Effects of angiogenesis inhibitors on multistage carcinogenesis in mice

Science

Volumn 284, Issue 5415, 1999, Pages 808-812

  Bergers, Gabriele ^a   Javaherian, Kashi ^b   Lo, Kin Ming ^c   Folkman, Judah ^b   Hanahan, Douglas ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b BOSTON CHILDREN S HOSPITAL   (United States)

^c Lexigen Pharmaceuticals Corp   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANGIOGENESIS INHIBITOR; ANGIOSTATIN; BATIMASTAT; ENDOSTATIN; FUMAGILLOL CHLOROACETYLCARBAMATE;

ANGIOGENESIS; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CANCER INVASION; CARCINOGENESIS; CONTROLLED STUDY; MOUSE; NONHUMAN; PANCREAS ISLET CELL CARCINOMA; PRECANCER; PRIORITY JOURNAL; SOLID TUMOR; TRANSGENIC MOUSE; TUMOR VASCULARIZATION;

ANGIOSTATINS; ANIMALS; ANTICARCINOGENIC AGENTS; ANTINEOPLASTIC AGENTS; APOPTOSIS; CARCINOMA, ISLET CELL; COLLAGEN; CYCLOHEXANES; DISEASE PROGRESSION; DRUG EVALUATION, PRECLINICAL; ENDOSTATINS; FEMALE; MALE; MICE; MICE, INBRED C57BL; MICE, TRANSGENIC; NEOPLASM STAGING; NEOVASCULARIZATION, PATHOLOGIC; PANCREATIC NEOPLASMS; PEPTIDE FRAGMENTS; PHENYLALANINE; PLASMINOGEN; SESQUITERPENES; THIOPHENES;

EID: 0033617532     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.284.5415.808     Document Type: Article

References (31)

