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  • Review Article
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FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy?

Nature Reviews Cancer volume 8, pages 942–956 (2008)Cite this article

Key Points

  • Angiogenesis inhibitors that target vascular endothelial growth factor (VEGF) signalling pathways have proved successful for the clinical treatment of various types of cancer. However, a substantial fraction of tumours is resistant or escapes current anti-angiogenic therapies. Moreover, VEGFA is a trophic factor for healthy vessels, and therefore anti-angiogenic therapies cause side effects that although well managed, can also lead to life-threatening conditions in a subset of patients with cancer.

  • VEGFR2 (also known as FLK1) is the primary receptor that binds VEGFA, and therefore controls angiogenesis in both healthy and diseased tissues. By contrast, VEGFR1 (also known as FLT1) binds VEGFA, VEGFB and placental growth factor (PlGF). The expression of FLT1 and its two ligands, PlGF and VEGFB, is increased in various tumours, which correlates with disease progression and can predict poor prognosis, metastasis and recurrent disease in humans.

  • PlGF signals directly through FLT1 in various cell types, including endothelial cells, smooth-muscle cells, fibroblasts, angiogenesis-competent myeloid progenitors, macrophages and tumour cells, and thereby promotes tumour angiogenesis, lymphangiogenesis, tumour growth and the formation of the premetastatic niche. Therefore deletion of tyrosine-kinase activity in Flt1TK−/− mice or treatment with FLT1- and PlGF-specific inhibitors, such as a monoclonal antibody against PlGF (αPlGF), impairs inflammation and pathological angiogenesis, and suppresses tumour growth and metastasis.

  • Myeloid cells confer resistance to therapies that target VEGF by secreting additional pro-angiogenic factors. αPlGF enhances the responsiveness to VEGF-targeted therapies by inhibiting macrophage recruitment. Therefore, owing to its complementary activities, αPlGF eliminates the source of angiogenic factors that contributes to anti-angiogenic escape of tumours.

  • Gene-deletion studies have revealed that PlGF is redundant for vascular development and physiological vessel maintenance in healthy adults, but contributes to the angiogenic and inflammatory switch in cancer. In support of the concept that PlGF is a disease-specific factor, αPlGF selectively inhibits pathological angiogenesis without affecting healthy vessels and thus does not cause the side effects that are typically observed during current anti-angiogenic therapies.

  • Genetic and pharmacological studies have thus identified FLT1 and PlGF as attractive therapeutic targets for anticancer therapy, which might provide an answer to some of the challenges and unmet needs that are faced by current anti-angiogenic therapies: how to increase efficacy, avoid resistance and minimize toxicity.

Abstract

Less than 5 years ago, it was still not clear whether anti-angiogenic drugs would prove successful in the clinic. After numerous patients with cancer or age-related macular degeneration have been treated with these drugs, they have now become part of the standard range of therapeutic tools. Despite this milestone, anti-angiogenic therapy still faces a number of clinical hurdles, such as improving efficacy, avoiding escape and resistance, and minimizing toxicity. Hopefully, other agents with complementary mechanisms, such as those that target placental growth factor, will offer novel opportunities for improved treatment.

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Figure 1: Indirect and direct angiogenic effects of vascular endothelial growth factor B (VEGFB) and placental growth factor (PlGF) on endothelial cells.
Figure 2: Pleiotropic cellular activities of vascular endothelial growth factor B (VEGFB) and placental growth factor (PlGF).
Figure 3: Molecular mechanisms of placental growth factor (PlGF).
Figure 4: Pleiotropic roles of placental growth factor (PlGF) in tumour growth, angiogenesis and metastasis.
Figure 5: Mechanisms of resistance or escape from anti-placental growth factor (PlGF) and anti-vascular endothelial growth factor (VEGF) therapies.
Figure 6: Anti-placental growth factor (PlGF) does not prune quiescent vessels.

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  1. Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin, Berlin, Campus Virchow, Klinikum, 13353, Berlin, Germany

    Christian Fischer

  2. Vesalius Research Center, Flanders Institute for Biotechnology (VIB), B-3000, Leuven, Belgium

    Massimiliano Mazzone, Bart Jonckx & Peter Carmeliet

  3. Vesalius Research Center, Campus Gasthuisberg, Katholieke Universiteit Leuven, Herestraat 49, B-3000, Leuven, Belgium

    Massimiliano Mazzone, Bart Jonckx & Peter Carmeliet

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Fischer, C., Mazzone, M., Jonckx, B. et al. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy?. Nat Rev Cancer 8, 942–956 (2008). https://doi.org/10.1038/nrc2524

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