Identification of secreted proteins that mediate cell-cell interactions in an in vitro model of the lung cancer microenvironment

Li Zhong, Jonathon Roybal, Raghothama Chaerkady, Wan Zhang, Kuicheon Choi, Cristina A. Alvarez, Hai Tran, Chad J. Creighton, Shaoyu Yan, Robert M. Strieter, Akhilesh Pandey, Jonathan M. Kurie

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Non-small cell lung cancer (NSCLC) cells with somatic mutations in K-ras recruit to the tumor a variety of cell types (hereafter collectively termed "stromal cells") that can promote or inhibit tumorigenesis by mechanisms that have not been fully elucidated. Here, we postulated that stromal cells in the tumor microenvironment alter the tumor cell secretome, including those proteins required for tumor growth and dissemination, and we developed an in vitro model to test this hypothesis. Coculturing a murine K-ras mutant lung adenocarcinoma cell line (LKR-13) with a murine lung stromal cell (macrophage, endothelial cell, or fibroblast) enhanced stromal cell migration, induced endothelial tube formation, increased LKR-13 cell proliferation, and regulated the secretion of proteins involved in angiogenesis, inflammation, cell proliferation, and epithelial-to-mesenchymal transition. Among these proteins, CXCL1 has been reported to promote NSCLC development, whereas interleukin-18 (IL-18) has an undefined role. Genetic and pharmacologic strategies to inhibit CXCL1 and IL-18 revealed that stromal cell migration, LKR-13 cell proliferation, and LKR-13 cell tumorigenicity required one or both of these proteins. We conclude that stromal cells enhanced LKR-13 cell tumorigenicity partly through their effects on the secretome of LKR-13 cells. Strategies to inhibit tumor/stromal cell interactions may be useful as therapeutic approaches in NSCLC patients.

Original languageEnglish (US)
Pages (from-to)7237-7245
Number of pages9
JournalCancer research
Volume68
Issue number17
DOIs
StatePublished - Sep 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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