1. J. M. Adams and S. Cory, Science 254, 1161 (1991); D. Hanahan, G. Christofori, P. Naik, J. Arbeit, Eur. J. Cancer 42A, 2386 (1996); M. P. Rosenberg, Mol. Carcinogen. 20, 262 (1997); S. D. Hursting, Curr. Opin. Oncol. 9, 487 (1997).
2. J. M. Adams and S. Cory, Science 254, 1161 (1991); D. Hanahan, G. Christofori, P. Naik, J. Arbeit, Eur. J. Cancer 42A, 2386 (1996); M. P. Rosenberg, Mol. Carcinogen. 20, 262 (1997); S. D. Hursting, Curr. Opin. Oncol. 9, 487 (1997).
3. J. M. Adams and S. Cory, Science 254, 1161 (1991); D. Hanahan, G. Christofori, P. Naik, J. Arbeit, Eur. J. Cancer 42A, 2386 (1996); M. P. Rosenberg, Mol. Carcinogen. 20, 262 (1997); S. D. Hursting, Curr. Opin. Oncol. 9, 487 (1997).
4. J. M. Adams and S. Cory, Science 254, 1161 (1991); D. Hanahan, G. Christofori, P. Naik, J. Arbeit, Eur. J. Cancer 42A, 2386 (1996); M. P. Rosenberg, Mol. Carcinogen. 20, 262 (1997); S. D. Hursting, Curr. Opin. Oncol. 9, 487 (1997).
5. D. Hanahan, Nature 315, 115 (1985); J. Folkman, K. Watson, D. Ingber, D. Hanahan, ibid. 339, 58 (1989); C. Bergers, D. Hanahan, L. M. Coussens, Int. J. Dev. Biol. 42, 995 (1998); A.-K. Perl, P. Wilgenbus, U. Dahl, H. Semb, C. Christofori, Nature 392, 190 (1998); J. H. Hager and D. Hanahan, in Mechanisms of Cell Death, Z. Zakeri, L. Benitez-Bribiesca, R. A Lockshin, Eds. (New York Academy of Sciences, New York, in press).
6. D. Hanahan, Nature 315, 115 (1985); J. Folkman, K. Watson, D. Ingber, D. Hanahan, ibid. 339, 58 (1989); C. Bergers, D. Hanahan, L. M. Coussens, Int. J. Dev. Biol. 42, 995 (1998); A.-K. Perl, P. Wilgenbus, U. Dahl, H. Semb, C. Christofori, Nature 392, 190 (1998); J. H. Hager and D. Hanahan, in Mechanisms of Cell Death, Z. Zakeri, L. Benitez-Bribiesca, R. A Lockshin, Eds. (New York Academy of Sciences, New York, in press).
7. D. Hanahan, Nature 315, 115 (1985); J. Folkman, K. Watson, D. Ingber, D. Hanahan, ibid. 339, 58 (1989); C. Bergers, D. Hanahan, L. M. Coussens, Int. J. Dev. Biol. 42, 995 (1998); A.-K. Perl, P. Wilgenbus, U. Dahl, H. Semb, C. Christofori, Nature 392, 190 (1998); J. H. Hager and D. Hanahan, in Mechanisms of Cell Death, Z. Zakeri, L. Benitez-Bribiesca, R. A Lockshin, Eds. (New York Academy of Sciences, New York, in press).
8. D. Hanahan, Nature 315, 115 (1985); J. Folkman, K. Watson, D. Ingber, D. Hanahan, ibid. 339, 58 (1989); C. Bergers, D. Hanahan, L. M. Coussens, Int. J. Dev. Biol. 42, 995 (1998); A.-K. Perl, P. Wilgenbus, U. Dahl, H. Semb, C. Christofori, Nature 392, 190 (1998); J. H. Hager and D. Hanahan, in Mechanisms of Cell Death, Z. Zakeri, L. Benitez-Bribiesca, R. A Lockshin, Eds. (New York Academy of Sciences, New York, in press).
9. D. Hanahan, Nature 315, 115 (1985); J. Folkman, K. Watson, D. Ingber, D. Hanahan, ibid. 339, 58 (1989); C. Bergers, D. Hanahan, L. M. Coussens, Int. J. Dev. Biol. 42, 995 (1998); A.-K. Perl, P. Wilgenbus, U. Dahl, H. Semb, C. Christofori, Nature 392, 190 (1998); J. H. Hager and D. Hanahan, in Mechanisms of Cell Death, Z. Zakeri, L. Benitez-Bribiesca, R. A Lockshin, Eds. (New York Academy of Sciences, New York, in press).
10. J. Folkman, K. Watson, D. Ingber, D. Hanahan, Nature 339, 58 (1989).
11. S. Parangi et al., Proc. Natl. Acad. Sci. U.S.A. 93, 2002 (1996).
12. B. A. Teicher et al., Int. J. Cancer 57, 920 (1994); B. A. Teicher, Y. Emi, Y. Kakeji, Eur. J. Cancer 32A, 2461 (1996); P. Vajkoczy et al., Neoplasia 1, 31 (1999).
13. B. A. Teicher et al., Int. J. Cancer 57, 920 (1994); B. A. Teicher, Y. Emi, Y. Kakeji, Eur. J. Cancer 32A, 2461 (1996); P. Vajkoczy et al., Neoplasia 1, 31 (1999).
14. B. A. Teicher et al., Int. J. Cancer 57, 920 (1994); B. A. Teicher, Y. Emi, Y. Kakeji, Eur. J. Cancer 32A, 2461 (1996); P. Vajkoczy et al., Neoplasia 1, 31 (1999).
15. M. S. O'Reilly et al., Cell 79, 314 (1994); M. S. O'Reilly, L. Holmgren, C. Chen, J. Folkman, Nature Med. 2, 689 (1996).
16. M. S. O'Reilly et al., Cell 79, 314 (1994); M. S. O'Reilly, L. Holmgren, C. Chen, J. Folkman, Nature Med. 2, 689 (1996).
17. M. S. O'Reilly et al., Cell 88, 277 (1997); T. Boehm, J. Folkman, T. Browder, M. S. O'Reilly, Nature 390, 404 (1997).
18. M. S. O'Reilly et al., Cell 88, 277 (1997); T. Boehm, J. Folkman, T. Browder, M. S. O'Reilly, Nature 390, 404 (1997).
