Rho-associated kinase signalling and the cancer microenvironment: novel biological implications and therapeutic opportunities

Abstract

The Rho/ROCK pathway is involved in numerous pivotal cellular processes that have made it an area of intense study in cancer medicine, however, Rho-associated coiled-coil containing protein kinase (ROCK) inhibitors are yet to make an appearance in the clinical cancer setting. Their performance as an anti-cancer therapy has been varied in pre-clinical studies, however, they have been shown to be effective vasodilators in the treatment of hypertension and post-ischaemic stroke vasospasm. This review addresses the various roles the Rho/ROCK pathway plays in angiogenesis, tumour vascular tone and reciprocal feedback from the tumour microenvironment and explores the potential utility of ROCK inhibitors as effective vascular normalising agents. ROCK inhibitors may potentially enhance the delivery and efficacy of chemotherapy agents and improve the effectiveness of radiotherapy. As such, repurposing of these agents as adjuncts to standard treatments may significantly improve outcomes for patients with cancer. A deeper understanding of the controlled and dynamic regulation of the key components of the Rho pathway may lead to effective use of the Rho/ROCK inhibitors in the clinical management of cancer.

Figure 1.

Key components of the Rho/ Rho-associated coiled-coil containing protein kinase (ROCK) signalling pathway. Various extracellular stimuli (growth factors and hormones) bind to cell membrane receptors, which subsequently act upon guanine-nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs) to regulate activation of Rho GTPase proteins. Once in its GTP-bound ‘active’ state, Rho GTPase binds to ROCK (ROCK1/2) to stimulate key downstream effectors (Refs 7, 12, 21). ROCK-mediated phosphorylation of myosin light-chain (MLC) promotes phosphorylation of myosin and increased actomyosin contraction. Activation of LIMK by ROCK leads to phosphorylation and inactivation of the actin-depolymerising protein cofilin, altering actin filament organisation. Collectively, activation of key downstream effectors of Rho causes changes in motility, proliferation and other essential cellular processes.

Figure 2.

Rho/ Rho-associated coiled-coil containing protein kinase (ROCK) signalling and the tumour microenvironment: unexplored treatment opportunities. (a) Schematic illustrating key events that lead to tumour progression and metastasis. (b) In the presence of ROCK inhibitors, invasion and metastasis are impaired: the Rho/ROCK pathway as a mediator and therapeutic target of cancer metastasis. Within cancer cells, ROCK inhibitors prevent the phosphorylation of LIMK and p- myosin light-chain (MLC) which results in impaired actin-myosin filament bundling. This in turn affects cellular proliferation, morphology, adhesion, motility and gene transcription. ROCK is essential in cancer-associated fibroblasts (CAF) associated invasion and also in cell- extracellular matrix (ECM) signalling.