Placental Growth Factor Upregulation Is a Host Response to Antiangiogenic Therapy

Abstract

Purpose: Placental growth factor (PlGF) is an angiogenic protein. Upregulation of PlGF has been observed in the clinic following antiangiogenic regimens targeting the VEGF pathway. PlGF has been proposed as a therapeutic target for oncology. sFLT01 is a novel fusion protein that neutralizes mouse and human PlGF (mPlGF, hPlGF) and mouse and human VEGF-A (mVEGF-A, hVEGF-A). It was tested in syngeneic and xenograft tumor models to evaluate the effects of simultaneously neutralizing PlGF and VEGF-A and to investigate changes observed in the clinic in preclinical models. Experimental Design: Production of PlGF and VEGF-A by B16F10 and A673 cancer cells in vitro was assessed. Mice with subcutaneous B16F10 melanoma or A673 sarcoma tumors were treated with sFLT01. Tumor volumes and microvessel density (MVD) were measured to assess efficacy. Serum levels of hVEGF-A, hPlGF, and mPlGF at early and late time points were determined by ELISA. Results: Exposure of cancer cell lines to sFLT01 caused a decrease in VEGF secretion. sFLT01 inhibited tumor growth, prolonged survival, and decreased MVD. Analysis of serum collected from treated mice showed that sFLT01 administration caused a marked increase in circulating mPlGF but not hPlGF or hVEGF. sFLT01 treatment also increased circulating mPlGF levels in non–tumor-bearing mice. Conclusion: With the tumor cell lines and mouse models we used, antiangiogenic therapies that target both PlGF and VEGF may elicit a host response rather than, or in addition to, a malignant cell response that contribute to therapeutic resistance and tumor escape as suggested by others. Clin Cancer Res; 17(5); 976–88. ©2011 AACR.

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

“…PlGF mRNA and protein levels correlate with tumor stage, invasion and/or metastasis, tumor recurrence, and inversely with survival in several although not all tumor types (Fischer et al 2008;Bagley et al 2011). Exceptions include colon and lung carcinoma, where PlGF expression is low because of epigenetic silencing (Xu and Jain 2007).…”

“…Exceptions include colon and lung carcinoma, where PlGF expression is low because of epigenetic silencing (Xu and Jain 2007). Not only can the tumor cells themselves produce PlGF, but also most types of stromal cells, including endothelial cells, smooth muscle cells, pericytes, cancerassociated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and inflammatory cells (Yonekura et al 1999;Carmeliet et al 2001;Luttun et al 2002;Fischer et al 2007;Bagley et al 2011;Rolny et al 2011). Moreover, recent studies document a tumor cell $ stroma cross talk, in which tumor cells can "educate" stroma cells to produce PlGF.…”

“…However, the precise involvement of PlGF/FLT1 in the premetastatic niche formation remains to be further resolved because divergent effects of FLT1 inhibition have been reported (Kaplan et al 2009;Duda and Jain 2010). Of note, plasma levels of PlGF are often increased in cancer patients receiving VEGF(R)-inhibition therapy, raising the question of whether PlGF is a factor contributing to the acquistion of "resistance" (evasive escape) against anti-VEGF therapy (Bergers and Hanahan 2008;Jain et al 2009;Bagley et al 2011;Carmeliet and Jain 2011a). Experimental models using human tumor xenografts in mice show elevated murine PlGF (but not human PlGF) levels following anti-VEGF treatment, suggesting that PlGF up-regulation by VEGF blockade is at least in part a host reponse (Bagley et al 2011).…”

“…Of note, plasma levels of PlGF are often increased in cancer patients receiving VEGF(R)-inhibition therapy, raising the question of whether PlGF is a factor contributing to the acquistion of "resistance" (evasive escape) against anti-VEGF therapy (Bergers and Hanahan 2008;Jain et al 2009;Bagley et al 2011;Carmeliet and Jain 2011a). Experimental models using human tumor xenografts in mice show elevated murine PlGF (but not human PlGF) levels following anti-VEGF treatment, suggesting that PlGF up-regulation by VEGF blockade is at least in part a host reponse (Bagley et al 2011). Consistent herewith, inhibition or 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.…”

“…Phenocopying the effects seen upon PlGF blockade by gene inactivation or RNA interference (Carmeliet et al 2001;Van de Veire et al 2010;Laurent et al 2011), pharmacological PlGF inhibition by neutralizing antibodies (anti-PlGF antibodies 5D11D4, 3C7A5) or by PlGF/FLT1 peptide antagonists reduced tumor growth, angiogenesis, lymphangiogenesis, inflammation, and metastasis in different ectopically and orthotopically implanted tumors in mouse models, in the absence of adverse side effects (Fischer et al 2007;Taylor and Goldenberg 2007;Coenegrachts et al 2010;Bagley et al 2011). PlGF is also diffusely expressed in medulloblastoma, the most common malignant brain tumor of childhood, and genetic and pharmacologic inhibition of PlGF leads to growth delay and regression of medulloblastoma models in mice as well (Snuderl et al 2010).…”