RETROSPECTIVE A review of Judah Folkman’s remarkable achievements in biomedicine Yihai Cao*† and Robert Langer‡ *Department of Microbiology and Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden; and ‡Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 n January 14th of this year, the biomedical research com- munity lost Judah Folkman, O the father of angiogenesis research. Folkman’s warm and humble personality, inspirational teaching, un- limited creativity, and vast clinical expe- rience have been described elsewhere (1). Here, we focus on Folkman’s in- effaceable scientific achievements in angiogenesis research, which revolution- ized biomedical research and clinical drug development. Folkman founded an entirely new field of basic and clinical research and discovered a previously unknown family of angiogenesis regulatory molecules. He showed experimentally how these molecules provide a fundamental mech- anism that controls the growth of virtually all tumors. He showed that expansion of tissue mass, whether Judah Folkman. (Image courtesy of Jon Chase/Harvard News Office.) neoplastic or nonneoplastic, critically depends on continuous endothelial rep- This 1971 report was the first to intro- the cornea, a methodology that was crit- lication and neovascularization. duce the concept of a novel form of tu- ical for proof of angiogenic bioactivity Those discoveries paved new avenues mor dormancy caused by blockage of of a given molecule in vivo (5). His re- for the development of a new class of angiogenesis. In that paper, Folkman search also identified the existence of a drugs, angiogenesis inhibitors, which have also introduced the concept of ‘‘anti- family of angiogenic peptides (6), and already provided novel therapies for hu- angiogenesis’’ as a potential novel anti- he showed that removing an angiogenic man cancer and age-related macular cancer therapy. stimulus leads to regression of degeneration. Folkman wrote in 1971, ‘‘If a tumor neovascularization (7). Professor Donald S. Coffey of The could be held indefinitely in the non- Folkman’s 1971 supposition initiated a Johns Hopkins University (Baltimore, vascularized dormant state...itispossi- field of angiogenesis research that has MD) recently said about professor Folk- ble that metastases will not arise.’’ He produced Ͼ35,000 reports on angiogen- man: ‘‘Few ever get to see their lifetime also predicted that a therapeutic agent esis in peer-reviewed journals, and Ͼ70 thoughts, insights, creativity, and long could be made against a putative tumor- monographs and books. effort explode across science and into derived angiogenic factor. He con- This single hypothesis has been re- the clinics as [his] many contributions cluded, ‘‘It has not been appreciated markably fruitful. During the subse- have.’’ that the population of tumor cells and quent 37 years, it led to an almost un- Fortunately, we are among those few the population of capillary endothelial interrupted series of new findings and who had the privilege to see and work cells within a neoplasm may constitute a discoveries, not only in the Folkman with Dr. Folkman, who changed not highly integrated ecosystem. In this eco- laboratory but in hundreds of laborato- only our lives but those of millions of system, the mitotic index of the two cell ries worldwide. others. populations may depend on each other.’’ Folkman followed his 1971 hypothesis Molecular Basis of the Discovery Early Evidence of Tumor Angiogenesis with supporting evidence indicating that Folkman showed that human and ani- In 1971, Folkman proposed a hypothesis tumors secreted diffusible endothelial mal tumors produce a defined set of that tumor growth is angiogenesis- mitogens in vivo (3), which could induce proangiogenic and antiangiogenic pro- dependent (2). In that report, Folkman angiogenesis in neighboring micro- teins. When the expression, secretion, or showed preliminary evidence that tu- vessels. He and his colleagues then generation of these proteins is in equi- mors could not enlarge beyond millime- showed that tumor growth could be in- librium so that their proangiogenic and ter diameters without recruiting new hibited by blocking angiogenesis, and capillary blood vessels (microvessels). they proved that diffusible angiogenesis His hypothesis stated that tumors se- inhibitory factors existed (4). Author contributions: Y.C. and R.L. wrote the paper. creted a diffusible substance that could Folkman and colleagues also reported †To whom correspondence should be addressed. E-mail: stimulate endothelial cell proliferation in that macromolecules and proteins can [email protected]. host capillary blood vessels. be released from polymers implanted in © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0806582105 