Review
A new paradigm for mechanobiological mechanisms in tumor metastasis

https://doi.org/10.1016/j.semcancer.2012.05.002Get rights and content

Abstract

Tumor metastases and epithelial to mesenchymal transition (EMT) involve tumor cell invasion and migration through the dense collagen-rich extracellular matrix surrounding the tumor. Little is neither known about the mechanobiological mechanisms involved in this process, nor the role of the mechanical forces generated by the cells in their effort to invade and migrate through the stroma. In this paper we propose a new fundamental mechanobiological mechanism involved in cancer growth and metastasis, which can be both protective or destructive depending on the magnitude of the forces generated by the cells. This new mechanobiological mechanism directly challenges current paradigms that are focused mainly on biological and biochemical mechanisms associated with tumor metastasis. Our new mechanobiological mechanism describes how tumor expansion generates mechanical forces within the stroma to not only resist tumor expansion but also inhibit or enhance tumor invasion by, respectively, inhibiting or enhancing matrix metalloproteinase (MMP) degradation of the tensed interstitial collagen. While this mechanobiological mechanism has not been previously applied to the study of tumor metastasis and EMT, it may have the potential to broaden our understanding of the tumor invasive process and assist in developing new strategies for preventing or treating cancer metastasis.

Introduction

Breast cancer is the most commonly diagnosed malignancy and leading cause of cancer mortality among women in the United States [1]. Ninety percent of all cancer deaths arise from tumor metastases, the process in which abnormal tumor cells proliferate, expand, reorganize, degrade and migrate through the surrounding stroma's microenvironment (extracellular matrix (ECM)) into the circulation to invade other tissues. Triple negative breast cancer (TNBC), an aggressive subtype of invasive breast cancer that responds less well to current chemotherapeutic agents, is associated with an increased risk of tumor relapse, metastasis, and a poorer overall patient prognosis [2]. A better understanding of the tumor invasive process is essential to developing more effective and targeted therapies to both treat and prevent metastatic breast cancer, especially the TNBC subtype.

The delamination and spread of tumor cells are prerequisites for metastatic disease. To develop new strategies for the prevention and treatment of cancer metastasis, including TNBC, it is important to understand the basic molecular mechanisms that control how cells from a primary tumor leave their neighboring cells, break into the vascular bed, migrate into the blood or lymph stream, reattach to a distant site and develop into a metastatic tumor. The early steps of the metastatic process are characterized by migration and invasion of the tumor cells into and through the stroma to enter the circulation through a process known as epithelial to mesenchymal transition (EMT) [3]. An ever-expanding literature is now evolving to describe the mechanisms controlling this process [4]. During EMT, cells acquire a more spindle-like fibroblastic morphology, lose their adhesive properties, gain enhanced motility, increase their stroma interactions and invasive behavior in a process that involves increased cell traction forces to reorganize and degrade the extracellular matrix [4], [5], [6], [7]. To increase their traction force on the ECM, the epithelial cells must incorporate α-smooth muscle actin (α-SMA) into stress fibers by synthesizing TGFβ-1 or activating it from the surrounding ECM [5]. As the cells increase their traction force on the ECM in response to increasing ECM stiffness as the tumor expands, the epithelial cells will transition from a more fibroblastic phenotype to a differentiated mesenchymal/myofibroblastic phenotype. Degradation of the ECM is a necessity for invasion and dispersion of cells and has been thoroughly studied during the last decade. Matrix metalloproteinases (MMPs) have been identified as key enzymes in this process as they are capable of degrading the ECM components, specifically proteoglycan, basement membrane, fibronectin and collagen [8], [9].

