.
11. Gullino, P. M. Angiogenesis and oncogenesis. J. Natl Cancer Inst. 61, 639-643 (1978).
12. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57-70 (2000).
13. Bouck, N., Stellmach, V. & Hsu, S. C. How tumors become angiogenic. Adv. Cancer Res. 69, 135-174 (1996).
14. Kerbel, R. S. Tumor angiogenesis: past, present and the near future. Carcinogenesis 21, 505-515 (2000).
15. Maniotis, A. J. et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am. J. Pathol. 155, 739-752 (1999). The first paper to report the concept of vasculogenic mimicry by aggressive human melanoma cells.
16. Folberg, R., Hendrix, M. J. C. & Maniotis, A. J. Vasculogenic mimicry and tumor angiogenesis. Am. J. Pathol. 156, 361-381 (2000).
17. Folberg, R. et al. The prognostic value of tumor blood vessel morphology in primary uveal melanoma. Ophthalmology 100, 1389-1398 (1993).
18. Makitie, T., Summanen, P., Tarkkanen, A. & Kivela, T. Microvascular loops and networks as prognostic indicators in choroidal and ciliary body melanomas. J. Natl Cancer Inst. 91, 359-367 (1999).
19. Sakamoto, T. et al. Histologic findings and prognosis of uveal malignant melanoma in Japanese patients. Am. J. Ophthalmol. 121, 276-283 (1996).
20. Seregard, S., Spangberg, B., Juul, C. & Oskarsson, M. Prognostic accuracy of the mean of the largest nuclecli, vascular patterns, and PC-10 in posterior uveal melanoma. Ophthalmology 105, 485-491 (1998).
21. Thies, A., Mangold, U., Moll, I. & Schumacher, U. PAS-positive loops and networks as a prognostic indicator in cutaneous malignant melanoma. J. Pathol. 195, 537-542 (2001).
22. Warso, M. A. et al. Prognostic significance of periodic acid-Schiff-positive patterns in primary cutaneous melanoma. Clin. Cancer Res. 7, 473-477 (2001).
23. Rummelt, V. et al. Microcirculation architecture of metastases from primary ciliary body and choroidal melanomas. Am. J. Ophthalmol. 126, 303-305 (1998).
24. Shirakawa, K. et al. Hemodynamics in vasculogenic mimicry and angiogenesis of inflammatory breast cancer xenograft. Cancer Res. 62, 560-566 (2002). This study reports a haemodynamic connection between vasculogenic mimicry in inflammatory breast cancer and angiogenesis.
25. Garber, K. Angiogenesis inhibitors suffer new setback. Nature Biotech. 20, 1067-1068 (2002).
26. van der Schaft, D. W. J. et al. The differential effects of angiogenesis inhibitors on vascular network formation by endothelial cells versus aggressive melanoma tumor cells. Proc. Am. Assoc. Cancer Res. 44, 696A (2003).
27. McDonald, D. M., Munn, L. & Jain, R. K. Vasculogenic mimicry: how convincing, how novel, and how significant? Am. J. Pathol. 156, 383-388 (2000).
28. Hess, A. R. et al. Molecular regulation of tumor cell vasculogenic mimicry by tyrosine phosphorylation: role of epithelial cell kinase (Eck/EphA2). Cancer Res. 61, 3250-3255 (2001).
29. Ramalho-Santos, M. et al. 'Stemness': transcriptional profiling of embryonic and adult stem cells. Science 298, 597-600 (2002).
30. Tachibana, M. et al. Ectopic expression of MITF, a gene for Waardenburg syndrome type 2, converts fibroblasts to cells with melanocytes characteristics. Nature Genet. 14, 50-54 (1996).
31. Hendrix, M. J. C. et al. Expression and functional significance of VE-cadherin in aggressive human melanoma cells: role in vasculogenic mimicry. Proc. Natl Acad. Sci. USA 98, 8018-8023 (2001). This study provides direct evidence for the importance of vascular endothelial (VE)-cadherin expression by aggressive melanoma cells involved in vasculogenic mimicry.
