Expression and prognostic significance of placental growth factor in hepatocellular carcinoma and peritumoral liver tissue

Abstract

Vascular endothelial growth factor‐targeted therapy is a promising treatment for hepatocellular carcinoma (HCC), but its clinical benefit is often accompanied by acquired resistance. In animal studies, antiplacental growth factor therapy is effective with less resistance. The role of placental growth factor (PlGF) in the progression of HCC is not clear. In our study, we used immunohistochemistry in tissue microarrays to investigate PlGF expression in tumor and peritumoral liver tissues from 105 patients with HCC. Intratumoral and peritumoral PlGF mRNA expression was analyzed in another cohort of 37 patients. Peritumoral PlGF expression was significantly higher than intratumoral PlGF expression (p < 0.001). Intratumoral PlGF expression was not associated with patients' overall survival (OS) or time to recurrence (TTR). However, peritumoral PlGF expression, which was associated with tumor size, presence of intrahepatic metastasis, TNM stage and Barcelona Clinic Liver Cancer stage, was an independent risk factor for OS (p = 0.026) and TTR (p = 0.041). The prognostic value of peritumoral PlGF expression was further validated in a validation cohort (n = 394). We inferred that the elevation of PlGF in peritumoral liver might be induced by hypoxia. We found that peritumoral PlGF expression was associated with hypoxia‐inducible factor‐1α (p = 0.017). PlGF expression was elevated in L02, a hepatic cell line, under hypoxic conditions in vitro. These findings indicate that high peritumoral PlGF expression is associated with tumor recurrence and survival after resection of HCC. PlGF could be a target of adjuvant therapy and deserves further investigations.

Epigenetic control of hypoxia inducible factor-1α-dependent expression of placental growth factor in hypoxic conditions

“…On the other hand, it has been reported that in the peritumor area of human hepatocellular carcinoma, the level of PlGF was significantly increased and correlated with augmented levels of HIF-1α. 55 Finally, since PlGF also positively modulates HIF-1α expression in ECs, 56 a positive loop may be established to maintain high levels of PlGF expression when required.…”

Expression of placental growth factor in regenerating livers after partial hepatectomy in the rat

“…PlGF plays a role in angiogenesis only under pathological conditions, such as in hepatocellular carcinoma in which they have investigated the role of the PlGF/Flt-1 pathway [31,32]. There is a synergistic co-operation between PlGF and VEGF.…”

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

“…The identification and regulation of factors responsible for these angiogenic processes are areas of active investigation, as these pathways could provide valuable targets for therapeutic intervention, especially in HCC in which the multikinase inhibitor sorafenib (Nexavar) is currently the standard of care for advanced HCC patients [3][4][5]. The vascular endothelial growth factor (VEGF) has gathered extensive attention for its role in mediating tumour angiogenesis [6][7][8][9], but recently interest in the placental growth factor (PlGF) [10][11][12][13][14] has grown. PlGF is a VEGF homologue, which is only involved in pathologic angiogenesis; therefore, its inhibition does not induce side-effects [14,15].…”