Credit: IMAGE SOURCE

The roles of placental growth factor (PLGF; also known as PGF) in tumour growth and angiogenesis have been intensely debated. Rakesh Jain and colleagues investigated the function of PLGF in medulloblastoma and found that, in these tumours, PLGF may signal through a non-tyrosine kinase receptor, neuropilin 1 (NRP1), to promote tumour cell survival — without having a substantial effect on tumour-associated macrophages or angiogenesis.

PLGF was expressed in 90% of 32 clinical medulloblastoma samples, which included the four major subtypes (WNT, sonic hedgehog (SHH), Group 3 and Group 4) of this disease. Inhibition of PLGF with either of two dual-blocking antibodies against human and mouse PLGF in xenograft models classified as Group 3 (D341-MED) or Group 4 (D283-MED) led to the regression of established tumours and significantly improved survival. Smoothened (Smo/Smo) transgenic mice, which are a model of SHH group medulloblastomas, also expressed PLGF, and blocking this expression inhibited tumour growth.

NRP1 may be the key PLGF receptor in this system

In addition to increased levels of tumour-derived human PLGF, the xenograft models also had increased levels of mouse PLGF, suggesting production by the host. Mice bearing xenograft tumours from D283-MED cells with short hairpin RNA (shRNA)-mediated knockdown of human PLGF had reduced tumour growth and improved survival, as well as lower levels of mouse PLGF. Blockade of host PLGF with a mouse-PLGF-specific antibody, starting either at day 1 after D283-MED tumour implantation or at day 21 after D283-MED or D341-MED implantation once clinical symptoms were evident, inhibited tumour growth and improved survival. Furthermore, growth of Smo/Smo tumours was inhibited when they were implanted into the cerebellums of syngeneic Pgf−/− mice. Overall, these data suggest that both stromal and tumour-derived PLGF is important for medulloblastoma growth. In addition, the authors noted that D283-MED and D341-MED tumours secreted SHH, despite a lack of genetic changes in this pathway, and stimulation of isolated stromal cells with SHH or co-culture with D341-MED cells increased stromal cell secretion of PLGF. Importantly, D283-MED cells expressing SHH shRNA implanted in mice grew more slowly, and the mice lived longer, suggesting that SHH may promote stromal PLGF production and tumour growth.

What is the biological function of PLGF in medulloblastoma, and how does it signal? Several lines of evidence indicated that PLGF might prevent tumour cell apoptosis. Although vascular endothelial growth factor receptor 1 (VEGFR1) is the primary receptor for PLGF, NRP1 also has a role in this pathway, and typically requires VEGFRs for signalling. The authors noted high NRP1 expression in their medulloblastoma samples and mouse models, and relatively low levels of VEGFR1. Loss of VEGFR1 or its tyrosine kinase domain did not prevent tumour growth in the medulloblastoma mouse models, suggesting that this protein is not required. Furthermore, expression of an NRP1 mutant unable to bind adaptor signalling proteins in D283-MED cells, or treatment of mice with an antibody against NRP1, delayed tumour xenograft growth and improved the survival of the mice; so, NRP1 may be the key PLGF receptor in this system. High levels of NRP1 significantly correlated with reduced survival in a cohort of patients with medulloblastoma. Collectively, these findings indicate that PLGF might act through NRP1 in human medulloblastomas to promote tumour cell survival, and that it might be a valid therapeutic target.