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| We are pleased to present this annotated list of landmark papers from from the last 80 years. For their guidance in selecting these papers we are indebted to: A Adamis, M Bissel, N Bouck, N Boudreau, Y Cao, D Cheresh, D Dumont, J Folkman, R Herbst, T Hla, R Kerbel, E Keshet, S Libutti, D Losordo, S Rafii, D Senger, L Smith, J Varner, O Volpert, B Zetter, S Crawford. |
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| Browse: A starting point | VEGF | Promoting angiogenesis | Blocking angiogenesis | Therapeutic strategies | Hypoxia | ECM | Research tools | Cells involved |
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A Starting Point |
| In 1939, Ide et al. observed that tumor growth was accompanied by infiltration of newly formed blood vessels in a rabbit tumor model. |
Vascularization of the Brown Pearce rabbit epithelioma transplant as seen in the transparent ear chamber
Ide, A.G., Baker, N.H. & Warren, S.L.
Am. J. Roentgenol
42, 891-899
(1939) |
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| Clark and Clark placed glass-windowed chambers in the rabbit ear and made exquisite drawings of the branching patterns of the blood vessels that entered the wound. Their work established the field of vascular biology. |
Observations on living preformed blood vessels as seen in a transparent chamber inserted into the rabbit ear
Clark, E.R. & Clark, E.L.
Am. J. Anat.
49, 441-447
(1932)
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| The field of tumor angiogenesis is perceived to be a relatively new discipline in cancer research. However, these three papers from Algire at the National Cancer Institute in the 1940s show that critical observations were being made over 50 years ago. Algire and Chalkeley watched blood vessels migrate toward tumors in wound chambers. This was the first demonstration that tumors actively attract new blood vessels. More than 30 years later, this process would become known as 'tumor angiogenesis'. |
Vascular reactions of normal and malignant tumors in vivo. I. Vascular reactions of mice to wounds and to normal and neoplastic transplants
Algire, G.H. Chalkley, H.W. Legallais, F.Y. & Park, H.D.
J. Natl. Cancer Inst.
6, 73-85
(1945)
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An adaptation of the transparent-chamber technique to the mouse
Algire, G.H.
J. Natl. Cancer Inst.
4, 1-11
(1943)
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Microscopic studies of the early growth of a transplantable
melanoma of the mouse, using the transparent-chamber technique
Algire, G.H.
J. Natl. Cancer Inst.
4, 13-20
(1943)
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| This is a landmark paper from decades before the term 'angiogenic factor' was coined. It is an insightful first description of an angiogenic activity, regulated by oxygen, elaborated by the retina and mediating abnormal, retinopathic vessel growth. Michelson's 'factor X' was eventually identified as VEGF and confirmed to be the underlying causal factor of retinopathies. |
The mode of development of the vascular system of the retina with some observations on its significance for certain retinal disorders
Michelson, I.C.
Trans. Ophthalmol. Soc. UK
68, 137-180
(1948)
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| By placing a membrane between the tumor and the vascular supply, two independent studies hypothesized and demonstrated that tumors release a 'diffusible factor' that attracts new blood vessels to the tumor site. |
Tumor angiogenesis: transfilter diffusion studies in the hamster by the transparent chamber technique
Greenblatt, M & Shubi, P.
J. Natl. Cancer Inst.
41, 111-124
(1968)
PubMed |
Choriocarcinoma. Transfilter stimulation of vasoproliferation in the hamster cheek pouch. Studied by light and electron microscopy
Ehrmann, R.L. & Knoth, M.
J. Natl. Cancer Inst.
41, 1329-1341
(1968)
PubMed |
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| This review defined the brand-new field of tumor angiogenesis, clearly laying out its goals and promises. It introduced the concept that angiogenesis inhibitors could be used in cancer. Although received with considerable skepticism when first presented, it is now revered as brilliantly prescient. Folkman also outlined the utility of antiangiogenesis in other 'angiogenesis-dependent diseases' such as diabetic retinopathy. |
Tumor angiogenesis: therapeutic implications
Folkman, J.
N. Engl. J. Med.
285, 1182-1186
(1971)
PubMed |
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| In this second pivotal paper in 1971, Folkman and collaborators presented an experimental protocol to isolate a fraction of ascites fluid that stimulated blood vessel growth. This discovery changed cancer research forever, and ultimately created an entirely new field of investigation. |
Isolation of a tumor factor responsible for angiogenesis
Folkman, J., Merler, E., Abernathy, C. & Williams, G.
J. Exp. Med.
133, 275-288
(1971)
PubMed |
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| These very early experiments show that small balls of living tumor cells do not increase in size when they are suspended in the anterior chamber of the eye where they cannot become vascularized. The amazing twist to the story is that when such dormant balls of cells are moved from the anterior chamber to a nearby spot in the eye where they can attract vessels from the iris, they then grow exponentially. This is the first paper to go beyond circumstantial evidence to show that the progressive growth of a tumor can indeed be absolutely dependent on angiogenesis. |
Tumor dormancy in vivo by prevention of neovascularization
Gimbrone, M.A., Jr., Leapman, S.B., Cotran, R.S. & Folkman, J.
J. Exp. Med.
136, 261-276
(1972)
PubMed |
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