RRC ID 34846
Author Neri S, Ishii G, Hashimoto H, Kuwata T, Nagai K, Date H, Ochiai A.
Title Podoplanin-expressing cancer-associated fibroblasts lead and enhance the local invasion of cancer cells in lung adenocarcinoma.
Journal Int. J. Cancer
Abstract Cancer-associated fibroblasts (CAFs) communicate with cancer cells and play important roles in cancer invasion. We previously reported that local invasion of cancer cells was frequently observed in lung adenocarcinoma patients with podoplanin (PDPN)-expressing CAFs. However, the underlying mechanisms of this phenomenon have remained unclear. In this study, we established a novel collagen invasion assay model in which cancer cells and CAFs were cocultured; we analyzed the mechanisms governing how cancer cell invasion was promoted by PDPN(+)CAFs. By observing the dynamic movement of both CAFs and cancer cells in the collagen matrix, we found that PDPN(+)CAFs invaded the matrix to a greater extent, with more cancer cells invading within the "tracks" created by the CAFs, compared with control CAFs. The knockdown of PDPN in CAFs decreased the invasion of both the CAFs and the cancer cells. PDPN(+)CAFs displayed a higher RhoA activity and treatment with a ROCK inhibitor cancelled the increased invasion ability of PDPN(+)CAFs and subsequently decreased the number of invaded cancer cells. After intravenous injection in the mouse tail vein, PDPN(+)CAFs invaded and promoted cancer cell invasion into the lung parenchyma, compared with control CAFs. Among the patients with lung adenocarcinoma, we observed some cases with PDPN(+)CAFs at the invasive front of the tumor. These cases predominantly exhibited pleural invasion of cancer cells, known as pathological invasiveness. Our results indicated that PDPN(+)CAFs were tumor-promoting CAFs that lead and enhance the local invasion of cancer cells, suggesting that the invasion activity of CAFs themselves could be rate-determining for cancer cell invasion.
Volume 137(4)
Pages 784-96
Published 2015-8-15
DOI 10.1002/ijc.29464
PMID 25648219
MeSH Adenocarcinoma / genetics* Adenocarcinoma / pathology Adenocarcinoma of Lung Animals Biomarkers, Tumor / biosynthesis* Biomarkers, Tumor / genetics Female Fibroblasts / metabolism* Fibroblasts / pathology Gene Expression Regulation, Neoplastic Humans Lung Neoplasms / genetics* Lung Neoplasms / pathology Lymphatic Metastasis Male Membrane Glycoproteins / biosynthesis* Membrane Glycoproteins / genetics Mice Neoplasm Invasiveness / genetics Neoplasm Invasiveness / pathology Neoplasm Staging Prognosis
IF 7.36
Times Cited 16
WOS Category ONCOLOGY
Resource
DNA material pENTR4-H1 (RDB04395) CSII-CMV-RfA-IRES2-Venus (RDB04388) CS-RfA-EG (RDB04391) CSII-CMV-mRFP1 (RDB06386) pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393)