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Tumor cell migration in complex microenvironments

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Abstract

Tumor cell migration is essential for invasion and dissemination from primary solid tumors and for the establishment of lethal secondary metastases at distant organs. In vivo and in vitro models enabled identification of different factors in the tumor microenvironment that regulate tumor progression and metastasis. However, the mechanisms by which tumor cells integrate these chemical and mechanical signals from multiple sources to navigate the complex microenvironment remain poorly understood. In this review, we discuss the factors that influence tumor cell migration with a focus on the migration of transformed carcinoma cells. We provide an overview of the experimental and computational methods that allow the investigation of tumor cell migration, and we highlight the benefits and shortcomings of the various assays. We emphasize that the chemical and mechanical stimulus paradigms are not independent and that crosstalk between them motivates the development of new assays capable of applying multiple, simultaneous stimuli and imaging the cellular migratory response in real-time. These next-generation assays will more closely mimic the in vivo microenvironment to provide new insights into tumor progression, inform techniques to control tumor cell migration, and render cancer more treatable.

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Abbreviations

CAF:

Cancer-associated fibroblast

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

EMT:

Epithelial to mesenchymal transition

FAK:

Focal adhesion kinase

IF:

Interstitial flow

IFP:

Interstitial fluid pressure

LEGI:

Local excitation, global inhibition

LIMK1:

LIM domain kinase 1

LOX:

Lysyl oxidase

MMP:

Matrix metalloproteinase

ROCK:

Rho-associated kinase

RPTK:

Receptor protein kinase

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Acknowledgments

The authors would like to thank members of the Kamm lab for critically reading the manuscript. Funding from The National Cancer Institute (R21CA140096), The Charles Stark Draper Laboratory University Research and Development Program (N.DL-H-550151) is greatly appreciated. W.J.P. was supported by a National Science Foundation Graduate Research Fellowship.

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  1. Department of Mechanical Engineering, MIT, 77 Massachusetts Ave. Room NE47-315, Cambridge, MA, 02139, USA

    William J. Polacheck

  2. Department of Mechanical Engineering, MIT, 77 Massachusetts Ave. Room NE47-319, Cambridge, MA, 02139, USA

    Ioannis K. Zervantonakis

  3. Departments of Mechanical Engineering and Biological Engineering, MIT, 77 Massachusetts Ave. Room NE47-321, Cambridge, MA, 02139, USA

    Roger D. Kamm

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  1. William J. Polacheck
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Correspondence to Roger D. Kamm.

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Polacheck, W.J., Zervantonakis, I.K. & Kamm, R.D. Tumor cell migration in complex microenvironments. Cell. Mol. Life Sci. 70, 1335–1356 (2013). https://doi.org/10.1007/s00018-012-1115-1

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