PNAS ͉ September 9, 2008 ͉ vol. 105 ͉ no. 36 ͉ 13203–13205 Downloaded by guest on October 2, 2021 antiangiogenic activities are balanced, or naturally occurring angiogenic and anti- tional imaging methods. This platelet an- oppose each other, tumor mass cannot angiogenic molecules existed, a new bi- giogenesis proteome is now being studied expand beyond the limited distance that ology of microvascular endothelial cells in clinical trials at Harvard (Cambridge, oxygen can diffuse from the nearest was emerging, a new form of tumor dor- MA) in collaboration with St. Jude’s Can- open capillary blood vessel (Ͻ250 mi- mancy was caused by angiogenic block- cer Center (Memphis, TN) for ultra-early crons). As a result of these metabolic ade, and tumor growth and metastases detection of recurrent cancer years before restrictions, the development of most were angiogenesis-dependent. it is symptomatic or can be anatomically human cancer is usually arrested at a Around that time, Folkman and his located. microscopic, dormant mass of 1–2 mm3 associates began experiments that laid Folkman and his associates (20) also or less. This early stage is also called in the groundwork for translation of these showed that infants with a life- situ cancer. molecules and mechanisms to clinical threatening condition called hemangio- Many humans harbor these micro- application. He demonstrated that the matosis, which results from an abnormal scopic tumors in various organs through- rapid growth of metastases after surgical proliferation of blood vessels in any vas- out life (8), and the vast majority of removal or radiation therapy of certain cularized tissue, could be successfully such tumors never expand further. They primary tumors, a phenomenon previ- treated by antiangiogenic therapy, and remain nonangiogenic, dormant, and ously called ‘‘concomitant immunity’’ or that experimental endometriosis could harmless (9). They may contain up to ‘‘concomitant resistance’’ is in fact also be inhibited by antiangiogenic Ϸ 1 million tumor cells that are prolifer- caused by withdrawal of angiostasis (14). therapy (21). ating and undergoing apoptosis, but the He also reported that human leukemia A Beautiful Approach microscopic tumors do not invade lo- is angiogenic, and he showed in animal cally and do not metastasize. models that leukemia is angiogenesis- Folkman hypothesized that certain In the rare event that a shift in the dependent (15). Before Folkman and col- nonneoplastic diseases such as pso- balance of proangiogenic and antiangio- leagues’ reports, physicians believed that riasis, rheumatoid arthritis, and ocu- genic proteins occurs, so that the total because leukemic cells circulated in blood, lar neovascularization could also be output of these proteins renders the tu- the growth of leukemia cells did not need angiogenesis-dependent. He suggested mor mass proangiogenic, the tumor is neovascularization. Folkman showed that that angiogenesis inhibitors developed then enabled to ‘‘switch to an angio- neovascularization in the bone marrow for cancer therapy could possibly be genic phenotype’’ (10). As first eluci- used to treat nonneoplastic angiogene- was critical for expansion of leukemic dated by Folkman, the tumor itself sis-dependent diseases (22). mass in the marrow. expresses and secretes this excess of A beautiful example of this translational proangiogenic proteins or, alternatively, approach is the concerted effort launched it enzymatically mobilizes proangiogenic in 1992 by the Folkman laboratory with peptides from host proteins in the circu- “Angiogenesis research their collaborators to find the molecular lation or the supportive framework of target for choroidal and retinal neovascu- an organ or gland (stroma). will probably change the larization in humans. This target was The angiogenic switch can also be mod- face of medicine in the unknown before the mid-1990s. ulated by host cells in the stroma or the Ophthalmologists had previously used circulation. After the angiogenic switch, next decades.” the term ‘‘X-factor’’ to indicate a putative both benign and malignant tumors can diffusible molecule that mediated neovas- expand their tumor mass. Malignant an- cular age-related macular degeneration. In giogenic tumors, however, invade locally, the mid-1990s, Folkman and colleagues metastasize to remote sites, and are po- Folkman and colleagues (16) also published a series of papers (e.g., see ref. tentially lethal. In the absence of the an- showed for the first time that certain con- 23) demonstrating that vascular endothe- giogenic switch, even tumors that are ventional cytotoxic chemotherapeutic lial growth factor (VEGF) is a critical malignant by all other criteria