32. Seftor, R. E. B. et al. Cooperative interactions of laminin 5 γ2 chain, matrix metalloproteinase-2, and membrane type-1-matrix/metallopreteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma. Cancer Res. 61, 6322-6327 (2001).
33. Hynes, R. O., Bader, B. L. & Hodivala-Diike, K. Integrins in vascular development. Braz. J. Med. Biol. Res. 32, 501-510 (1999).
34. Hynes, R. O. Specificity of cell adhesion in development: the cadherin superfamily. Curr. Opin. Genet. Dev. 2, 621-624 (1992).
35. Kemler, R. Classical cadherins. Semin. Cell Biol. 3, 149-155 (1992).
36. Lampugnani, M. G. A novel endothelial-specific membrane protein is a marker of cell-cell contacts. J. Cell Biol. 118, 1511-1522 (1992).
37. Gumbiner, B. M. Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell 4, 345-357 (1996).
38. Pasquale, E. B. The Eph family of receptors. Curr. Opin. Cell Biol. 9, 608-615 (1997).
39. Rosenburg, I. M., Goke, M., Kanai, M., Reinecker, H. C. & Podolsky, D. K. Epithelial cell kinase-B-61: an autocrine loop modulating intestinal epithelial migration and barrier function. Am. J. Physiol. 273, G824-G832 (1997).
40. Straume, O. & Akslen, L. A. Importance of vascular phenotype by basic fibroblast growth factor, and influence of the angiogenic factors basic fibroblast growth factor/fibroblast growth factor receptor-1 and Ephnn-A1/EphA2 on melanoma progression. Am. J. Pathol. 160, 1009-1019 (2001).
41. Easty, D. J. et al. Up-regulation of ephrin-A1 during melanoma progression. Int. J. Cancer 84, 494-501 (1999).
42. Malinda, K. M. & Kleinman, H. K. The laminins. Int. J. Biochem. Cell Biol. 28, 957-959 (1996).
43. Colognato, H. & Yurchenco, P. D. Form and function: the laminin family of heterotrimers. Dev. Dynamics 218, 213-234 (2000).
44. Malinda, K. M. et al. Identification of laminin α1 and β1 chain peptides active for endothelial cell adhesion, tube formation, and aortic sprouting. FASEB J. 13, 53-62 (1999).
45. Koshikawa, N., Giannelli, G., Cirulli, V., Miyazaki, K. & Quaranta, V. Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5. J. Cell Biol. 148, 615-624 (2000).
46. Giannelli, G., Falk-Marzillier, J., Schiraldi, O., Stetler-Stevenson, W. G. & Quaranta, V. Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science 277, 225-228 (1997).
47. Seftor R. E. B., Seftor, E. A., Kirschmann, D. A. & Hendrix, M. J. C. Targeting the tumor microenvironment with chemically modified tetracyclines: inhibition of laminin 5 γ2 chain promigratory fragments and vasculogenic mimicry. Mol. Cancer Ther. 1, 1173-1179 (2002). This article shows the effectiveness of inhibiting the formation of pro-migratory signals in the tumour microenvironment, which results in the abrogation of melanoma vasculogenic mimicry.
48. Korpelainen, E. I. & Alitalo, K. Signaling angiogenesis and lymphangiogenesis. Curr. Opin. Cell Biol. 10, 159-164 (1998).
49. Yancopoulos, G. D. et al. Vascular-specific growth factors and blood vessel formation. Nature 407, 242-248 (2000).
50. Hess, A. R., Seftor E. A., Seftor, R. E. B. & Hendrix, M. J. C. Phosphoinositide 3-kinase acts downstream of EphA2 to regulate the membrane-type 1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase-2 (MMP-2) promoting vasculogenic mimicry in vitro. Mol. Biol. Cell 13, 210A (2002).
51. Annual Review of Cell and Developmental Biology (eds Schekman, R., Goldstein, L., McKnight, S. L. & Rossant, J.) (Annual Reviews, Palo Alto, California, 2001).
52. Shubik, P. & Warren, B. A. Additional literature on 'vasculogenic mimicry' not cited. Am. J. Pathol. 156, 736 (2000).
53. Warren, B. A. & Shubik, P. The growth of the blood supply to melanoma transplants in the hamster cheek pouch. Lab. Invest, 15, 464-478 (1966).
