DOI: 10.1126/science.284.5415.808. Effects of Angiogenesis Inhibitors on Multistage Carcinogenesis in Mice

Effects of Angiogenesis Inhibitors on Multistage Carcinogenesis in Mice

10.1126/science.284.5415.808

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

Solid tumors depend on angiogenesis for their growth. In a transgenic mouse model of pancreatic islet cell carcinogenesis (RIP1-Tag2), an angiogenic switch occurs in premalignant lesions, and angiogenesis persists during progression to expansive solid tumors and invasive carcinomas. RIP1-Tag2 mice were treated so as to compare the effects of four angiogenesis inhibitors at three distinct stages of disease progression. AGM-1470, angiostatin, BB-94, and endostatin each produced distinct efficacy profiles in trials aimed at preventing the angiogenic switch in premalignant lesions, intervening in the rapid expansion of small tumors, or inducing the regression of large end-stage cancers. Thus, anti-angiogenic drugs may prove most efficacious when they are targeted to specific stages of cancer.

Bibliography

Bergers, G., Javaherian, K., Lo, K.-M., Folkman, J., & Hanahan, D. (1999). Effects of Angiogenesis Inhibitors on Multistage Carcinogenesis in Mice. Science, 284(5415), 808â812.

Authors 5

Gabriele Bergers (first)
Kashi Javaherian (additional)
Kin-Ming Lo (additional)
Judah Folkman (additional)
Douglas Hanahan (additional)

References 36 Referenced 791

10.1126/science.1957168
10.1016/S0959-8049(96)00401-7
10.1002/(SICI)1098-2744(199711)20:3<262::AID-MC2>3.0.CO;2-N
10.1097/00001622-199709050-00015
10.1038/315115a0
Folkman J., Watson K., Ingber D., Hanahan D., ibid. 339, 58 (1989); / ibid. by Folkman J. (1989)
Bergers G., Hanahan D., Coussens L. M., Int. J. Dev. Biol. 42, 995 (1998); / Int. J. Dev. Biol. by Bergers G. (1998)
10.1038/32433
; 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).
10.1038/339058a0
10.1073/pnas.93.5.2002
10.1002/ijc.2910570624
10.1016/S0959-8049(96)00380-2
10.1038/sj.neo.7900006
M. S. O'Reilly et al. Cell 79 314 (1994); M. S. O'Reilly
10.1038/nm0696-689
M. S. O'Reilly et al. Cell 88 277 (1997) (10.1001/jama.1997.03540250096052)
T. Boehm J. Folkman T. Browder M. S. O'Reilly Nature 390 404 (1997). (10.1038/37126)
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 [
10.1126/science.7053564
]. 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.
10.1038/348555a0
10.1016/S1074-5521(97)90198-8
10.1073/pnas.94.12.6099
10.1016/S0959-8049(96)00388-7
10.1016/S0959-8049(96)00398-X
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).
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.
In the intervention and regression trials animals were killed at the end of each trial and tumors were microdissected from freshly excised pancreases. Tumor volume (in cubic millimeters) was measured with calipers and the formula [volume = 0.52 × (width) 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 [
Parangi S., et al., Cancer Res. 55, 66071 (1995)]. / Cancer Res. by Parangi S. (1995)
Microdissected tumors and pancreases were immersion-fixed in 4% paraformaldehyde and embedded in paraffin. Apoptotic index and vessel density were assessed by combined TUNEL [
10.1101/gad.10.17.2105
] 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.
G. Bergers K. Javaherian K.-M. Lo J. Folkman D. Hanahan data not shown.
Grant S. N., Seidman I., Hanahan D., Cancer Res. 51, 4917 (1991). / Cancer Res. by Grant S. N. (1991)
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.

Dates

Type	When
Created	23 years, 1 month ago (July 27, 2002, 5:40 a.m.)
Deposited	1 year, 7 months ago (Jan. 13, 2024, 4:21 a.m.)
Indexed	3 weeks, 5 days ago (Aug. 2, 2025, 1:27 a.m.)
Issued	26 years, 3 months ago (April 30, 1999)
Published	26 years, 3 months ago (April 30, 1999)
Published Print	26 years, 3 months ago (April 30, 1999)

Funders 0

None

BibTeX

@article{Bergers_1999, title={Effects of Angiogenesis Inhibitors on Multistage Carcinogenesis in Mice}, volume={284}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.284.5415.808}, DOI={10.1126/science.284.5415.808}, number={5415}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Bergers, Gabriele and Javaherian, Kashi and Lo, Kin-Ming and Folkman, Judah and Hanahan, Douglas}, year={1999}, month=apr, pages={808–812} }

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