PlGF Blockade Does Not Inhibit Angiogenesis during Primary Tumor Growth

Abstract

It has been recently reported that treatment with an anti-placenta growth factor (PlGF) antibody inhibits metastasis and primary tumor growth. Here we show that, although anti-PlGF treatment inhibited wound healing, extravasation of B16F10 cells, and growth of a tumor engineered to overexpress the PlGF receptor (VEGFR-1), neutralization of PlGF using four novel blocking antibodies had no significant effect on tumor angiogenesis in 15 models. Also, genetic ablation of the tyrosine kinase domain of VEGFR-1 in the host did not result in growth inhibition of the anti-VEGF-A sensitive or resistant tumors tested. Furthermore, combination of anti-PlGF with anti-VEGF-A antibodies did not result in greater antitumor efficacy than anti-VEGF-A monotherapy. In conclusion, our data argue against an important role of PlGF during primary tumor growth in most models and suggest that clinical evaluation of anti-PlGF antibodies may be challenging.

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

“…The importance of PlGF in the response of the tumor to VEGF inhibition may, however, be tumor type-specific or context-dependent, as VEGF(R)-inhibitor treatment did not result in an up-regulation of PlGF mRNA or protein in several preclinical tumor models (Bais et al 2010).…”

“…For instance, not all antibodies with neutralizing capacity in in vitro assays proved to be effective in vivo, either alone as monotherapy or as combination therapy with anti-VEGF mAb, nor did all tumor types respond to anti-PlGF mAb treatment (Bais et al 2010;Van de Veire et al 2010;Yao et al 2011). The precise reasons for these discrepancies remain to be further uncovered (Bais et al 2010;Van de Veire et al 2010), but may in part depend on the expression of FLT1 by the tumor cells .…”

Emerging paradigms and questions on pro-angiogenic bone marrow-derived myelomonocytic cells

“…Blocking PlGF results in the inhibition of monocyte/macrophage recruitment to tumor sites, reduced tumor angiogenesis and tumor growth, in particular in combination with anti-VEGF therapy (Fischer et al, 2007). The role of PlGF in tumor angiogenesis, and its value as potential therapeutic target, however, is matter of controversy (Bais et al, 2010;Van de Veire et al, 2010). Of interest, inhibition of PlGF activity results in reduced formation of lung metastases (Bais et al, 2010).…”

“…The role of PlGF in tumor angiogenesis, and its value as potential therapeutic target, however, is matter of controversy (Bais et al, 2010;Van de Veire et al, 2010). Of interest, inhibition of PlGF activity results in reduced formation of lung metastases (Bais et al, 2010). MMP-9, besides being an essential mediator of the angiogenic switch through the release of matrix-bound VEGF at tumor sites, can also promote BMD cell mobilization though the release of c-Kit ligand (or stem cell factor) form bone marrow stromal cells (Heissig et al, 2002).…”

sFLT01: A Novel Fusion Protein with Antiangiogenic Activity

“…Hence, neutralizing PlGF in addition to VEGF at the onset may be more effective than a single target approach. However, this strategy is not without controversy, as conflicting reports exist on the basis of results generated in preclinical studies (35,36). The value of a combinatorial approach against VEGF and PlGF will ultimately need to be determined in a clinical setting in a heterogeneous patient population that receives not only antiangiogenic therapy but also other modalities of treatment such as radiation and chemotherapy.…”