What Does Radiotherapy Do to Endothelial Cells?

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Science  13 Jul 2001:
Vol. 293, Issue 5528, pp. 227-228
DOI: 10.1126/science.1062892

Radiotherapy [HN1] has been used to successfully treat a variety of solid tumors [HN2]. The conventional explanation for why radiotherapy is so effective is that tumor cells are the principal target of ionizing radiation [HN3], which damages their DNA causing them to undergo programmed cell death (apoptosis) (1) [HN4]. Similarly, it has been presumed that the side effects of radiotherapy are caused by radiation damage [HN5] to the DNA of normal cells. For example, the severe gastrointestinal side effects of radiotherapy have been attributed to the radiation-induced death of epithelial stem cells [HN6] residing in the crypts of the gut [HN7] (see the figure).

Endothelial cells take center stage.

Microvascular endothelial cells that line capillary blood vessels are situated very close to normal tissue cells such as epithelial cells in the gut mucosa. This close apposition enables endothelial cells and epithelial cells to communicate with each other by release of growth factors and hormones. Epithelial cells are also able to derive oxygen and nutrients from blood vessels. (A) Islet cells of the pancreas are sandwiched between two capillary vessels (fat cells and most muscle cells are similarly arranged). (B) Liver cord cells are arranged around a central capillary. (C) Epithelial stem cells of the gut mucosa reside in the crypts of Lieberkühn (box) and are separated from the microvasculature by a very short distance (∼100 μm), which enables oxygen to diffuse from the blood vessels into the crypts. (D) In contrast, tumor cells form multiple layers around a capillary blood vessel such that the most remote tumor cells are oxygen-deprived (hypoxic or anoxic). [Modified from (3)]

On page 293 of this issue, Paris et al. (2) [HN8] turn this scenario on its head. They report that a single large dose of radiation administered to the mouse gastrointestinal tract preferentially damages the endothelial cells [HN9] of the gut microvasculature. The investigators conclude that the death of epithelial stem cells may be a secondary event resulting from the demise of the endothelial cells on which they depend. This is analogous to the endothelial-dependent growth of tumor cells, which depend for their survival on new blood vessels formed by proliferating endothelial cells (angiogenesis) (3) [HN10].

Paris and colleagues established in previous work that (i) systemic administration of basic fibroblast growth factor (bFGF) [HN11] enhances murine epithelial stem cell survival and decreases mouse mortality after whole-body irradiation, and (ii) irradiation of microvascular endothelial cells generates ceramide [HN12], a proapoptotic lipid that facilitates endothelial cell death (4). In their new experiments, the authors show that systemic administration of bFGF, an endothelial cell mitogen and survival factor, overrides the apoptotic signal from ceramide, protecting gut endothelial cells and epithelial stem cells from the effects of whole-body irradiation. The bFGF did not protect bone marrow, however, and animals subsequently died from destruction of bone marrow stem cells. Microvascular endothelial cells express the receptor for bFGF, whereas epithelial stem cells in the intestinal crypts do not (2), suggesting that bFGF protects the gut mucosa from radiation damage through its effects on endothelial cells. In the authors' most compelling experiment, mice lacking the gene for acid sphingomyelinase [HN13]—an enzyme required for ceramide production that is highly expressed in endothelium—are protected from the radiation-induced destruction of the gut mucosa. When wild-type mice that are able to generate ceramide were irradiated, the death of endothelial cells in the microvasculature preceded that of epithelial stem cells in the crypts.

These findings are consistent with a two-compartment model for the irradiation-induced death of intestinal cells: endothelial cells in the gut microvasculature die first, followed by epithelial stem cells that depend on endothelial cell support. This two-compartment model is reminiscent of the way in which tumor growth is inhibited by endothelial cell blockers (antiangiogenic therapy) (5) [HN14]. Tumor cells grow as a perivascular cuff around a blood vessel (see the figure). They stimulate endothelial cell proliferation and the growth of new blood vessels by releasing endothelial mitogens and chemotactic factors, such as bFGF and vascular endothelial growth factor [HN15]. Endothelial cells, in turn, protect tumor cells by releasing at least 20 growth and survival factors including heparin-binding epithelial growth factor and interleukin 6 (6). If mice bearing tumors are treated with antiangiogenic therapy—which targets proliferating endothelial cells in newly forming blood vessels—endothelial cell apoptosis precedes tumor cell apoptosis by 3 to 5 days, suggesting that tumor cells are dependent on endothelial cells for survival (7). A similar two-compartment model has also been proposed for growth of normal tissue, which seems to depend on the prior expansion of endothelial cells and angiogenesis. Expansion of the endothelial cell population in the microvasculature of prostate (8, 9), fat (10), and regenerating liver (11) is required before these tissues can grow, expand, or regenerate.

