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The Multifunctional Roles of TGF-β in Navigating the Metastatic Cascade

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TGF-β in Human Disease

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Abstract

The role of TGF-β during tumorigenesis is best characterized by the diverse functions this multifunctional cytokine exhibits in early-stage versus late-stage cancers. For instance, during the initial stages of tumorigenesis, TGF-β uniformly acts as a potent tumor suppressor, even in low-grade carcinomas capable of evading the cytostatic activities of TGF-β. However, as carcinoma cells continue to evolve and progress towards more aggressive disease states they typically acquire the ability to surmount the last vestiges of the tumor suppressing activities of TGF-β, ultimately gaining a selective advantage that enables TGF-β to promote their metastatic progression and production of recurrent secondary tumor lesions that are refractory to standard chemotherapies. The molecular, cellular, and microenvironmental mechanisms that permit metastatic carcinoma cells to usurp and commandeer TGF-β for oncogenic activities are highly diverse and remain incompletely understood. Here we review recent advances that provide new insights into how aggressive carcinoma cell populations are selected to respond to the oncogenic activities of TGF-β, focusing specifically on its essential functions coupled to metastatic outgrowth and the acquisition of chemoresistance.

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Abbreviations

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

EMT:

Epithelial-mesenchymal transition

ERK:

Extracellular signal-regulated kinase

FAK:

Focal adhesion kinase

JNK:

c-Jun N-terminal kinase

LAP:

Latency-associated peptide

MAP kinase:

Mitogen-activated protein kinase

MEC:

Mammary epithelial cell

MET:

Mesenchymal–epithelial transition

NF-κB:

Nuclear factor-κB

PI3K:

Phosphoinositide-3-kinase

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 receptors

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Acknowledgments

Members of the Schiemann Laboratory are thanked for critical reading of the manuscript. W.P.S. was supported in part by grants from the National Institutes of Health (CA129359), the Department of Defense (BC084561), and pilot funding from the Case Comprehensive Cancer Center (P30 CA043703), while M.K.W. was supported by the National Institutes of Health (CA166140).

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  1. 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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  2. William P. Schiemann
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Correspondence to William P. Schiemann .

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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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Wendt, M.K., Schiemann, W.P. (2013). The Multifunctional Roles of TGF-β in Navigating the Metastatic Cascade. In: Moustakas, A., Miyazawa, K. (eds) TGF-β in Human Disease. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54409-8_7

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