54. Tímár, J. & Tóth, J. Tumor sinuses - vascular channels. Pathol. Oncol. Res. 6, 83-86 (2000).
55. Hashizuma, H. et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156, 1363-1380 (2000).
56. Mueller, A. J. et al. An orthotopic model for human uveal melanoma in SCID mice. Microvasc. Res. 64, 207-213 (2002).
57. Clarij, R., Otte-Holler, I., Ruiter, D. J. & de Waal, R. M. W. Presence of a fluid-conducting meshwork in xenografted cutaneous and primary human uveal melanoma. Invest. Ophthalmol. Vis. Sci. 43, 912-918 (2002). The first report of an extracellular-matrix, fluid-conducting meshwork in xenografts of human cutaneous and uveal melanoma.
58. Maniotis, A. J. et al. Control of melanoma morphogenesis, endothelial survival, and perfusion by extracellular matrix. Lab. Invest 82, 1031-1043 (2002). This study provides evidence of plasma in the laminin-positive, fluid-conducting meshwork in aggressive melanoma, which indicates the presence of an extracellular-matrix conducting system.
59. Potgens, A. J. G. van Altena, M. C., Lubsen, N. H., Ruiter, D. J. & de Waal, R. M. W. Analysis of the tumor vasculature and metastatic behavior of xenografts of human melanoma cell lines transfected with vascular permeability factor. Am. J. Pathol. 148, 1203-1217 (1996).
60. Chang, Y. S. et al. Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc. Natl Acad. Sci. USA 97, 14608-14613 (2000).
61. Döme, B., Paku, S., Somlai, B. & Tímár J. Vascularization of cutaneous melanoma involves vessel co-option and has clinical significance. J. Pathol. 197, 355-362 (2002).
62. Hendrix, M. J. C. et al. The plasticity of aggressive melanoma tumor cells: recapitulation of an embryonic stem cell program. Rec. Adv. Res. Updates 3, 191-200 (2002).
63. + stem cells from bone-marrow microenvironment. Nature Med. 8, 841-849 (2002).
64. Clarijs, R., Schalkwijk, L., Ruiter, D. J. & de Waal, R. M. W. Lack of lymphangiogenesis despite coexpression of VEGF-C and its receptor Flt-4 in uveal melanoma. Invest. Ophthalmol. Vis. Sci. 42, 1422-1428 (2001).
65. Witte, M. H., Bernas, M. J., Martin, C. P. & Witte, C. L. Lymphangiogenesis and lymphangiodysplasia: from molecular to clinical lymphology. Microscopy Res. Tech. 55, 122-145 (2001).
66. Alitalo, K. & Carmeliet, P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 1, 219-227 (2002).
67. Padera, T. P. et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296, 1883-1886 (2002).
68. Laakkonen, P., Porkka, K., Hoffman, J. A. & Ruoslahti, E. A tumor-homing peptide with a targeting specificity related to lymphatic vessels. Nature Med. 8, 751-755 (2002). This paper provides evidence that tumour lymphatics express specific markers that can be targeted and used effectively to destroy lymphatic vessels.
69. Hendrix, M. J. C. et al. Transendothelial function of human metastatic melanoma cells: role of the microenvironment in cell-fate determination. Cancer Res. 62, 665-668 (2002). This study shows that human metastatic melanoma cells can carry out a transendothelial function and participate in the neovascularization of ischaemic tissue.
70. Uyttendaele, H., Ho, J., Rossant, J. & Kitajewski, J. Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium. Proc. Natl Acad. Sci. USA 98, 5643-5648 (2001).
71. Gridley, T. Notch signaling during vascular development. Proc. Natl Acad. Sci. USA 98, 10733-10738 (2001).
72. Ellisen, L. W. et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66, 649-661 (1991).
73. Zagouras, P., Stifani, S., Blaumueller, C. M., Carcangiu, M. L. & Artavanis-Tsakonas, S. Alterations in Notch signaling in neoplastic lesions of the human cervix. Proc. Natl Acad. Sci. USA 92, 6414-6418 (1995).