In the Paris et al. work, a single large dose of radiation caused endothelial cell apoptosis in the intestinal mucosa. If a similar effect is seen with fractionated radiotherapy [HN16] (a more clinically relevant treatment), this could have profound implications for cancer therapy. For example, if the microvascular endothelial cell is the principal target of radiotherapy and damage to the epithelial stem cell is a secondary event, this relationship may also hold for endothelial cells and the tumor cells they support. This scenario would explain the synergistic effects obtained when radiotherapy is combined with antiangiogenic therapy (12, 13). Even if the endothelial cell response is only a component of the tumor response to radiation, attacking both compartments is a logical therapeutic strategy.

A poorly understood feature of radiotherapy treatment is that some tumors are very radiosensitive in vivo (for example, Hodgkin's lymphoma [HN17]) and others are very radioresistant (for example, glioblastoma [HN18]), whereas in vitro these tumors have similar or overlapping radiosensitivities (14). In vitro, tumor cells are the only target and ionizing radiation directly damages their DNA, inducing them to undergo apoptosis. However, in vivo, there are a multitude of supporting cells (including endothelial cells) that may be more sensitive to ionizing radiation than tumor cells, which then die not because of DNA damage but because they require endothelial cell support. The Paris et al. report prepares the stage for studying the effects of radiation on microvascular endothelial cells recruited to the tumor bed during angiogenesis. It may be possible to modify the radiosensitivity of a tumor by increasing or decreasing circulating endothelial inhibitors or stimulators, thereby making the tumor microvasculature more radiosensitive. If further evidence supports the idea that the microvascular endothelial cell is the principal target of ionizing radiation, as indicated by the provocative results of Paris et al., then treating tumors first with angiogenesis inhibitors may sensitize the tumors to ionizing radiation, allowing lower radiation doses to be used.

HyperNotes Related Resources on the World Wide Web

General Hypernotes

The On-line Medical Dictionary is made available by CancerWEB.

Biology Links are provided by the Department of Molecular and Cellular Biology, Harvard University.

The WWW Virtual Library of Cell Biology is maintained by G. Fenteany, Department of Chemistry, University of Illinois at Chicago.

P. Gannon's Cell & Molecular Biology Online is a collection of annotated links to Internet resources.

The Karolinska Institutet Library, Stockholm, provides links to Internet biomedical information resources and services.

MEDLINEplus is a health information resource provided by the U.S. National Library of Medicine.

HealthWeb, a collaborative project of health sciences libraries, offers annotated listings of evaluated Internet resources.

The Merck Manual of Diagnosis and Therapy and the Merck Manual of Medical Information—Home Edition are made available on the Web by Merck & Co.

The University of Pennsylvania Cancer Center's OncoLink is a cancer information resource for patients and health care professions. A collection of radiation oncology resources is provided

CancerNet is an information service of the National Cancer Institute (NCI). A dictionary of cancer terms is provided. provides links to Internet resources on radiology and radiation oncology.

The Online Biology Book is provided by M. Farabee, Estrella Mountain Community College, Avondale, AZ.

J. Kimball maintains Kimball's Biology Pages, an online biology textbook and glossary.

The Medical Biochemistry Page is provided by M. King, Terre Haute Center for Medical Education, IN.

M. Blend, Department of Radiology, University of Illinois at Chicago, provides lecture notes for a course on medical radiation biology.

The Digital Microscopy Project of the National Library of Medicine offers lecture notes by R. Shikes titled “Neoplasia I: Benign and malignant states” and lecture notes by G. Miller titled “Neoplasia II: Metastasis and differentiation.”

