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Healing hemangiomasLena Claesson-Welsh

Defective signaling of vascular endothelial growth factor seems to underlie the development of hemangiomas, disfiguring tumors arising early in life (pages 1236–1246).

Lena Claesson-Welsh is in the Department of

Genetics and Pathology, Uppsala University, Dag

Hammarskjölds väg 20, 751 85 Uppsala, Sweden.

e-mail: Lena.Welsh@genpat.uu.se

Hemangiomas are common, benign tumors that appear in particular locations, com-monly in the face and neck region1. As they form, endothelial cells—the cells that form the inner lining of blood vessels—lose their ability to organize in lumenized structures and instead form a proliferating mass of cells. Inconspicuous at birth, they grow to a some-times severely disfiguring mass that occasion-ally can be life-threatening by disturbing or destroying surrounding tissues and organs. In the majority of cases, the tumors involute but may leave behind adipose deposits. Current therapy, such as systemic or local application of steroids, works in many cases; however, a third of the patients do not respond to this treatment.

In a study in the current issue of Nature Medicine, Jinnin et al.2 examine the mecha-nism underlying endothelial cell malfunction in hemangioma. These data strongly suggest that hemanigiomas could be treated by block-ing the function of vascular endothelial growth factor (VEGF), which is uniquely required for blood vessels to form and survive3,4.

VEGF binds to two related receptor tyrosine kinases VEGFR receptor-1 (VEGFR1; encoded by Flt1) and VEGFR2 (also denoted KDR in the human and Flk1 in the mouse). VEGFR2 is essential for endothelial cell func-tion3. In contrast, the tyrosine kinase activ-ity of VEGFR1 seems not to be required in endothelial cells5. Instead, VEGFR1 may serve as a negative regulator of VEGFR2 by acting as a sink for VEGF, that is, by bind-ing the growth factor without transmitting a signal6. Knocking out Flt1 leads to increased

formation of endothelial cells and death of the embryo due to vessel occlusion4.

In a panel of hemangioma-derived endothelial cell lines, Jinnin et al.2 observed that decreased expression of VEGFR1 caused increased availability of VEGF. As a result, VEGFR2 activity and signal transduction was enhanced in these cell lines.

The researchers next traced this decrease in VEGFR1 expression to discrete germline muta-tions in affected individuals2. The mutations occurred in the gene encoding VEGFR2 as well as in the gene encoding TEM8 (the anthrax receptor), an integrin-like molecule previously

implicated in pathological angiogenesis7. The effects of these mutations converged on a path-way involving a complex between VEGFR2, TEM8 and integrins, which suppressed the activity of nuclear factor of activated T cells (NFAT), a transcription factor that regulates the expression of VEGFR1. Each component in this multiprotein complex was required for the NFAT-dependent reduction in VEGFR1 expression.

Jinnin et al.2 went on to treat the cell lines with neutralizing antibodies to VEGF. This treatment normalized the VEGF signaling profile to mimic that of primary endothe-

nature medicine volume 14 | number 11 | november 2008 1147

Normal endothelial cells (ECs)

VEGF boundto VEGFR2

VEGF boundto VEGFR1

VEGF boundto VEGFR1

VEGF boundto VEGFR2

Hemangioma ECs

VEGFR1

EC proliferation

VEGFR2

VEGFR1

NFAT

MutatedmultiproteincomplexesVEGFR2

TEM8

?

Integrin

EC proliferation

Hemangioma

VEGFR2

a b

Figure 1 Imbalanced VEGFR1 and VEGFR2 function in hemangioma. (a) In normal endothelial cells (ECs), VEGF binds to VEGFR1 with higher affinity than to VEGFR2. VEGFR1, which is expressed both as soluble and transmembrane forms, acts as a sink for VEGF, thereby decreasing VEGFR2 activity and downstream signals for endothelial cells to proliferate. (b) Endothelial cells derived from hemangiomas express aberrant multiprotein complexes—containing integrins and mutated variants of VEGFR2 and TEM8 and possibly also other molecular components (indicated by question mark). These complexes decrease the activity of NFAT, resulting in the downregulation of VEGFR1 expression. As a consequence, more VEGF is available to bind and activate VEGFR2, causing enhanced endothelial cell proliferation.

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lial cultures. A similar effect was obtained by expressing a kinase-dead VEGFR1 unable transduce signal into hemangioma endothe-lial cells, suggesting that hemangiomas do not arise as a consequence of loss of VEGFR1 intracellular signaling. Instead, the key is in the imbalance in VEGFR1 expression and VEGFR2 function (see Fig. 1).

Other point mutations have been identified previously in hemangiomas8, such as those in the Tek gene, which encodes another impor-tant angiogenic regulator9. Interestingly the Tek mutation also results in increased amounts of VEGF available to activate VEGFR2. It is pos-sible that a variety of mutations in gene prod-ucts involved in the angiogenic process can feed into the same pathway of regulating VEGF accessibility or VEGFR1 expression.

Unexpectedly, the mutation in VEGFR2 identified by Jinnin et al.2 is located in the VEGFR2 extracellular domain and does not change the catalytic function of the receptor. Instead, abnormal multiprotein complexes involving VEGFR2, TEM8, integrins, and maybe also other components, may be estab-lished, given the possibly of altered confirma-tion imposed by the mutations (Fig. 1).

