Inhibition of the placental growth factor decreases burden of cholangiocarcinoma and hepatocellular carcinoma in a transgenic mouse model

Abstract

The use of monoclonal antibodies targeting PlGF could thus offer a potential systemic treatment for patients who suffer from primary liver tumours.

Placental growth factor in cancer

“…Pharmacological inhibition phenocopied the effects observed upon PLGF gene deficiency [44,61,86]. Both vascularization and tumor inflammation were reduced in 5D11D4 treated HCC and cholangiocarcinoma lesions [61,86]. Of note, a neutralizing antibody (16D3) raised against human PLGF reduced tumor growth in human xenograft models [44], and similar findings were reported with other anti-human PLGF antibodies (see below) [12,47].…”

“…Pharmacological inhibition phenocopied the effects observed upon PLGF gene deficiency [44,61,86]. Both vascularization and tumor inflammation were reduced in 5D11D4 treated HCC and cholangiocarcinoma lesions [61,86].…”

“…Furthermore, combination therapy of PLGF inhibition with VEGF(R) inhibition (anti-VEGFR2 antibody) or tyrosine kinase inhibitors resulted in superior tumor inhibition compared to the respective monotherapies in different tumor models [43,61,86], and anti-VEGFR2 neutralizing antibody could partially be replaced by anti-PLGF 5D11D4 without reduction in treatment efficacy [43]. These observations are, however, in contrast with findings that forced PLGF overexpression in tumor cells provided sensitization to anti-VEGF (R) treatment, which could be explained by PLGF/VEGF heterodimer formation at the expense of angiogenic VEGF homodimers, and thereby more efficient inhibition of the remaining angiogenic VEGF by the anti-VEGF(R) treatment [13,24,25].…”

Placental growth factor supports neuroendocrine tumor growth and predicts disease prognosis in patients

“…Compelling preclinical evidence established blocking PlGF using anti-PlGF antibodies as effective strategy to inhibit tumor growth and metastasis (Fischer et al 2007, Coenegrachts et al 2010, Van de Veire et al 2010, Schmidt et al 2011, Yao et al 2011a, Heindryckx et al 2012. As PlGF is a disease-specific factor and redundant for physiological vessel growth (Carmeliet et al 2001, Fischer et al 2007, inhibition of PlGF is likely to exhibit less side effects than VEGF-A/VEGFR2-based therapies (Fischer et al 2007, Verheul & Pinedo 2007.…”

“…Thereby, PlGF can activate AKT and ERKmediated canonical signaling pathways, ultimately leading to enhanced tumor cell survival, proliferation, migration, and invasiveness (Fischer et al 2008). Conversely, blocking PlGF using anti-PlGF antibodies emerged as therapeutic strategy to inhibit growth and metastasis in various preclinical tumor models (Fischer et al 2007, Coenegrachts et al 2010, Van de Veire et al 2010, Schmidt et al 2011, Yao et al 2011a, Heindryckx et al 2012.…”