The Computer Assisted Teaching System (CATS) provided by the Department of Pathology, University of Vermont College of Medicine, offers resource materials for biomedical topics including lecture notes on general and systemic pathology.

NOVA Online provides a companion Web site to the public television program “Cancer Warrior” about Judah Folkman's research. A FAQ about angiogenesis is included.

The September 1996 issue of Scientific American had an article by J. Folkman titled “Fighting cancer by attacking its blood supply.”

The 24 January 1997 issue of Science had a Research News article by M. Barinaga titled “Designing therapies that target tumor blood vessels.”

Numbered Hypernotes

1. OncoLink provides an introduction to radiotherapy. The Encyclopædia Britannica article on radiology includes a section on radiation therapy. The American Cancer Society provides an introduction to the principles of radiation therapy. NCI provides an introduction to radiotherapy. The University of New South Australia Library provides a collection of Internet resources on medical radiation.

2. offers Encyclopædia Britannica articles on tumors and cancer. The Weill Education Center of Cornell University Medical College offers a lecture by R. Mellors on neoplasia. CATS from the University of Vermont College of Medicine provides an introduction to neoplasia and lecture notes on the molecular pathobiology of neoplasia for a general pathology course. The September 1996 issue of Scientific American was a special issue on cancer; an article by R. Weinberg titled “How cancer arises” was included. NOAH (New York Online Access to Health) provides a collection of links to Internet resources on cancer.

3. The Health Physics Society provides a definition of ionizing radiation, which is also defined in the glossary provided by the Low Dose Radiation Research Program. Kimball's Biology Pages include a presentation on radiation. The Uranium Information Centre, Melbourne, Australia, offers a presentation by E. Hall titled “Radiation and life.” The Radiation and Health Physics Page, maintained by the Student Chapter of the Health Physics Society of the University of Michigan, contains information and links related to radiation. The Department of Diagnostic Radiology, Dalhousie University, Halifax, Nova Scotia, Canada, offers a series of lecture notes on experimental and human radiobiology for a course on radiation protection, dosimetry and radiobiology.

4. The Cell Death Society defines apoptosis. The NIH Apoptosis Interest Group offers an introduction to apoptosis. Kimball's Biology Pages offer a presentation on apoptosis. A student Web project on apoptosis was prepared by M. Ali, K. Loh, and K. Schwarz for a course on the structure and function of organisms taught by J. Palmer, School of Biological Sciences, University of Texas. The molecular genetics review Web site sponsored by the Clinical Molecular Genetics Society includes lecture notes on apoptosis. H. Ibelgaufts' Cytokines Online Pathfinder Encyclopaedia (COPE) includes a presentation on apoptosis. The Virtual World of Development, provided by L. Browder, Department of Biological Sciences, University of Calgary, includes a presentation on apoptosis. OncoLink makes available an article by W. G. McKenna titled “Apoptosis, radiosensitivity and the cell cycle.” The November 1997 issue of the Proceedings of the National Academy of Sciences had an article by M. Peter, A. Heufelder, and M. Hengartner titled “Advances in apoptosis research.”

5. The online Merck Manual of Diagnosis and Therapy includes a section on radiation reactions and injuries. The HBCU/MI Environmental Technology Consortium at Clark Atlanta University and Northern Arizona University offers lecture notes on the biological effects of radiation (parts one, two, three, four, and five) for an Internet course on the fundamentals of radioactive waste management. CancerNet provides information on radiation enteritis for health professionals; a version for patients is also available. The Crohn's and Colitis Foundation of America offers an article by A. Rogers titled “Radiation injury to the gut.”

6. The Mayo Clinic provides an introduction to stem cells. provides a Encyclopædia Britannica article on the epithelium. M. Farabee's Online Biology Book includes a section on epithelial tissue. The Blue Histology Web site of L. Slomianka, Department of Anatomy and Human Biology, University of Western Australia, offers lecture notes on epithelia. Frontiers in Bioscience makes available a 15 March 1999 review article by S. Karam titled “Lineage commitment and maturation of epithelial cells in the gut.” J. Scott, Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, provides lecture notes on stem cells for a course on molecular physiology. The 25 February 2000 issue of Science was a special issue on stem cells that had a review by J. M. W. Slack titled “Stem cells in epithelial tissues,” as well as a review by F. Watt and B. Hogan titled “Out of Eden: Stem cells and their niches” and a review by D. van der Kooy and S. Weiss titled “Why stem cells?”