The importance and role of biomechanical forces within the tumor and stroma in the EMT process have not been extensively studied. We introduce a new paradigm for how biomechanical forces can modify the ECM's molecular conformation during tumor growth and how these forces can be both protective and destructive depending on the stage of tumor growth. We describe how tumor expansion generates mechanical forces (tensile and compressive) within the stroma to resist tumor expansion and how these same forces can inhibit or enhance tumor invasion of the stroma. We also propose a possible biomechanical trigger for EMT based on the magnitude of traction force exerted by the tumor and stroma cells to deform and unwind the collagen molecule for enzyme cleavage. These conceptual force-based mechanisms have not been previously described, and we believe they will have application to the study of the tumor invasive process. In this paper we focused on breast cancer and the cells and tissues involved in the metastatic process. Our paradigm was developed in the context of breast cancer because the mechanics of tumor expansion, ECM deformation, and cellular traction forces were easiest to conceptualize. However the proposed biomechanical force mechanism is intrinsic to the collagen molecule itself, as well as other ECM components, and as such is applicable to many different cell types, tissues and disease processes. In the broader sense, we are proposing a new biomechanical mechanism for ECM degradation based on previous literature and our own research, with the hope that this will provide new and useful insights into not only cancer biology but also many other disease processes.

Section snippets

Tumor metastasis and biomechanical forces

Biomechanical forces within the microenvironment at the tumor–stroma interface may be a key mechanism driving EMT, and ultimately lead to metastatic spread to target organs. In this section we will explore the role and importance of mechanobiological (cell–matrix) and mechanochemical (cell–enzyme) mechanisms for eliciting EMT and subsequent degradation of the surrounding stroma. We will discuss possible biomechanical triggers that may be involved in tumor expansion in the early stages of the

Mechanical forces and properties of soft tissues

Loads or forces are commonly exerted and sensed by cells attached to the ECM (Fig. 1). External cellular forces are generated by the extracellular matrix at the cell's ECM contact sites (focal adhesions) between the cell's integrins and their ECM ligands (e.g., α2β1 and α5β1 and collagen and fibronectin, respectively). On the other hand, internal cellular forces are intracellularly generated, through cytoskeletal proteins or filaments (e.g., actin filaments, microtubles). These forces act as

Tumor invasion and migration through the ECM

Degradation of the ECM by tumor and stroma cells is necessary for tumor invasion of the stroma, and the interaction between both cell types and with their surrounding ECM are recognized as primary factors in the EMT process [9]. The most significant ECM components that inhibit cell motility through the ECM are collagen, fibronectin (FN) and proteoglycan (PG). Two primary cellular mechanisms exist for tumor invasion and migration through the ECM, cellular catabolism of the ECM by enzymatic

Steered molecular dynamics suggests cell-assisted collagen unwinding

Collagen is one of the most abundant matrix proteins in the body and at the cellular level (nano and microscales) collagen and fibronectin are the primary ECM components that physically connect the cell to the surrounding matrix through attachments such as integrins. Therefore these matrix proteins serve as key structural elements through which intracellular systems physically attach to and connect with the extracellular environment.

Based on the ECM structure, basic mechanics principles imply

A new paradigm based on Cellular Assisted Enzyme MechanoKinetics

Our SMD results clearly showed that the collagen triple helix could easily be unwound at a force well below what a cell can exert, thus suggesting that cells can physically assist in the enzymatic cleavage of collagen. Based on our SMD and EMK findings, we can now postulate a new paradigm for tumor cell invasion and migration through the collagen-dense stroma, shown schematically in Fig. 12. We term this new cell–matrix interaction a Cellular Assisted Enzyme MechanoKinetic (CAEMK) effect or

Summary

So what is the influence of biomechanical forces on the invasive capacity of tumor cells in the metastatic process? In this paper we have proposed a new and exciting paradigm about fundamental biomechanical (force) and biophysical (molecular conformation) mechanisms involved in cancer growth and metastasis, and how these mechanisms are interrelated to be both protective (EMK effect) and destructive (CAEMK effect). These mechanobiological mechanisms directly challenge current paradigms that are

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgments

Support for this study was made possible by Grant Numbers AR46574 (PAT), AR45748 (PAT), AR059203 (PAT) and AR051636 (PAT) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH), Grant Numbers TL1RR024998 (JWB) and UL1RR024996 (PAT) from the Weill Cornell Medical College's National Center for Research Resources (NIH) Clinical and Translational Science Center, and the Weill Cornell Graduate School of Medical Sciences (JWB). CTV

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