Interaction with colon cancer cells hyperactivates TGF-β signaling in cancer-associated fibroblasts

LJAC Hawinkels, M Paauwe, HW Verspaget, E Wiercinska, JM van der Zon, K van der Ploeg, PJ Koelink, JHN Lindeman, W Mesker, P ten Dijke and CFM Sier.

Oncogene (2014) 33, 97–107

Speaker: Hsin-I Wang (汪欣儀)                            Time: 15:00~16:00, March 18, 2015

Commentator: Dr. Yao Chang (張堯 博士)               Place: Room 601

Abstract :

       Worldwide, more than 1 million individuals will develop colorectal cancer (CRC) every year, and the disease-specific mortality rate is nearl 33%. The interaction between tumor cells and fibroblasts within the tumor microenvironment contributes to tumor growth, angiogenesis, invasion, and metastasis in many cancer types (1). Cancer-associated fibroblasts (CAFs), which expressing vimentin, fibroblast-activating protein and α-smooth muscle actin (α-SMA), play an important role in this interaction (2). Compared to normal mucosa, the number of CAFs is increased in CRC and by which the immune responses are altered (3). How these CAFs affect the secretion of the chemokines, cytokines, proteolytic enzymes and extracellular matrix are still unknown. Transforming growth factor-β (TGF-β) is one of crucial mediators which are involved in tumor progression/metastasis by inducing tumor angiogenesis, increasing production of extracellular matrix, proteolytic enzymes and immune suppression (4). Based on results deduced from in vitro studies, the authors hypothesized that TGF-β induced CAFs trans-differentiation from normal fibroblast. The results showed that TGF-β1 stimulation up-regulated various proteinase, such as the expression of matrix metalloproteinases (MMPs) and plasminogen activator inhibitor (PAI)-1, and the invasion ability of spheroid in CAFs. It also leaded to the initiation of intracellular signaling through phosphorylation of Smad2. The results showed that the interaction between CAFs and tumor cell can induce hyperactivation of TGF-β signaling in CAFs, and increase the expression of invasion-related proteinases. Through this feedback loop, tumor cells and CAFs can synergistically enhance their invasiveness.

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