The 2016 John J. Abel Award Lecture: Targeting the Mechanical Microenvironment in Cancer

Abstract

Past decades of cancer research have mainly focused on the role of various extracellular and intracellular biochemical signals on cancer progression and metastasis. Recent studies suggest an important role of mechanical forces in regulating cellular behaviors. This review first provides an overview of the mechanobiology research field. Then we specially focus on mechanotransduction pathways in cancer progression and describe in detail the key signaling components of such mechanotransduction pathways and extracellular matrix components that are altered in cancer. Although our understanding of mechanoregulation in cancer is still in its infancy, some agents against key mechanoregulators have been developed and will be discussed to explore the potential of pharmacologically targeting mechanotransduction in cancer.

Fig. 1.

A summary of various molecules implicated in mechanoregulation of cancer and the therapeutics developed against these targets. Current strategies to target mechanotransduction in cancer focus on two areas: one is to target biomechanical molecules activated by mechanotransduction, and the other one is to target the altered ECM components themselves. The first startegy has largely focused on inhibiting the well-established mechanoactivators such as integrins, FAK, and Src, and the known mechanotransducers such as RHO/ROCK. Recently, some mechanotransduction effectors such as YAP/TAZ proteins have also been experimentally targeted and show benefits in inhibiting tumor growth and metastasis. For the ECM components, most therapies are designed to inhibit the molecules responsible for creating stiffer tumor-associated matrices, including regulators of collagen synthesis such as collagen prolyl 4 hydroxylase, the LOX family of collagen cross-linking enzymes, and HA and its regulator hyaluronidase. Individual mechanoregulators are labeled in the figure, and the therapeutic agents are listed in the boxes.