Multifaceted Role of the Placental Growth Factor (PlGF) in the Antitumor Immune Response and Cancer Progression.

The sharing of molecules function that affects both tumor growth and neoangiogenesis with cells of the immune system creates a mutual interplay that impairs the host's immune response against tumor progression. Increasing evidence shows that tumors are able to create an immunosuppressive microenvironment by recruiting specific immune cells. Moreover, molecules produced by tumor and inflammatory cells in the tumor microenvironment create an immunosuppressive milieu able to inhibit the development of an efficient immune response against cancer cells and thus fostering tumor growth and progression. In addition, the immunoediting could select cancer cells that are less immunogenic or more resistant to lysis. In this review, we summarize recent findings regarding the immunomodulatory effects and cancer progression of the angiogenic growth factor namely placental growth factor (PlGF) and address the biological complex effects of this cytokine. Different pathways of the innate and adaptive immune response in which, directly or indirectly, PlGF is involved in promoting tumor immune escape and metastasis will be described. PlGF is important for building up vascular structures and functions. Although PlGF effects on vascular and tumor growth have been widely summarized, its functions in modulating the immune intra-tumoral microenvironment have been less highlighted. In agreement with PlGF functions, different antitumor strategies can be envisioned.

Dendrobium nobile Lindley and its bibenzyl component moscatilin are able to protect retinal cells from ischemia/hypoxia by dowregulating placental growth factor and upregulating Norrie disease protein.

BACKGROUND: Presumably, progression of developmental retinal vascular disorders is mainly driven by persistent ischemia/hypoxia. An investigation into vision-threatening retinal ischemia remains important. Our aim was to evaluate, in relation to retinal ischemia, protective effects and mechanisms of Dendrobium nobile Lindley (DNL) and its bibenzyl component moscatilin. The therapeutic mechanisms included evaluations of levels of placental growth factor (PLGF) and Norrie disease protein (NDP). METHODS: An oxygen glucose deprivation (OGD) model involved cells cultured in DMEM containing 1% O2, 94% N2 and 0 g/L glucose. High intraocular pressure (HIOP)-induced retinal ischemia was created by increasing IOP to 120 mmHg for 60 min in Wistar rats. The methods included electroretinogram (ERG), histopathology, MTT assay and biochemistry. RESULTS: When compared with cells cultured in DMEM containing DMSO (DMSO+DMEM), cells subjected to OGD and pre-administrated with DMSO (DMSO+OGD) showed a significant reduction in the cell viability and NDP expression. Moreover, cells that received OGD and 1 h pre-administration of 0.1 µM moscatilin (Pre-OGD Mos 0.1 µM) showed a significant counteraction of the OGD-induced decreased cell viability. Furthermore, compared with the DMSO+OGD group (44.54 ± 3.15%), there was significant elevated NDP levels in the Pre-OGD Mos 0.1 µM group (108.38 ± 29.33%). Additionally, there were significant ischemic alterations, namely reduced ERG b-wave, less numerous retinal ganglion cells, decreased inner retinal thickness, and reduced/enhanced amacrine's ChAT/Müller's GFAP or vimentin immunolabelings. Moreover, there were significantly increased protein levels of HIF-1α, VEGF, PKM2, RBP2 and, particularly, PLGF (pg/ml; Sham vs. Vehicle: 15.11 ± 1.58 vs. 39.53 ± 5.25). These ischemic effects were significantly altered when 1.0 g/Kg/day DNL (DNL1.0 + I/R or I/R+ DNL1.0) was applied before and/or after ischemia, but not vehicle (Vehicle+I/R). Of novelty and significance, the DNL1.0 action mechanism appears to be similar to that of the anti-PLGF Eylea [PLGF (pg/ml); DNL1.0 vs. Eylea+I/R: 19.93 ± 2.24 vs. 6.44 ± 0.60]. CONCLUSIONS: DNL and moscatilin are able to protect against retinal ischemic/hypoxic changes respectively by downregulating PLGF and upregulating NDP. Progression of developmental retinal vascular disorders such as Norrie disease due to persistent ischemia/hypoxia might be thus prevented.

Knockdown of placental growth factor (PLGF) mitigates hyperoxia-induced acute lung injury in neonatal rats: Suppressive effects on NFκB signaling pathway.

Although supplemental high-level oxygen treatment can promote the survival of premature infants, hyperoxia may adversely induce acute lung injury (ALI) in newborns. Our prior work illustrated that hyperoxic exposure could enhance the release of placental growth factor (PLGF) in the lungs of neonatal rats. We therefore postulated that PLGF contributed to hyperoxic ALI in newborns and evaluated the anti-PLGF treatment mediated by systematic delivery of lentivirus in hyperoxic ALI in this study. Lentivirus particles containing PLGF specific shRNA were injected into neonatal rats prior to hyperoxic exposure (90% oxygen for 72h) to inhibit PLGF expression. Hyperoxia induced oxidative damages in lung tissues as evidenced by the increased malondialdehyde and myeloperoxidase, and the decreased antioxidant superoxide dismutase. Also, hyperoxia caused excessive infiltration of inflammatory cells and overproduction of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1ß and interleukin-6) in rat lung tissue. These pathological alterations were partly reversed by PLGF shRNA delivery. The expression levels and activities of metalloproteinase (MMP)-2 and MMP9 were up-regulated in response to hyperoxia, whereas down-regulated when PLGF was inhibited. Moreover, PLGF shRNA inhibited nuclear factor kappa B (NFκB) signaling delivery in hyperoxic rat lungs. Additionally, exogenous PLGF-induced activation of MMPs in rat RLE-6TN alveolar epithelial cells was suppressed by NFκB inhibitor pyrrolidine dithiocarbamate. These results suggest that therapy targeting PLGF may be beneficial for infants with hyperoxic ALI.