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TGF-β as Tumor Suppressor: Lessons from Mouse Models

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TGF-β in Human Disease

Abstract

Transforming growth factor-β (TGF-β) signals through serine/threonine-kinase receptors to activate several intracellular signaling pathways, including the “canonical” Smad signaling pathway. TGF-β has tumor-suppressive functions through its capacity to induce growth arrest and apoptosis. Escape from the anti-proliferative effects of TGF-β is a hallmark of almost all tumors of epithelial origin. This chapter first depicts the genetic alterations ablating the TGF-β tumor-suppressive functions in human tumors. Then, the chapter presents the genetically engineered mouse models that have been developed by introducing genetic alterations found in humans. These mouse models demonstrated the tumor-suppressive role of TGF-β in vivo shedding light on its intricate relationship with the tumor microenvironment. In all, the presented mouse models of cancer with an impaired TGF-β signaling pathway provide an integrated view of the complex tumor-suppressive role of TGF-β and represent valuable tools for preclinical studies.

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Abbreviations

ALK5:

Activin receptor-like kinase 5

AOM:

Azoxymethane

APC:

Adenomatous polyposis coli

BMP:

Bone morphogenetic protein

BMPR1A:

Bone morphogenetic protein receptor, type IA

CTGF:

Connective tissue growth factor

DEN:

Diethylnitrosamine

DMBA:

7,12-Dimethylbenz(α)anthracene

DPC4:

Deleted in pancreatic carcinoma 4

ELF:

Embryonic liver fodrin

EMT:

Epithelial-to-mesenchymal transition

FAP:

Familial adenomatous polyposis

HoCC:

Homotypic cell cannibalism

IPMN:

Intraductal papillary mucinous neoplasms

KSSTT:

Pdx1-Cre; KRASG12D; Smad4-KOL/L; TIF1γ-KOL/L

LOH:

Loss of heterozygosity

LRP:

Low-density lipoprotein receptor-related protein

LSL:

Lox-stop-lox

MAPK:

Mitogen-activated protein kinase

MCN:

Mucinous cystic neoplasms

Min:

Multiple intestinal neoplasia

MMP:

Matrix metalloproteinase

MMTV:

Mouse mammary tumor virus

MSI:

Microsatellite instability

PanIN:

Pancreatic intraepithelial neoplasms

PDAC:

Pancreatic ductal adenocarcinoma

PDGF:

Platelet-derived growth factor

PyVmT:

Polyoma virus middle T antigen

SCC:

Squamous cell carcinoma

TGF-β:

Transforming growth factor β

TGF-α:

Transforming growth factor α

TIF1:

Transcriptional intermediary factor 1

TPA:

12-O-tetradecanoylphorbol-13-acetate

TβRI:

TGF-β type I receptor

TβRII:

TGF-β type II receptor

WAP:

Whey acidic protein

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  1. TGF-β and Pancreatic Cancer Lab, Centre de Recherche en Cancérologie de LYON (CRCL), UMR INSERM 1052, CNRS 5286, Lyon I University UMR S 1052, Centre Léon Bérard, 28, rue Laënnec, 69373, LYON Cedex 08, France

    Ulrich Valcourt, David F. Vincent & Laurent Bartholin

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  1. Ulrich Valcourt
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  2. David F. Vincent
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  1. , Dept Medical Biochem Microbiol, Uppsala University, Box 582, Uppsala, SE-751 23, Sweden

    Aristidis Moustakas

  2. , Interdiscip. Grad. Sch. Med. Eng., University of Yamanashi, 1110 Shimokato, Chuo, 409-3898, Yamanashi, Japan

    Keiji Miyazawa

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Valcourt, U., Vincent, D.F., Bartholin, L. (2013). TGF-β as Tumor Suppressor: Lessons from Mouse Models. In: Moustakas, A., Miyazawa, K. (eds) TGF-β in Human Disease. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54409-8_6

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