19. The mice used in this study were males and females of the RIP1-Tag2 transgenic mouse lineage (2) inbred in the C57Bl/6J background. All control mice received subcutaneous (s.c.) or intraperitoneal (i.p.) saline injections. Subcutaneous injections were specifically directed to a region above the tail at the right or left flank known to be permissive for systemic delivery [R. Auerbach and W. Auerbach, Science 215, 127 (1982)]. In the prevention trial, animals were treated from 5 to 10.5 weeks of age; in the intervention trial, from 10 to 13.5 weeks of age; and in the regression trial, from 12 to 16 weeks of age. All mice were maintained in accord with the University of California, San Francisco, institutional guidelines governing the care of laboratory mice and were killed after the respective treatment period.
20. D. Ingber et al., Nature 348, 555 (1990); E. C. Griffith et al., Chem. Biol., 4, 461 (1997); N. Sin et al., Proc Natl. Acad. Sci U.S.A. 94, 6099 (1997); V. Castronovo and O. Belotti, Eur. J. Cancer 32A, 2520 (1996).
21. D. Ingber et al., Nature 348, 555 (1990); E. C. Griffith et al., Chem. Biol., 4, 461 (1997); N. Sin et al., Proc Natl. Acad. Sci U.S.A. 94, 6099 (1997); V. Castronovo and O. Belotti, Eur. J. Cancer 32A, 2520 (1996).
22. D. Ingber et al., Nature 348, 555 (1990); E. C. Griffith et al., Chem. Biol., 4, 461 (1997); N. Sin et al., Proc Natl. Acad. Sci U.S.A. 94, 6099 (1997); V. Castronovo and O. Belotti, Eur. J. Cancer 32A, 2520 (1996).
23. D. Ingber et al., Nature 348, 555 (1990); E. C. Griffith et al., Chem. Biol., 4, 461 (1997); N. Sin et al., Proc Natl. Acad. Sci U.S.A. 94, 6099 (1997); V. Castronovo and O. Belotti, Eur. J. Cancer 32A, 2520 (1996).
24. D. C. Talbot and P. D. Brown, Eur. J. Cancer 32A, 2528 (1996).
25. Z. Werb, T. H. Vu, J. L. Rinkenberger, L. M. Coussens, in Protease and Protease Inhibitors in Cancer Therapy, L. Matrisian, N. Brunner, K. Dano, Eds. (Acta Pathologica, Microbiologica, et Immunologica Scandinavica, Human Press, Totowa, NJ, in press).
26. Additional information on the production and purification of murine angiostatin and endostatin as Fc fusion proteins is available at www.sciencemag.org/feature/data/990055.shl.
27. 2 × (length)] for approximating the volume of a spheroid was applied. Tumor burden per mouse was calculated by accumulating the tumor volumes of every mouse. In the prevention trial, angiogenic islets were isolated by retrograde perfusion with collagenase solution and counted. Angiogenic islets were identified as those that exhibited a reddish patch or patches (caused by hemorrhaging) in a white nodular background (3). The visual scoring scheme has been confirmed by histology as described [S. Parangi et al., Cancer Res. 55, 66071 (1995)].
28. Microdissected tumors and pancreases were immersion-fixed in 4% paraformaldehyde and embedded in paraffin. Apoptotic index and vessel density were assessed by combined TUNEL [P. Naik et al., Genes Dev. 10, 2105 (1996)] and CD31 staining. Apoptotic labeling was followed by CD31 staining with a 1:100 dilution of a rat anti-mouse CD31 monoclonal antibody (Pharmingen). Reaction products were visualized with an ABC kit, using as chromophores 3,3-diaminobenzidine (for TUNEL-positive cells) and alkaline phosphatase substrate (for CD31 staining). Proliferating cells were detected with a mouse antibody against human proliferation-associated nuclear antigen (Biogenex). Ten to 20 fields of the respective sections were scored under oil immersion light microscopy.
29. G. Bergers, K. Javaherian, K.-M. Lo, J. Folkman, D. Hanahan, data not shown.
30. S. N. Grant, I. Seidman, D. Hanahan, Cancer Res. 51, 4917 (1991).
31. We thank British Biotech Pharmaceuticals, Oxford, UK, for BB-94 and Takeda-Abbott Pharmaceuticals for AGM1470; S. Gillies of Letigan Pharmaceuticals for advice and support of the production of Fc-endostatin and Fc-angiostatin; E. Soliven for excellent technical assistance; A. McMillan for statistical analysis; and R. Weinberg, R. Klausner, J. M. Bishop, J. D. Watson, S. Parangi, J. Hager, E. Bergsland, and H. Ee for comments and critical reading of the manuscript. Supported by grants from the National Cancer Institute.