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Cancers (Basel). 2018 Feb 27;10(3). pii: E61. doi: 10.3390/cancers10030061.

Teaming Up for Trouble: Cancer Cells, Transforming Growth Factor-β1 Signaling and the Epigenetic Corruption of Stromal Naïve Fibroblasts.

Author information

1
Department of Clinical Biochemistry and Pharmacology, Ben Gurion University of the Negev, Beersheva 8410500, Israel. sergiol@bgu.ac.il.
2
Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva 8410500, Israel. sergiol@bgu.ac.il.
3
Institute of Gastroenterology and Hepatology, Soroka University Medical Center, Beersheva 8410100, Israel. sergiol@bgu.ac.il.
4
Department of Clinical Biochemistry and Pharmacology, Ben Gurion University of the Negev, Beersheva 8410500, Israel. sigalina@gmail.com.
5
Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva 8410500, Israel. sigalina@gmail.com.
6
Institute of Gastroenterology and Hepatology, Soroka University Medical Center, Beersheva 8410100, Israel. sigalina@gmail.com.
7
Department of Clinical Biochemistry and Pharmacology, Ben Gurion University of the Negev, Beersheva 8410500, Israel. shany@bgu.ac.il.
8
Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva 8410500, Israel. shany@bgu.ac.il.
9
Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva 8410500, Israel. naimaf@clalit.org.il.
10
Institute of Gastroenterology and Hepatology, Soroka University Medical Center, Beersheva 8410100, Israel. naimaf@clalit.org.il.
11
Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva 8410500, Israel. ling@bgu.ac.il.
12
Pediatrics Department B, Soroka University Medical Center, Beersheva 8410100, Israel. ling@bgu.ac.il.
13
International Institute of Anticancer Research, Kapandriti, Athens 19014, Greece. editor@iiar-anticancer.org.
14
Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva 8410500, Israel. atiask@post.bgu.ac.il.
15
Institute of Gastroenterology and Hepatology, Soroka University Medical Center, Beersheva 8410100, Israel. atiask@post.bgu.ac.il.
16
International Institute of Anticancer Research, Kapandriti, Athens 19014, Greece. iiar@iiar-anticancer.org.
17
Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva 8410500, Israel. fich@bgu.ac.il.
18
Institute of Gastroenterology and Hepatology, Soroka University Medical Center, Beersheva 8410100, Israel. fich@bgu.ac.il.

Abstract

It is well recognized that cancer cells subvert the phenotype of stromal naïve fibroblasts and instruct the neighboring cells to sustain their growth agenda. The mechanisms underpinning the switch of fibroblasts to cancer-associated fibroblasts (CAFs) are the focus of intense investigation. One of the most significant hallmarks of the biological identity of CAFs is that their tumor-promoting phenotype is stably maintained during in vitro and ex vivo propagation without the continual interaction with the adjacent cancer cells. In this review, we discuss robust evidence showing that the master cytokine Transforming Growth Factor-β1 (TGFβ-1) is a prime mover in reshaping, via epigenetic switches, the phenotype of stromal fibroblasts to a durable state. We also examine, in detail, the pervasive involvement of TGFβ-1 signaling from both cancer cells and CAFs in fostering cancer development, taking colorectal cancer (CRC) as a paradigm of human neoplasia. Finally, we review the stroma-centric anticancer therapeutic approach focused on CAFs-the most abundant cell population of the tumor microenvironment (TME)-as target cells.

KEYWORDS:

cancer; cancer-associated fibroblasts; colorectal cancer; epigenetics; transforming growth factor-β; tumor microenvironment

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