Fibroblast-led cancer cell invasion is activated by epithelial–mesenchymal transition through platelet-derived growth factor BB secretion of lung adenocarcinoma

Publication date: 1 June 2017
Source:Cancer Letters, Volume 395
Author(s): Shinya Neri, Tomoyuki Miyashita, Hiroko Hashimoto, Yoshitaka Suda, Masayuki Ishibashi, Hiroaki Kii, Hirotada Watanabe, Takeshi Kuwata, Masahiro Tsuboi, Koichi Goto, Toshi Menju, Makoto Sonobe, Hiroshi Date, Atsushi Ochiai, Genichiro Ishii
Cancer-associated fibroblast (CAF)-dependent local invasion is the process by which cancer cells invade the extracellular matrix using tracks that have been physically remodeled by CAFs. In the present study, we investigated the process by which the epithelial–mesenchymal transition (EMT) of cancer cells affect CAF-dependent local invasion. Using an in vitro collagen invasion assay, we showed cancer cells undergoing EMT to promote the matrix-remodeling ability of CAFs and thereby enhance CAF-dependent local cancer cell invasion. Platelet-derived growth factor (PDGF)-BB secretion was significantly elevated in cancer cells undergoing EMT, and this induced an increase in the invasion ability of both CAFs and cancer cells. Conversely, knockdown of PDGF-B expression in cancer cells undergoing EMT, or treatment with a PDGF-receptor inhibitor, decreased the invasion ability of both CAFs and cancer cells. By analyzing the gene expression profiles of 442 patients with lung adenocarcinomas, we established that high expression of PDGF-B and presentation of mesenchymal-like tumors were significantly associated with a high rate of disease recurrence and poor patient prognosis. Thus, cancer cells undergoing EMT may accelerate their own ability to invade local tissues via PDGF-BB secretion to promote CAF matrix remodeling. Therefore, targeting PDGF signaling between cancer cells undergoing EMT and CAFs is a promising therapeutic target to inhibit cancer progression and improve patient prognosis.



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