a new weapon for attacking tumor blood vessels

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Volume 358:2066-2067

May 8, 2008

Number 19

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A New Weapon for Attacking Tumor Blood VesselsGregg L. Semenza, M.D., Ph.D.

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The approval by the Food and Drug Administration of bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF),1 sparked enormous excitement among oncologists. Bevacizumab, the first cancer therapy that acts by blocking angiogenesis, is the result of the successful translation of pioneering work by the late Judah Folkman and his colleagues, who proposed that vascularization is essential for the growth of clinically relevant invasive carcinomas. A recent study by Fischer and colleagues2 indicates that a monoclonal antibody against another angiogenic protein, placental growth factor (PlGF), may also be a useful antiangiogenic therapy for cancer in humans. Tumor cells produce and secrete, in various amounts, many different angiogenic factors, including VEGF, PlGF, stromal-cellderived factor 1, and angiopoietin-2. Transcription of the genes encoding these proteins is mediated by hypoxia-inducible factor 1, which is expressed at high levels in many tumors in response to the reduced availability of oxygen and as a consequence of genetic alterations that activate oncogenes and inactivate tumor-suppressor genes.3 Once produced, the angiogenic factors stimulate angiogenesis through two mechanisms. First, they have local effects by binding to their cognate receptors on peritumoral vascular endothelial cells. Receptor binding triggers these cells to engage in the budding of new capillary branches that supply blood to the tumor from existing host blood vessels. Second, the secreted angiogenic factors bind to receptors on cells located at distant sites, including the bone marrow, and they stimulate the mobilization of these cells into the circulation and their subsequent homing to the tumor. These recruited cells promote vascularization either by incorporation into nascent blood vessels or by the paracrine production of additional angiogenic factors. Although VEGF and PlGF have been shown to contribute to both of these mechanisms, the overall body of data suggests that VEGF binding to VEGF receptor 2 (VEGFR-2) is critical because it activates endothelial-cell proliferation and survival. PlGF binding to VEGF receptor 1 (VEGFR-1) is also pivotal in that it results in the recruitment of macrophages and other bone marrowderived proangiogenic cells. The functional distinction between these proteins is highlighted by the observation that VEGF is essential for normal embryonic vascularization and development in mice, whereas PlGF is dispensable for these processes. Fischer and colleagues report that in mouse models of cancer, treatment with anti-PlGF antibodies inhibited tumor growth, angiogenesis, and recruitment of macrophages (which express VEGFR-1). In contrast, treatment with antiVEGFR-2 antibodies inhibited tumor growth and angiogenesis but did not inhibit macrophage recruitment. The recruitment of myeloid cells is a major mechanism of tumor resistance to anti-VEGF therapy. As might be expected, some tumor models showed a greater response to antiVEGFR-2 antibodies, whereas others responded better to anti-PlGF treatment. Combination therapy with both antibodies resulted in greater inhibition of tumor growth than inhibition with either antibody alone, suggesting that the two antibodies have different mechanisms of action. Combination therapy also resulted in a greater inhibition of lymphangiogenesis than inhibition with either treatment alone. Thus, both vascular and lymphatic metastasis may be affected. These results provide compelling preclinical data to support clinical trials of a humanized anti-PlGF antibody. However, dramatic results were observed in preclinical studies with bevacizumab, which has shown significant but modest effects in clinical trials, and with other antiangiogenic agents that have not shown efficacy in humans. Limitations are associated with the tumor models used in preclinical studies in which a million cancer cells are injected into the subcutaneous tissue (in a xenograft) or organ of origin (by means of orthotopic transplantation). The resulting rapid tumor growth induces an enormous requirement for angiogenesis. This requirement cannot be satisfied by the activation of local vascular cells; it also requires the recruitment of bone marrowderived angiogenic cells. In contrast, tumors spontaneously arising in mice bearing a mutation in the Pten tumor-suppressor gene or treated with chemical carcinogens develop more slowly over a longer period of time and are not dependent on the recruitment of bone marrowderived cells for angiogenesis.4 Since most cancers in humans develop slowly over the course of many years, the mouse transplantation models seem likely to overestimate the therapeutic effect of antiangiogenic agents, especially those that block the recruitment of bone marrowderived cells. In mice treated with anti-PlGF antibodies, Fischer et al. did not observe the side effects that are typically observed after treatment with anti-VEGFR-2 antibodies. This result is consistent with the hypothesis that, as compared with VEGF, PlGF is not required for the establishment and maintenance of what the authors describe as "healthy vessels." Although this may be so, Fischer and colleagues have previously shown that PlGF, like VEGF, plays an important role in ischemia-induced angiogenesis.5 Thus, treatment with either antibody (and especially with both) may exacerbate coexisting coronary artery disease or peripheral-artery disease. All these caveats aside, the weight of evidence indicates that tumor-associated macrophages play an important role in the pathogenesis of many human cancers and suggests that anti-PlGF therapy may represent an important new weapon in the war against cancer. As we continue to add to the armamentarium, determining the combination of weapons to be used in any given battle (i.e., the patient) to most effectively exploit the weaknesses of the enemy (i.e., the cancer) may become the greatest challenge in prolonging the survival of patients. No potential conflict of interest relevant to this article was reported.

Source Information

From Johns Hopkins University School of Medicine, Baltimore. References

1. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005;438:967-974.[CrossRef]

HYPERLINK "http://content.nejm.org/cgi/external_ref?access_num=16355214&link_type=MED" \t "ISI" [Medline]

2. Fischer C, Jonckx B, Mazzone M, et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 2007;131:463-475.[CrossRef]

HYPERLINK "http://content.nejm.org/cgi/external_ref?access_num=000250618500015&link_type=ISI" \t "ISI" [ISI]


3. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003;3:721-732.[CrossRef]



4. Alani RM, Silverthorn CF, Orosz K. Tumor angiogenesis in mice and men. Cancer Biol Ther 2004;3:498-500.[ISI]


5. Luttun A, Tjwa M, Moons L, et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 2002;8:831-840.[CrossRef]



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a new weapon for attacking tumor blood vessels

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