74. Robbins, J., Blonel, B. J., Gallahan, D. & Callahan, R. Mouse mammary tumor gene Int-3: a member of the Notch gene family transforms mammary epithelial cells. J. Virol. 66, 2594-2599 (1992).
75. Shou, J., Ross, S., Koeppen, H., de Sauvage, F. J. & Gao, W.-Q. Dynamics of Notch expression during murine prostate development and tumorigenesis. Cancer Res. 61, 7291-7297 (2001).
76. Weijzen, S. et al. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nature Med. 8, 979-986 (2002).
77. Qin, J.-Z. et al. Interrupting activated Notch signaling triggers apoptosis in melanoma cells. Proc. J. Invest. Dermatol. 185A, 78 (2003).
78. Allenspach, E. J., Maillard, I., Aster, J. C. & Pear, W. S. Notch signaling in cancer. Cancer Biol. Ther. 1, 466-476 (2002).
79. Pasqualini, R., Arap, W. & McDonald, D. M. Probing the structural and molecular diversity of tumor vasculature. Trends Mol. Med. 8, 563-571 (2002).
80. Shirakawa, K. et al. Absence of endothelial cells, central necrosis, and fibrosis are associated with aggressive inflammatory breast cancer. Cancer Res 61, 445-451 (2001).
81. Pezzella, F. P. et al. Evidence for novel non-angiogenic pathway in breast-cancer metastasis. Lancet 355, 1787-1788 (2000).
82. Sood, A. K. et al. Molecular determinants of ovarian cancer plasticity. Am. J. Pathol. 158, 1279-1288 (2001).
83. Sood, A. K. et al. The clinical significance of tumor cell-lined vasculature in ovarian carcinoma: implications for antivasculogenic therapy. Cancer Biol. Ther. 1, 511-517 (2002).
84. Sharma, N. et al. Prostatic tumor cell plasticity involves cooperative interactions of distinct phenotypic subpopulations: role in vasculogenic mimicry. Prostate 50, 189-201 (2002).
85. Liu, C. et al. Prostate-specific membrane antigen directed selective thrombotic infarction of tumors. Cancer Res. 62, 5470-5475 (2002). This study reports a successful prostatic tumour-ablation strategy directed against prostate-specific membrane antigen-positive tumour cells that partially line the microvasculature, in combination with doxorubicin.
86. Passalidou, E. et al. Vascular phenotype in angiogenic and non-angiogenic lung non-small cell carcinomas. Br. J. Cancer 88, 244-249 (2002).
87. Hao, X., Sun, B., Zhang, S. & Zhao, X. Microarray study of vasculogenic mimicry in bi-directional differentiation malignant tumor. Zhonghua Yi Xue Za Zhi 82, 1298-1302 (2002) (in Chinese).
88. Favier, J., Plouin, P. F., Corvol, P. & Gasc, J. M. Angiogenesis and vascular architecture in pheochromocytomas: distinctive traits in malignant tumors. Am. J. Pathol. 161, 1235-1246 (2002).
89. Potter, C. J., Turenchalk, G. S. & Xu, T. Drosophila in cancer research: an expanding role. Trends Genet. 16, 33-39 (2000).
90. Hendrix, M. J. C., Seftor, E. A., Kirschmann, D. A. & Seftor, R. E. B. Molecular biology of breast cancer metastasis. Molecular expression of vascular markers by aggressive breast cancer cells. Breast Cancer Res. 2, 417-422 (2000).
91. Chen, X., Maniotis, A. J., Majumdar, D., Peler, J. & Folberg, R. Uveal melanoma cells staining for CD34 and assessment of tumor vascularity. Invest. Ophthalmol. Vis. Sci. 43, 2533-2539 (2002).
92. Hoang, M. P., Selim, M. A., Bentley, R. C., Burchette, J. L. & Shea, C. R. CD34 expression in desmoplastic melanoma. J. Cutan. Pathol. 28, 508-512 (2001).
93. Zhou, Y. et al. Human cytotrophoblasts adopt a vascular phenotype as they differentiate: a strategy for successful endovascular invasion? J. Clin. Invest. 99, 2139-2151 (1997).
