Forcing through Tumor Metastasis: The Interplay between Tissue Rigidity and Epithelial–Mesenchymal Transition

Trends

Physical properties of the tumor microenvironment and of tumor cells have functional roles in driving tumor metastasis.

Matrix stiffness regulates tumor dissemination and metastasis through induction of epithelial–mesenchymal transition.

Extracellular matrix remodeling of the primary and secondary tumor microenvironment represents a key step in tumor metastasis.

Mechanical cues are sensed by a repertoire of cellular mechanosensors, with integrins being key cellular mechanosensors of matrix stiffness.

Extracellular matrix deposition and remodeling are mediated by a variety of cell types, including both tumor and stromal cells.

The mechanical properties of the tumor microenvironment have been increasingly recognized as potent modulators of cell behavior and function. In particular, tissue rigidity is functionally important during tumor progression. In this review, we survey recent advances in our understanding of the role of tissue rigidity in tumor progression and metastasis, the mechanisms by which mechanical cues integrate with biochemical signals from the microenvironment, and the underlying mechanotransduction pathways involved in tumor progression. These findings highlight the importance of understanding and defining cellular mechanotransduction pathways and the breadth of signals derived from the tumor microenvironment that influence tumor progression.

Introduction

The tumor microenvironment presents cancer cells with a diverse set of extracellular cues to potently influence tumor cell behavior and function. Past decades of cancer research have mainly focused on the role of various extracellular and intracellular biochemical signals in cancer cell proliferation, invasion, and metastasis. Increasingly, mechanical properties of the extracellular matrix (ECM) have been recognized as also being functionally important during tumor progression 1, 2. Recently, tumor mechanics, and tissue rigidity in particular, has emerged as an important factor during tumor progression and metastasis [3]. In the patient setting, increasing tissue rigidity of primary breast tumors correlates with metastatic recurrence and poor patient survival 4, 5, 6. Studies in 3D culture systems and mouse tumor models showed that increased tissue rigidity has a functional role in driving tumor invasion and malignancy 2, 7, 8. Understanding the function and mechanisms of mechanical cues in this diverse set of contexts will be critical and may elucidate essential signaling pathways regulating tumor progression. Many critical aspects of tumor mechanosensing remain undetermined. For example, how do disseminated tumor cells react to the diverse biochemical and mechanical properties of the environments they invade? Do the same rules apply in metastatic sites versus the primary tumor?