ALK1 as an emerging target for antiangiogenic therapy of cancer

Abstract

Members of the TGF-β family act on many, if not all, cell types within the body, producing diverse and complex cellular outcomes. Activation of the endothelial cell-restricted TGF-β type I receptor ALK1 results from the binding of several different ligands of the TGF-β family, including bone morphogenetic protein (BMP) 9, BMP10, and TGF-β. Mounting genetic, pharmacologic, and histopathologic evidence supports a critical role for ALK1 signaling in regulation of both developmental and pathologic blood vessel formation. However, the precise function of TGF-β family signaling in endothelial cells is difficult to predict and appears highly context dependent because of the multitude of ligands and receptors influencing the final outcome. Pharmacologic inhibitors of ALK1 have recently been developed and will allow for more accurate studies of ALK1 function in vivo, as well as for assessment of ALK1 as a target for suppression of angiogenesis during tumor development. Herein, we will summarize the current view of ALK1 regulation of endothelial cell phenotype in vitro and in vivo as well as provide an outlook for the ongoing clinical trials of ALK1 inhibitors in malignant disease.

Figure 1

Illustration of TGF-β family signaling in ECs. TGF-β activates both ALK1 and ALK5 type I receptor expressed by ECs, whereas BMP9 only binds ALK1. The affinity of BMP9 for ALK1 is greater than that of TGF-β, making it likely that ALK1 will predominantly bind BMP9 when both ligands are available. In addition, endoglin acts as a coreceptor modulating signaling through ALK1. Smad 1, 5, and 8 are preferentially phosphorylated and activated by ALK1, whereas Smad 2 and 3 act downstream of ALK5. Subsequently, Smads are translocated to the nucleus, where they regulate specific gene expression.

Figure 2

The outcome of signaling by TGF-β family members in ECs is highly context dependent. The net effect of stimulation or inhibition of EC migration, proliferation, and survival is illustrated by images from immunostaining of tumor sections for the vascular marker CD31 (red; images are only representations and are not derived from actual experimental settings). (A) TGF-β signaling through ALK1 predominantly acts to stimulate EC growth and migration. TGF-β signaling through ALK5 predominantly acts to inhibit EC growth and migration. BMP9 stimulation of ALK1 has been reported to be either inhibitory or stimulatory in terms of EC growth and migration. Stimulation of ECs with both TGF-β and BMP9, thus engaging both ALK1 and ALK5 simultaneously, primes ECs to an angiogenic stimulus by prototypical angiogenic inducers such as VEGF. (B) Representation of paracrine interaction between ALK1 expressed by ECs and ALK5 expressed by mural cells. (C) Illustration of the large complexity of BMP ligands and type I receptors that collectively regulate EC functionality in a context-dependent manner.

Figure 3

Immunostaining for ALK1 (brown) of a section from human prostate cancer reveals a vascular staining pattern. Cell nuclei are counterstained with hematoxylin (blue). Image taken from the Human Protein Atlas (http://www.proteinatlas.org).