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Regulation of TGF-β Signaling and Metastatic Progression by Tumor Microenvironments

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Signaling Pathways and Molecular Mediators in Metastasis

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Abstract

The TGF-β signaling system comprises a complex and dynamic cascade of molecular interactions that invoke a variety of intracellular and extracellular reactions that coalesce to maintain tissue homeostasis. A rapidly accumulating body of scientific literature clearly demonstrates a conversion in TGF-β function from that of a powerful tumor suppressor in normal epithelium and early-stage carcinomas to that of a prometastatic molecule in their late-stage counterparts. Collectively, this malicious switch in TGF-β behavior is termed the “TGF-β Paradox.” Historically, cell autonomous changes that transpire during tumor development and progression have been studied extensively as a means to decipher the “TGF-β Paradox.” Although highly informative and intriguing, these findings have yet to unravel the molecular underpinnings of the “TGF-β Paradox,” thereby suggesting involvement of additional signaling components and players that originate beyond the confines of developing carcinomas. Indeed, recent studies have been directed at interrogating the microenvironments of developing carcinomas and how changes within this unique cellular niche manifest the “TGF-β Paradox.” For instance, tumor microenvironments house an array of essential cellular, structural, and humoral factors that include stromal cells and altered elastic moduli, integrins and their engagement of matrix proteins, hypoxic zones, and a host of cytokines, growth factors, and chemokines that collectively influence the response of carcinoma cells to TGF-β. Here we review recent findings demonstrating the importance of the tumor microenvironment to regulate TGF-β signaling and its stimulation of metastatic progression. In addition, we also highlight recent in vitro and in vivo scientific advances capable of recapitulating various aspects of the metastatic process and its regulation by TGF-β. Indeed, incorporating and extending these novel systems to analyses of the “TGF-β Paradox” may offer new inroads in resolving this enigma and improving the overall survival of cancer patients.

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Abbreviations

2D:

2-Dimensional

3D:

3-Dimensional

CSF-1:

Colony stimulating factor-1

Dab2:

Disabled-2

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

EMT:

Epithelial-mesenchymal transition

ERK:

Extracellular signal-regulated kinase

FAK:

Focal adhesion kinase

Hgs:

Hepatocyte growth factor-regulated tyrosine kinase substrate

IHC:

Immunohistochemistry

JNK:

c-Jun N-terminal kinase

LOX:

Lysyl oxidase

MAPK:

Mitogen-activated protein kinase

MEC:

Mammary epithelial cell

MMP:

Matrix metalloproteinase

PTK:

Protein tyrosine kinase

RBM:

Reconstituted basement membrane

SARA:

Smad anchor for receptor activation

TAK-1:

TGF-β-activated kinase 1

TGF-β:

Transforming growth factor-β

TβR-I:

TGF-β type I receptor

TβR-II:

TGF-β type II receptor

TβR-III:

TGF-β type III receptor

VEGF:

Vascular endothelial growth factor

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Acknowledgements

We thank members of the Schiemann Laboratory for critical comments and reading of the manuscript. W.P.S. was supported by grants from the National Institutes of Health (CA129359), the Komen Foundation (BCTR0706967), the Department of Defense (BC084651); and the Case Comprehensive Cancer Center and the University Hospitals Seidman Cancer Center. M.K.W. was supported by the American Cancer Society (PF-09-120-01-CS).

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  1. Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH, 44106, USA

    Michael K. Wendt & William P. Schiemann

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  1. Michael K. Wendt
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Correspondence to William P. Schiemann .

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  1. Drexel University College of Medicine, N. 15th Street 245, Philadelphia, 19102, Pennsylvania, USA

    Alessandro Fatatis

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Wendt, M.K., Schiemann, W.P. (2011). Regulation of TGF-β Signaling and Metastatic Progression by Tumor Microenvironments. In: Fatatis, A. (eds) Signaling Pathways and Molecular Mediators in Metastasis. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2558-4_5

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