One clear strength of the model of Jinnin et al.2 is that it makes room for previously

described molecular changes in hemangiomas, such as increased expression of the glucose transporter protein GLUT1 (ref. 10), which has been used to differentially diagnose heman-gioma compared to other vascular anomalies also characterized by increased endothelial cell proliferation. GLUT1 is another NFAT-regulated gene product.

An important next step will be to ask whether an altered VEGFR1-VEGFR2 bal-ance occurs in hemangiomas in vivo. The current study cannot exclude the possibility that hemangioma stem cells, which mature into hemangioma-derived endothelial cells, constitute a more appropriate target in hemangiomas11. Does an altered balance of VEGFR1 and VEGFR2 activity establish or maintain such stem cells? If so, neutralization of VEGF may not only suppress but also cure hemangiomas.

A welcome, recently described heman-gioma animal model11, established by injec-tion of human hemangioma stem cells into immunocompromised mice, now allows for further exploration of such questions. The model may also be useful to examine whether changes in VEGF signaling seen in heman-giomas can promote other pathologies involv-ing exaggerated VEGFR2 signaling, such as

other forms of cancer or disorders involving chronic inflammation.

Systemic neutralization of VEGF —such as with the drug Avastin (bevacizumab), approved by the US Food and Drug Administration—is not a trivial therapy. In mice, complete block-ing of VEGF function leads to the deterioration of vessels in healthy tissues, since endothelial cells need VEGF both to form vessels and to survive12. Nonetheless, the data of Jinnin et al.2 provide a strong incentive to adopt and fine-tune anti-VEGF therapy to treat severe cases of infantile hemangioma.

1. Chang, L.C. et al. Pediatrics 122, 360–367 (2008).2. Jinnin, M. et al. Nat. Med. 14, 1236–1246 (2008).3. Olsson, A.K., Dimberg, A., Kreuger, J. & Claesson-Welsh,

L. Nat. Rev. Mol. Cell Biol. 7, 359–371 (2006).4. Fong, G.H., Rossant, J., Gertsenstein, M. & Breitman,

M.L. Nature 376, 66–70 (1995).5. Hiratsuka, S., Minowa, O., Kuno, J., Noda, T. &

Shibuya, M. Proc. Natl. Acad. Sci. USA 95, 9349–9354 (1998).

6. Ferrara, N. EXS 209–231 (2005).7. Nanda, A. et al. Cancer Res. 64, 817–820 (2004).8. Wang, H., Zhang, Y., Toratani, S. & Okamoto, T. Oncogene

23, 8700–8704 (2004).9. Eklund, L. & Olsen, B.R. Exp. Cell Res. 312, 630–641

(2006).10. North, P.E., Waner, M., Mizeracki, A. & Mihm, M.C., Jr.

Hum. Pathol. 31, 11–22 (2000).11. Khan, Z.A. et al. J. Clin. Invest. 118, 2592–2599

(2008).12. Kamba, T. & McDonald, D.M. Br. J. Cancer 96, 1788–

1795 (2007).

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Epstein-Barr virus sustains tumor killersRichard J O’Reilly

The immune system’s response to a latent and ubiquitous virus is harnessed to kill tumors in a small study of humans. The approach overcomes a major barrier to effective tumor immunotherapy—generating a sustained immune response (pages 1264–1270).

Richard J. O’Reilly is at the Memorial Sloan

Kettering Cancer Center, 1275 York Avenue,

New York, New York 10021, USA.

e-mail: oreillyr@mskcc.org

Over the last twenty years, tumor immu-nologists have identified antigens uniquely or overly expressed by tumor cells that can stimulate T cells that generate tumor-suppressive cytokines and can kill or sup-press the growth of targeted tumors in vitro. However, when these antigens are used to vaccinate tumor-bearing hosts, the T cell responses have almost invariably been short lived, without lasting immunity.

Similarly, when T cells immunized against these tumor antigens and expanded in vitro have been adoptively transferred into tumor-bearing animals or individu-

als with cancer, their antitumor effects and survival have been short lived. In contrast, certain viruses, such as Epstein-Barr virus (EBV), which causes infectious mononucle-osis, establish long-term latent infections that induce a sustained and rigorous pro-tective T cell immune response that persists for an individual’s lifetime.

In this issue of Nature Medicine, Pule et al.1 present a strategy for T cell immu-notherapy that takes advantage of this sus-tained response. In clinical experiments, they target tumors with EBV-specific T cells engineered to express a tumor-specific chi-meric antigen receptor (CAR)1. These cells persist and maintain their tumor-specific activity long after adoptive transfer and thereby allow a more sustained antitumor response.

The strategy of Pule et al.1 stems from the unique interactions of EBV with the immune system. Early in the course of infec-tion, the virus spreads from the oropharynx to infect B cells in the mucosa, leading to their transformation and immortalization. The T cell response to primary infection dispatches most of these B cells, but a small fraction survive, maintaining a state of latent infection and expressing only a limited array of viral proteins. The EBV–positive B cells continuously stimulate the generation of EBV-specific T cells throughout a person’s lifetime. The extraordinary magnitude of this T cell surveillance can be inferred by the fact that in seropositive asymptomatic car-riers of any age, 0.1–2% of the T cells in the circulation are specific for single epitopes of immunogenic latent or lytic EBV proteins2.

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