RRC ID 65122
著者 Kanzaki R, Naito H, Kise K, Takara K, Eino D, Minami M, Shintani Y, Funaki S, Kawamura T, Kimura T, Okumura M, Takakura N.
タイトル Gas6 derived from cancer-associated fibroblasts promotes migration of Axl-expressing lung cancer cells during chemotherapy.
ジャーナル Sci Rep
Abstract Alterations to the tumor stromal microenvironment induced by chemotherapy could influence the behavior of cancer cells. In the tumor stromal microenvironment, cancer-associated fibroblasts (CAFs) play an important role. Because the receptor tyrosine kinase Axl and its ligand Gas6 could be involved in promoting non-small cell lung cancer (NSCLC), we investigated the role of Gas6 secreted by CAFs during chemotherapy in NSCLC. In a murine model, we found that Gas6 expression by CAFs was upregulated following cisplatin treatment. Gas6 expression might be influenced by intratumoral hypoperfusion during chemotherapy, and it increased after serum starvation in a human lung CAF line, LCAFhTERT. Gas6 is associated with LCAFhTERT cell growth. Recombinant Gas6 promoted H1299 migration, and conditioned medium (CM) from LCAFhTERT cells activated Axl in H1299 cells and promoted migration. Silencing Gas6 in LCAFhTERT reduced the Axl activation and H1299 cell migration induced by CM from LCAFhTERT. In clinical samples, stromal Gas6 expression increased after chemotherapy. Five-year disease-free survival rates for patients with tumor Axl- and stromal Gas6-positive tumors (n = 37) was significantly worse than for the double negative group (n = 12) (21.9% vs 51.3%, p = 0.04). Based on these findings, it is presumed that Gas6 derived from CAFs promotes migration of Axl-expressing lung cancer cells during chemotherapy and is involved in poor clinical outcome.
巻・号 7(1)
ページ 10613
公開日 2017-9-6
DOI 10.1038/s41598-017-10873-2
PII 10.1038/s41598-017-10873-2
PMID 28878389
PMC PMC5587707
MeSH Aged Animals Axl Receptor Tyrosine Kinase Biomarkers, Tumor Cancer-Associated Fibroblasts / metabolism* Cancer-Associated Fibroblasts / pathology Cell Cycle Cell Line, Tumor Cell Movement / genetics Cell Proliferation Disease Models, Animal Female Gene Expression Regulation, Neoplastic* Humans Intercellular Signaling Peptides and Proteins / genetics Intercellular Signaling Peptides and Proteins / metabolism* Lung Neoplasms / drug therapy Lung Neoplasms / genetics* Lung Neoplasms / metabolism* Lung Neoplasms / pathology Male Mice Middle Aged Neoplasm Staging Proto-Oncogene Proteins / genetics* Receptor Protein-Tyrosine Kinases / genetics* Xenograft Model Antitumor Assays
IF 3.998
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