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

Chin VT, Nagrial AM, Chou A, Biankin AV, Gill AJ, Timpson P, Pajic M - Expert Rev Mol Med (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: The Kinghorn Cancer Centre,Cancer Division,Garvan Institute of Medical Research,384 Victoria St,Darlinghurst,Sydney,NSW 2010,Australia.

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.

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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.
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fig02: 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.

Mentions: The Rho/ROCK pathway has been shown to be an integral part of VEGF-mediated angiogenesis and is not only implicated in VEGF signalling, but also in numerous processes necessary for angiogenesis to occur, including EC migration, survival and cell permeability (Ref. 69) (Fig. 2). It has been shown that adherin junctions between ECs need to be loosened in order for EC migration and proliferation to occur (Ref. 66). Rho/ROCK signals via p-MLC break down intracellular junctions and thereby increase vascular permeability (Ref. 70). In order for ECs to invade surrounding tissue and form new vessels, the basement membrane (BM) and ECM must be disrupted via matrix metalloproteinase (MMP) secretion (Ref. 71). Rho/ROCK activation has been shown to directly stimulate MMP-9 secretion (Ref. 72) and is also associated with increased MMP expression in tumours (Refs 73, 74). Once the BM and ECM are disrupted, EC migration and tube formation can occur. van Nieuw Amerongen et al. (Ref. 75) used human umbilical vein endothelial cells (HUVECs) to show that not only do VEGF-induced changes in the EC cytoskeleton depend on RhoA, but also that growth of human microvascular endothelial cells (hMVECs) into a fibrin matrix in response to VEGF is inhibited by Y-27632, suggesting that the Rho/ROCK pathway is necessary for ingrowth of ECs. Bryan et al. (Ref. 76) showed that disruption of the Rho/ROCK pathway inhibits VEGF-mediated changes to the cytoskeleton in ECs and also that ECs treated with Y-27632 failed to assemble into recognisable vessel structures, highlighting the importance of the Rho/ROCK pathway in vasculogenesis. Hoang and Uchida (Refs 77, 78) both demonstrated that inhibiting Rho/ROCK prevented ECs from forming organised vascular structures by suppressing cellular motility. As the Rho/ROCK pathway has been established as being critical to multiple steps in angiogenesis, many studies have attempted to elucidate the importance of its involvement in the cancer setting. Croft et al. (Ref. 79) used a conditionally active form of ROCK2 in colon carcinoma cells to show that increased ROCK signalling promoted tumour angiogenesis and tumour cell invasion in vivo. Using HUVEC and glioma cell co-culture techniques, Nakabayashi et al. (Ref. 38) further showed that the ROCK inhibitor fasudil suppressed tumour-induced angiogenesis and the migration of HUVEC cells through transwell plates. Moreover, the same group showed that the growth of T98G glioma xenografts was significantly inhibited when tumour-bearing mice were treated daily with fasudil (Ref. 38). ROCK inhibitors also showed significant promise as anti-angiogenic agents in additional in vivo models, for example Nakajima et al. (Ref. 40) showed that administration of the ROCK inhibitor Wf-536 reduced the number of spontaneous metastases and impaired angiogenesis in a Lewis lung carcinoma model. Further, Somlyo et al. (Ref. 47) showed that mice bearing xenotransplants of PC3 cells had a reduction in tumour volume and increased survival when treated with a combination of Wf-536 and Marimastat (an MMP inhibitor). ROCK inhibitors have not been evaluated in human trials to date. However, considerable clinical data exists regarding the effects of VEGF inhibitors on various cancer subtypes. Although anti-angiogenic therapies have shown variable efficacy in cancer treatment, a deeper understanding of the mechanisms of action has highlighted the potential importance of timing of administration on the anti-cancer effects. This hypothesis is an interesting new strategy to explore and test.Figure 2.


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

Chin VT, Nagrial AM, Chou A, Biankin AV, Gill AJ, Timpson P, Pajic M - Expert Rev Mol Med (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836205&req=5

fig02: 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.
Mentions: The Rho/ROCK pathway has been shown to be an integral part of VEGF-mediated angiogenesis and is not only implicated in VEGF signalling, but also in numerous processes necessary for angiogenesis to occur, including EC migration, survival and cell permeability (Ref. 69) (Fig. 2). It has been shown that adherin junctions between ECs need to be loosened in order for EC migration and proliferation to occur (Ref. 66). Rho/ROCK signals via p-MLC break down intracellular junctions and thereby increase vascular permeability (Ref. 70). In order for ECs to invade surrounding tissue and form new vessels, the basement membrane (BM) and ECM must be disrupted via matrix metalloproteinase (MMP) secretion (Ref. 71). Rho/ROCK activation has been shown to directly stimulate MMP-9 secretion (Ref. 72) and is also associated with increased MMP expression in tumours (Refs 73, 74). Once the BM and ECM are disrupted, EC migration and tube formation can occur. van Nieuw Amerongen et al. (Ref. 75) used human umbilical vein endothelial cells (HUVECs) to show that not only do VEGF-induced changes in the EC cytoskeleton depend on RhoA, but also that growth of human microvascular endothelial cells (hMVECs) into a fibrin matrix in response to VEGF is inhibited by Y-27632, suggesting that the Rho/ROCK pathway is necessary for ingrowth of ECs. Bryan et al. (Ref. 76) showed that disruption of the Rho/ROCK pathway inhibits VEGF-mediated changes to the cytoskeleton in ECs and also that ECs treated with Y-27632 failed to assemble into recognisable vessel structures, highlighting the importance of the Rho/ROCK pathway in vasculogenesis. Hoang and Uchida (Refs 77, 78) both demonstrated that inhibiting Rho/ROCK prevented ECs from forming organised vascular structures by suppressing cellular motility. As the Rho/ROCK pathway has been established as being critical to multiple steps in angiogenesis, many studies have attempted to elucidate the importance of its involvement in the cancer setting. Croft et al. (Ref. 79) used a conditionally active form of ROCK2 in colon carcinoma cells to show that increased ROCK signalling promoted tumour angiogenesis and tumour cell invasion in vivo. Using HUVEC and glioma cell co-culture techniques, Nakabayashi et al. (Ref. 38) further showed that the ROCK inhibitor fasudil suppressed tumour-induced angiogenesis and the migration of HUVEC cells through transwell plates. Moreover, the same group showed that the growth of T98G glioma xenografts was significantly inhibited when tumour-bearing mice were treated daily with fasudil (Ref. 38). ROCK inhibitors also showed significant promise as anti-angiogenic agents in additional in vivo models, for example Nakajima et al. (Ref. 40) showed that administration of the ROCK inhibitor Wf-536 reduced the number of spontaneous metastases and impaired angiogenesis in a Lewis lung carcinoma model. Further, Somlyo et al. (Ref. 47) showed that mice bearing xenotransplants of PC3 cells had a reduction in tumour volume and increased survival when treated with a combination of Wf-536 and Marimastat (an MMP inhibitor). ROCK inhibitors have not been evaluated in human trials to date. However, considerable clinical data exists regarding the effects of VEGF inhibitors on various cancer subtypes. Although anti-angiogenic therapies have shown variable efficacy in cancer treatment, a deeper understanding of the mechanisms of action has highlighted the potential importance of timing of administration on the anti-cancer effects. This hypothesis is an interesting new strategy to explore and test.Figure 2.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: The Kinghorn Cancer Centre,Cancer Division,Garvan Institute of Medical Research,384 Victoria St,Darlinghurst,Sydney,NSW 2010,Australia.

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.

Show MeSH
Related in: MedlinePlus