7. Crypts of Lieberkühn are defined in the Dictionary of Biology available from xrefer. R. Blystone, Department of Biology, Trinity University, San Antonio, TX, offers a slide presentation on the crypts of Lieberkühn for a microanatomy course. C. Bradley, Biological Sciences Group, Department of Pharmacy, La Trobe University, Bendigo, Australia, provides illustrated lecture notes on the structure of the gastrointestinal tract for a course on organ system physiology. Pathophysiology of the Digestive System, a tutorial provided by R. Bowen, Animal Reproduction and Biotechnology Laboratory, Colorado State University, includes a presentation on villi, crypts, and the life cycle of small intestinal enterocytes, as well as a section on the gross and microscopic anatomy of the large intestine. A section on gut stem cell biology is included in the draft report of the Stem Cells and Developmental Biology Planning Group, made available by the National Institute of Diabetes and Digestive and Kidney Diseases. A presentation on the lower intestinal tract in the Interactive Histology Atlas from the University of Oklahoma Health Sciences Center includes several slides showing the crypts of Lieberkühn (including slides of the jejunum, illeum, and colon).

8. F.-E. Paris, A. Kang, and R. Kolesnick are in the Laboratory of Signal Transduction; Z. Fuks and A. Haimovitz-Friedman are in the Laboratory of Radiation Oncology Research; and C. Cordon-Cardo is in the Laboratory of Urologic Oncology Research, Memorial Sloan-Kettering Cancer Center, New York.

9. Endothelium is defined in the medical dictionary provided by K. Ley, Department of Biomedical Engineering, University of Virginia, provides a definition of endothelium in a presentation on inflammation. The Abteilung Biotechnologie of the Institut für Biochemie, Darmstadt, Germany, offers an introduction to the biology of endothelial cells. L. Slomianka's Blue Histology Web site includes a presentation by J. McGeachie on endothelial cells. D. Tamarkin, School of Math, Science and Engineering, Springfield Technical Community College, MA, offers a presentation on the endothelium of capillaries in lecture notes on blood vessels for a course on anatomy and physiology. The Human Leucocyte Differentiation Antigens meetings Web site makes available a 1998 meeting presentation by J. Morrissey on endothelial cells.

10. The On-line Medical Dictionary defines angiogenesis. Angiogenesis is defined in the MedicineNet dictionary. The Nitric Oxide Research Group, St. George's Hospital Medical School, University of London, offers an introduction on angiogenesis. H. Ibelgaufts' COPE includes an article on angiogenesis. The Klagsbrun Lab, Children's Hospital Boston, provides a graphic introduction to angiogenesis. The Angiogenesis Foundation offers an introduction to angiogenesis and a presentation titled “Understanding angiogenesis in cancer.” Understanding Angiogenesis is a presentation by the NCI News Center. The Special Project Angiogenesis Web site at the Dipartimento di Scienze Biomediche e Biotecnologie, Università di Brescia, Italy, includes an introduction to angiogenesis, as well as a presentation on angiogenesis and cancer. The companion Web site for the textbook Developmental Biology by S. Gilbert, Department of Biology, Swarthmore College, provides two presentations on angiogenesis. The 4 July 1997 issue of Science had a Perspective by D. Hanahan titled “Signaling vascular morphogenesis and maintenance.”

11. InvivoGen offers a definition of basic fibroblast growth factor (bFGF/FGF2). The section on growth factors and cytokines of M. King's Medical Biochemistry Page includes a presentation on fibroblast growth factors. The WorldMedicus Web site provides information about bFGF. Entries for FGF2 appear in the GeneCards database, Online Mendelian Inheritance in Man (OMIM), and Jackson Laboratory's Mouse Genome Informatics database. M. Hill, School of Anatomy, University of New South Wales, Australia, provides information about fibroblast growth factors in the molecular development section of his embryology resource Web site. H. Ibelgaufts' COPE includes articles on FGF and basic FGF. The Special Project Angiogenesis Web site makes available a presentation by M. Presta on FGF2 and angiogenesis.

