Src-mediated morphology transition of lung cancer cells in three-dimensional organotypic culture

Nguyen, HT and Zhuang, Y and Sun, L and Kantrow, SP and Kolls, JK and You, Z and Zhuo, Y and Shan, B (2013) Src-mediated morphology transition of lung cancer cells in three-dimensional organotypic culture. Cancer Cell International, 13 (1).

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Abstract

A fribotic tumor microenvironment promotes progression of cancer. In this study, we utilize a reconstituted basement membrane mimics Matrigel based three-dimensional organotypic culture (rBM 3-D) to investigate the mechanisms that mediate the tumor promoting effects of the fibrogenic mediators TGF-β1 and type I collagen (Col-1) on lung adenocarcinoma cells. Similar to normal alveolar epithelial cells, the well-differentiated lung adenocarcinoma cells in rBM 3-D culture undergo acinar morphogeneis that features polarized epithelial cell spheres with a single central lumen. Either TGF-β1 or Col-1 modestly distorts acinar morphogenesis. On the other hand, TGF-β1 and Col-1 synergistically induce a transition from acinar morphology into stellate morphology that is characteristic of invasive and metastatic cancer cells. Inhibition of the Src kinase activity abrogates induction of stellate morphology, activation of Akt and mTOR, and the expression of tumor promoting genes by TGF-β1 and Col-1. To a similar extent, pharmacological inhibition of mTOR abrogates the cellular responses to TGF-β1 and Col-1. In summary, we demonstrate that TGF-β1 and Col-1 promote stellate morphogenesis of lung cancer cells. Our findings further suggest that the Src-Akt-mTOR axis mediates stellate morphogenesis. These findings also indicate that rBM 3-D culture can serve as an ideal platform for swift and cost-effective screening of therapeutic candidates at the interface of the tumor and its microenvironment. © 2013 Nguyen et al.; licensee BioMed Central Ltd.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Nguyen, HT Zhuang, Y Sun, L Kantrow, SP Kolls, JK jkk23@pitt.edu JKK23 You, Z Zhuo, Y Shan, B
Date:	14 February 2013
Date Type:	Publication
Journal or Publication Title:	Cancer Cell International
Volume:	13
Number:	1
DOI or Unique Handle:	10.1186/1475-2867-13-16
Schools and Programs:	School of Medicine > Pediatrics
Refereed:	Yes
Date Deposited:	06 Oct 2016 14:32
Last Modified:	29 Jan 2019 15:55
URI:	http://d-scholarship.pitt.edu/id/eprint/29759

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