Paracrine Placental Growth Factor Signaling in Response to Ionizing Radiation Is p53-Dependent and Contributes to Radioresistance

Abstract

Placental growth factor (PlGF) is a pro-angiogenic, N-glycosylated growth factor, which is secreted under pathologic situations. Here, we investigated the regulation of PlGF in response to ionizing radiation (IR) and its role for tumor angiogenesis and radiosensitivity. Secretion and expression of PlGF was induced in multiple tumor cell lines (medulloblastoma, colon and lung adenocarcinoma) in response to irradiation in a dose-and time-dependent manner. Early upregulation of PlGF expression and secretion in response to irradiation was primarily observed in p53 wild-type tumor cells, whereas tumor cells with mutated p53 only showed a minimal or delayed response. Mechanistic investigations with genetic and pharmacologic targeting of p53 corroborated regulation of PlGF by the tumor suppressor p53 in response to irradiation under normoxic and hypoxic conditions, but with so far unresolved mechanisms relevant for its minimal and delayed expression in tumor cells with a p53-mutated genetic background. Probing a paracrine role of IR-induced PlGF secretion in vitro, migration of endothelial cells was specifically increased towards irradiated PlGF wild type but not towards irradiated PlGF-knockout (PIGF-ko) medulloblastoma cells. Tumors derived from these PlGF-ko cells displayed a reduced growth rate, but similar tumor vasculature formation as in their wild-type counterparts. Interestingly though, high-dose irradiation strongly reduced microvessel density with a concomitant high rate of complete tumor regression only in the PlGF-ko tumors. IMPLICATIONS: Our study shows a strong paracrine vasculature-protective role of PlGF as part of a p53-regulated IR-induced resistance mechanism and suggest PlGF as a promising target for a combined treatment modality with RT.

Changes in Tumor Immune Microenvironment after Radiotherapy Resistance in Colorectal Cancer: A Narrative Review

“…Integrin β1 sialylation mediated by ST6Gal I contributes to cell adhesion was found to regulate CRC radiotherapy resistance [29]. Moreover, radiotherapy can stimulate CRC tumors to secrete placental growth factor (PlGF), which acts on nonirradiated paracrine tumor cells, resulting in radiotherapy resistance [30]. It was also discovered that patients with high expression of matrix metalloproteinase 1 (MMP1) and matrix metalloproteinase 2 (MMP2) in the ECM of CRC tumor cells developed distant metastases after radiotherapy [31].…”

Interfering with Tumor Hypoxia for Radiotherapy Optimization

“…Interestingly, not only VEGF but also other pro-angiogenic factors such as placental growth factor (PlGF) are secreted in response to irradiation and in a dose- and time-dependent manner. Our own recent studies showed a strong paracrine vasculature-protective role of PlGF as part of a p53-regulated IR-induced resistance mechanism and suggest PlGF as a promising target for a combined treatment modality with radiotherapy [ 323 ]. Furthermore, not only endothelial cell-directed compounds, but also tumor cell signaling-directed agents may contribute to a window of tumor vasculature normalization, e.g.…”