Placental growth factor (PlGF) enhances breast cancer cell motility by mobilising ERK1/2 phosphorylation and cytoskeletal rearrangement

Abstract

Background:During metastasis, cancer cells migrate away from the primary tumour and invade the circulatory system and distal tissues. The stimulatory effect of growth factors has been implicated in the migration process. Placental growth factor (PlGF), expressed by 30–50% of primary breast cancers, stimulates measurable breast cancer cell motility in vitro within 3 h. This implies that PlGF activates intracellular signalling kinases and cytoskeletal remodelling necessary for cellular migration. The PlGF-mediated motility is prevented by an Flt-1-antagonising peptide, BP-1, and anti-PlGF antibody. The purpose of this study was to determine the intracellular effects of PlGF and the inhibiting peptide, BP-1.Methods:Anti-PlGF receptor (anti-Flt-1) antibody and inhibitors of intracellular kinases were used for analysis of PlGF-delivered intracellular signals that result in motility. The effects of PlGF and BP-1 on kinase activation, intermediate filament (IF) protein stability, and the actin cytoskeleton were determined by immunohistochemistry, cellular migration assays, and immunoblots.Results:Placental growth factor stimulated phosphorylation of extracellular-regulated kinase (ERK)1/2 (pERK) in breast cancer cell lines that also increased motility. In the presence of PlGF, BP-1 decreased cellular motility, reversed ERK1/2 phosphorylation, and decreased nuclear and peripheral pERK1/2. ERK1/2 kinases are associated with rearrangements of the actin and IF components of the cellular cytoskeleton. The PlGF caused rearrangements of the actin cytoskeleton, which were blocked by BP-1. The PlGF also stabilised cytokeratin 19 and vimentin expression in MDA-MB-231 human breast cancer cells in the absence of de novo transcription and translation.Conclusions:The PlGF activates ERK1/2 kinases, which are associated with cellular motility, in breast cancer cells. Several of these activating events are blocked by BP-1, which may explain its anti-tumour activity.

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

“…Given that the known PlGF receptors, Flt1, and neuropilins were shown expressed in NETs (Terris et al 1998, von Marschall et al 2003, our current observation of stromal PlGF expression suggests the presence of auto-/paracrine signaling loops. Functionally, PlGF stimulated proliferation and migration of NET cells in vitro, which is in line with published results revealing stimulatory actions of PlGF on proliferation of pancreatic tumor cells (Fischer et al 2007), as well as on migration of glioma, breast, and lung cancer cells (Fischer et al 2008, Taylor et al 2010. More importantly, we were able to reduce the growth of BON NET xenograft tumors using neutralizing antibodies to functionally inactivate tumor cell-and stroma-derived PlGF.…”

GABA(A) Receptor Pi (GABRP) Stimulates Basal-like Breast Cancer Cell Migration through Activation of Extracellular-regulated Kinase 1/2 (ERK1/2)

“…Like calcium signaling, ERK1/2 signaling is pro-migratory (33,39,40), and importantly, regulates cytokeratin expression in non-breast cancer cell lines (34,41). These findings, in combination with the observation that BLBC cells are sensitive to ERK1/2 inhibition (42, 43), led us to predict that in BLBC, GABRP may maintain basal-like cytokeratin expression through the ERK1/2 pathway.…”

“…5A. As intermediate filaments, the cytokeratins are critical components of the cytoskeleton and cancer cell motility (33,34). Moreover, KRT5, KRT6B, KRT14, and KRT17 are all well-described BLBC markers (reviewed in Ref.…”

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

“…Cite this article as Cold Spring Harb Perspect Med 2012;2:a011056 growth and migration of tumor cells and protects them against cytotoxic injury by chemotherapeutics (Casalou et al 2007;Fischer et al 2007;Taylor et al 2010;Schmidt et al 2011). It also suppresses antitumor immune responses by reducing dendritic cell accumulation and function (Lin et al 2007;Rolny et al 2011).…”