PlGF: a multitasking cytokine with disease-restricted activity

Abstract

Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family that also comprises VEGF-A (VEGF), VEGF-B, VEGF-C, and VEGF-D. Unlike VEGF, PlGF is dispensable for development and health but has diverse nonredundant roles in tissue ischemia, malignancy, inflammation, and multiple other diseases. Genetic and pharmacological gain-of-function and loss-of-function studies have identified molecular mechanisms of this multitasking cytokine and characterized the therapeutic potential of delivering or blocking PlGF for various disorders.

Figure 1.

PlGF is a multitasking cytokine affecting various cellular activities. Scheme illustrating the pleiotropic actions of PlGF, including effects on survival, migration, proliferation, metabolism, and activation effects on vascular (endothelial cells, pericytes/smooth muscle cells) as well as nonvascular cells (macrophages, bone marrow–derived progenitors, tumor cells, dendritic cells, fibroblasts, hepatic stellate cells, epithelial cells, neurons, Shwann cells, astrocytes). BM, Bone marrow; SMC, smooth muscle cell; TAM, tumor-associated macrophage.

Figure 2.

Roles of PlGF in cancer and metastasis. PlGF affects various cellular components and processes in the tumor. It affects angiogenesis by promoting proliferation and migration of endothelial cells, maturation of the vessels by recruiting smooth muscle cells, mobilization of vasculogenic bone-marrow progenitors, and recruitment of macrophages, which produce additional angiogenic and lymphangiogenic factors. PlGF also enhances the “disorganization” of tumor vessels, characterized by an irregular appearance and discontinuous endothelial lining, including “sinusoidal capillarization” in HCC (see also Fig. 3). PlGF also promotes the proliferation and migration of activated hepatic stellate cells in HCC and liver fibrosis. PlGF reduces dendritic cell accumulation and function, thereby suppressing antitumor immune defense responses. PlGF directly stimulates proliferation of tumor cells, which cross talk to and activate stromal cells to produce PlGF (see also Fig. 4). PlGF was also implicated in the mobilization of bone marrow–derived progenitor cells to the “premetastic niche,” although conflicting data have been reported. TAM, Tumor-associated macrophage; VEGFA, vascular endothelial growth factor A; VEGFC, vascular endothelial growth factor C.

Figure 3.

Role of PlGF in sinusoidal disorganization in HCC. (A,B) In healthy liver, the hepatic microvascular units, the sinusoids (visualized by endoglin immunostaining in A), are characterized by a porous fenestrated endothelial lining and absence of a basement membrane, facilitating oxygen and metabolic exchange between the bloodstream and the hepatocytes; the latter are separated from the sinusoids by the perisinusoidal space (space of Disse), where quiescent hepatic stellate cells reside (B). (C,D) In hepatocellular carcinoma, sinusoids undergo “capillarization,” characterized by loss of fenestration, increased numbers of activated stellate cells that deposit matrix and release angiogenic factors, change of shape and size of the capillarized sinusoids to more tortuous vessels, and lumen loss in a fraction of the capillaries. These changes result in impaired blood flow (red arrow in D) along with reduced oxygen transfer from the blood to the liver parenchyma (gray arrow in D), resulting in increased hypoxia, which further promotes tumor cell proliferation resulting in enlarged intercapillary distances (C). (E,F) PlGF blockage by gene silencing or by inhibition with neutralizing antibody partially prevented this disorganization of hepatic sinusoids. The abnormal tortuous appearance, abnormal size, and loss of lumenization of the sinusoids were attenuated (E), and sinusoidal “capillarization” was reduced (F). This partial “normalization” by PlGF blockage functionally improved tissue oxygenation and reduced proliferation of HCC cells (Van de Veire et al. 2010; Rolny et al. 2011).

Figure 4.

Bidirectional cross talk between leukemia and bone marrow stromal cells. In chronic myeloid leukemia (CML), tumor cells “educate” bone marrow stromal cells to produce PlGF. This induction involves NF-κB activation in the stromal cells and requires leukemia cell/stromal cell contact, which is in part mediated by VLA-4/VCAM-1 interaction. VLA-4/VCAM-1 interaction is reported to activate NF-κB (Zohlnhofer et al. 2000), and NF-κB, in turn, up-regulates VCAM-1 (Rajan et al. 2008), suggesting a positive feedback loop reinforcing VLA4⁺ CML cell binding to the VCAM-1-expressing stromal cells, thereby ensuring PlGF production. Stromal cell-derived PlGF then promotes proliferation and metabolism of the CML cells. Overall, PlGF creates a fertile microenvironmental soil for the seeding tumor cells to foster cancer cell survival and expansive growth (Schmidt et al. 2011).