12. Ceramide is defined in the Academic Press Dictionary of Science and Technology. The Apoptosis Special Interest Site provided by Roche Diagnostics includes a description of ceramide. Apoptopedia from the Cohen Laboratory, Department of Pathology, University of Iowa, includes a presentation titled “Ceramide and other sphingolipids in apoptosis.” D. Andrews, Department of Biochemistry, McMaster University, offers a research presentation on apoptosis that includes a section on ceramide-induced apoptosis. S. Marchesini, Facoltà di Medicina e Chirurgia, Università di Brescia, Italy, makes available a molecular model of ceramide for a biochemistry course. The e-thesis Web site of the University of Helsinki makes available (in Adobe Acrobat format) an Institute of Biomedicine doctoral dissertation by J. Holopainen titled “Ceramide - A messenger of cell death.” The 13 December 1996 issue of Science had a article by Y. Hannun titled “Functions of ceramide in coordinating cellular responses to stress.”

13. The Ovarian Kaleidoscope Database, maintained by the Hsueh Laboratory, Division of Reproductive Biology, Stanford University Medical Center, includes information about acid sphingomyelinase. M. King's Medical Biochemistry Page includes a presentation on the metabolism of the sphingolipids.

14. The NCI's Cancer Information Service provides a fact sheet on angiogenesis inhibitors in the treatment of cancer. The NCI's Cancer Trials Web page includes a information page on angiogenesis inhibitors. Kimball's Biology Pages offer a presentation titled “Fighting cancer with angiogenesis inhibitors.” P. Romaniuk, Department of Biochemistry and Microbiology, University of Victoria, CA, offers a presentation on inhibiting angiogenesis for a course on the biochemistry of human health. The National Ovarian Cancer Association provides a collection of links to information on antiangiogenic research. The Midwest Institute for Interventional Therapy Web site offers a presentation by L. Machanand and J. Scholar titled “Angiogenesis inhibitors in interventional radiology.” The Why Files from the University of Wisconsin offer a presentation on angiogenesis inhibitors titled “Of mice and men: Positive signs for cancer treatment.”

15. OMIM has an entry for vascular endothelial growth factor (VEGF). H. Ibelgaufts' COPE includes an article on VEGF. The GeneCards database has an entry for VEGF. The Scientific Report 2000 of the Imperial Cancer Research Fund includes a presentation on endothelial cells and VEGF by the Endothelial Cell Biology Laboratory. The Angiogenesis Laboratory at the Ludwig Institute for Cancer Research, Melbourne, Australia, provides a presentation on VEGF.

16. NCI's glossary of cancer-related terms defines fractionation in radiotherapy. An introduction to fractionated radiotherapy is included in a book chapter on radiation therapy for acoustic neuroma made available by the UCSF Acoustic Neuroma Web page.

17. The American Cancer Society provides information resources on Hodgkin's disease (Hodgkin's lymphoma). CancerNet provides information about Hodgkin's disease. The online Merck Manual of Diagnosis and Therapy includes a section on Hodgkin's disease. The Memorial Sloan-Kettering Cancer Center provides information about Hodgkin's disease.

18. The glossary of neurosurgical terms provided by includes a definition of glioblastoma. The Fox Chase-Temple Joint Program in Neuro-oncology provides an introduction to glioblastoma multiforme. The Society for Neuroscience makes available a briefing on glioma brain tumors. The online Merck Manual of Diagnosis and Therapy includes a section on intracranial neoplasms. PathWeb from the University of Connecticut Health Center includes a presentation on glioblastoma (with a collection of images). The Memorial Sloan-Kettering Cancer Center provides information about brain tumors and their treatment.

19. M. Judah Folkman is in the Department of Surgery, Children's Hospital, and Kevin Camphausen is at the Joint Center for Radiation Therapy, Harvard Medical School, Boston.


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