94. Zhou, Y., Damsky, C. H. & Fisher, S. J. Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype: one cause of defective endovascular invasion in this syndrome? J. Clin. Invest. 99, 2152-2164 (1997).
95. Klausner, R. D. The fabric of cancer cell biology - weaving together the strands. Cancer Cell 1, 3-10 (2002). This article provides a global perspective of the many strands of cancer research and the future of intervention strategies.
96. Kim, C. J., Reintgen, D. S. & Yeatman, T. J. The promise of microarray technology in melanoma care. Cancer Control 9, 49-53 (2002).
97. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105-111 (2001).
98. Anderson, D. J., Gage, F. H. & Weissman, L. Can stem cells cross lineage boundaries? Nature Med. 7, 393-395 (2001).
99. Weissman, I. L. Stem cells: units of development, units of regeneration, and units in evolution. Cell 100, 157-168 (2000).
100. Ivanova, N. B. et al. A stem cell molecular signature. Science 298, 601-604 (2002).
101. Stocum, D. L. A tail of transdifferentiation. Science 298, 1901-1903 (2002).
102. LaBarge, M. A. & Blau, H. M. Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell 111, 589-601 (2002).
103. Kon, K. & Fujiwara, T. Transformation of fibroblasts into endothelial cells during angiogenesis. Cell Tissue Res. 278, 625-628 (1994).
104. Condorelli, G. et al. Cardiomyocytes induce endothelial cells to transdifferentiate into cardiac muscle: implications for myocardium regeneration. Proc. Natl Acad. Sci. USA 98, 10733-10738 (2001).
105. Nickoloff, B. J. & Foreman, K. E. Etiology and pathogenesis of Kaposi's sarcoma. Recent Results Cancer Res. 160, 332-342 (2002).
106. Bissell, M. J. & Radisky, D. Putting tumours in context. Nature Rev. Cancer 1, 46-54 (2001). An excellent overview of the interactions of tumour cells with their microenvironment, providing insights into new therapeutic strategies.
107. Liao, F. et al. Monoclonal antibody to vascular endothelial-cadherin is a potent inhibitor of angiogenesis, tumor growth, and metastasis. Cancer Res. 60, 6805-6810 (2000).
108. Jain, R. K. Normalizing tumor vasculature with antiangiogenic therapy: a new paradigm for combination therapy. Nature Med. 7, 987-989 (2001).
109. O'Reilly, M. S. Vessel maneuvers: vaccine targets tumor vasculature. Nature Med. 8, 1352-1354 (2002).
110. Miller, K. D., Sweeney, C. J. & Sledge, G. W. Jr. The Snark is a Boojum: the continuing problem of drug resistance in the antiangiogenic era. Ann. Oncol. 14, 20-28 (2003).
111. Scappaticci, F. A Mechanisms and future directions for angiogenesis-based cancer therapies. J. Clin. Oncol. 20, 3906-3927 (2002).
112. Gee, M. S. et al. Tumor vessel development and maturation impose limits on the effectiveness of anti-vascular therapy. Am. J. Pathol. 162, 183-193 (2003).
113. Goetz, D. E., Yu, J. L., Kerbel, R. S., Bums, P. N. & Foster, F. S. High-frequency Doppler ultrasound monitors the effects of antivascular therapy on tumor blood flow. Cancer Res. 62, 6371-6375 (2002).
114. Hood, J. D. et al. Tumor regression by targeted gene delivery to the neovasculature. Science 296, 2404-2407 (2002).
115. Grossman, D. & Altieri, D. C. Drug resistance in melanoma: mechanisms, apoptosis, and new potential therapeutic targets. Cancer Metastasis Rev. 20, 3-11 (2001).
116. Eberhard, A. et al. Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res. 60, 1388-1393 (2000).
117. Coussens, L. M., Fingleton, B. & Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295, 2387-2392 (2002).
118. Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nature Rev. Cancer 2, 161-174 (2002). A review of new functions associated with matrix metalloproteinases in cancer progression, with special emphasis on translational opportunities and strategies.
119. Liotta, L. A. & Kohn, E. C. The microenvironment of the tumour-host interface. Nature 411, 375-379 (2001).