Limits...
Rac1-regulated endothelial radiation response stimulates extravasation and metastasis that can be blocked by HMG-CoA reductase inhibitors.

Hamalukic M, Huelsenbeck J, Schad A, Wirtz S, Kaina B, Fritz G - PLoS ONE (2011)

Bottom Line: IR-stimulated TC-EC adhesion was blocked by the HMG-CoA reductase inhibitor lovastatin.Glycyrrhizic acid from liquorice root, which acts as a Sialyl-Lewis X mimetic drug, and the Rac1 inhibitor NSC23766 also reduced TC-EC adhesion.To examine the in vivo relevance of these findings, tumorigenic cells were injected into the tail vein of immunodeficient mice followed by total body irradiation (TBI).

View Article: PubMed Central - PubMed

Affiliation: Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

ABSTRACT
Radiotherapy (RT) plays a key role in cancer treatment. Although the benefit of ionizing radiation (IR) is well established, some findings raise the possibility that irradiation of the primary tumor not only triggers a killing response but also increases the metastatic potential of surviving tumor cells. Here we addressed the question of whether irradiation of normal cells outside of the primary tumor augments metastasis by stimulating the extravasation of circulating tumor cells. We show that IR exposure of human endothelial cells (EC), tumor cells (TC) or both increases TC-EC adhesion in vitro. IR-stimulated TC-EC adhesion was blocked by the HMG-CoA reductase inhibitor lovastatin. Glycyrrhizic acid from liquorice root, which acts as a Sialyl-Lewis X mimetic drug, and the Rac1 inhibitor NSC23766 also reduced TC-EC adhesion. To examine the in vivo relevance of these findings, tumorigenic cells were injected into the tail vein of immunodeficient mice followed by total body irradiation (TBI). The data obtained show that TBI dramatically enhances tumor cell extravasation and lung metastasis. This pro-metastatic radiation effect was blocked by pre-treating mice with lovastatin, glycyrrhizic acid or NSC23766. TBI of mice prior to tumor cell transplantation also stimulated metastasis, which was again blocked by lovastatin. The data point to a pro-metastatic trans-effect of RT, which likely rests on the endothelial radiation response promoting the extravasation of circulating tumor cells. Administration of the widely used lipid-lowering drug lovastatin prior to irradiation counteracts this process, likely by suppressing Rac1-regulated E-selectin expression following irradiation. The data support the concern that radiation exposure might increase the extravasation of circulating tumor cells and recommend co-administration of lipid-lowering drugs to avoid this adverse effect of ionizing radiation.

Show MeSH

Related in: MedlinePlus

Model of IR-induced tumor cell extravasation and metastasis and pharmacological strategies to prevent this adverse radiation effect.Ionizing radiation (IR) triggers the expression of different types of cell adhesion molecules on tumor (TC) and endothelial (EC) cells, which augment TC-EC adhesion and subsequent extravasation of tumor cells. By inhibiting Rac1-regulated activation of NF-κB, HMG-CoA reductase inhibitors (statins) specifically attenuate IR-induced expression of endothelial cell adhesion molecules, thereby antagonizing radiation-promoted adhesion of circulating tumor cells as well as subsequent extravasation and formation of lung metastases. TBI-promoted metastasis can also be reduced by targeting of the small GTPase Rac1 using the small molecule inhibitor NSC23766 and/or the Sialyl-Lewis X mimetic glycyrrhizic acid, which acts as E-selectin antagonist. CAF, cell adhesion factors; FPP, farnesylpyrophosphate; GGPP, geranylgeranylpyrophosphate; GL, Glycyrrhizic acid.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3198428&req=5

pone-0026413-g006: Model of IR-induced tumor cell extravasation and metastasis and pharmacological strategies to prevent this adverse radiation effect.Ionizing radiation (IR) triggers the expression of different types of cell adhesion molecules on tumor (TC) and endothelial (EC) cells, which augment TC-EC adhesion and subsequent extravasation of tumor cells. By inhibiting Rac1-regulated activation of NF-κB, HMG-CoA reductase inhibitors (statins) specifically attenuate IR-induced expression of endothelial cell adhesion molecules, thereby antagonizing radiation-promoted adhesion of circulating tumor cells as well as subsequent extravasation and formation of lung metastases. TBI-promoted metastasis can also be reduced by targeting of the small GTPase Rac1 using the small molecule inhibitor NSC23766 and/or the Sialyl-Lewis X mimetic glycyrrhizic acid, which acts as E-selectin antagonist. CAF, cell adhesion factors; FPP, farnesylpyrophosphate; GGPP, geranylgeranylpyrophosphate; GL, Glycyrrhizic acid.

Mentions: In summary, we provide evidence that IR largely stimulates EC-TC adhesion in vitro and that whole body irradiation of mice increases the probability of extravasation and subsequent formation of lung metastases of transplanted circulating tumorigenic cells of rodent and human origin. The pro-metastatic radiation effect appears to rest on the upregulation of both endothelial and tumor cell-specific adhesion factors (see Fig. 6). Importantly, the radiation response is a trans-effect since irradiation of mice prior to transplantation of non-irradiated tumor cells also stimulated metastasis. From this we infer that irradiation of the normal tissue is sufficient to trigger metastasis. Searching for pharmacological strategies counteracting the adverse radiation effect, we show that pre-administration of lovastatin, which is nowadays widely used as lipid-lowering drug, can antagonize pro-adhesive radiation effects in vitro and the pro-metastatic effects of TBI in vivo. The anti-metastatic statin effect is very likely due to inhibition of IR-induced normal tissue responses, in particular the IR-stimulated Rac-1-regulated increase in the expression of endothelial cell adhesion molecules (see Fig. 6). Thus, the proposed pharmacological strategy suitable to counteract pro-metastatic effects of RT is based on the inhibition of Rac1 signaling, either by statins (e.g. lovastatin) or Rac1-specific inhibitors, such as NSC23766 (see Fig. 6). Alternatively, radiation-stimulated binding of tumor cells to the endothelium can be blocked by Sialyl-LewisX mimetic drugs, which act as E-selectin antagonists (see Fig. 6). However, neither Sialyl-LewisX mimetics nor Rac1 inhibitors have thus far been established for clinical use. Therefore, we propose to focus on statins that are clinically well established, very well tolerated and widely used for lipid lowering purpose. We consider them as first choice drugs for short-term clinical application.


Rac1-regulated endothelial radiation response stimulates extravasation and metastasis that can be blocked by HMG-CoA reductase inhibitors.

Hamalukic M, Huelsenbeck J, Schad A, Wirtz S, Kaina B, Fritz G - PLoS ONE (2011)

Model of IR-induced tumor cell extravasation and metastasis and pharmacological strategies to prevent this adverse radiation effect.Ionizing radiation (IR) triggers the expression of different types of cell adhesion molecules on tumor (TC) and endothelial (EC) cells, which augment TC-EC adhesion and subsequent extravasation of tumor cells. By inhibiting Rac1-regulated activation of NF-κB, HMG-CoA reductase inhibitors (statins) specifically attenuate IR-induced expression of endothelial cell adhesion molecules, thereby antagonizing radiation-promoted adhesion of circulating tumor cells as well as subsequent extravasation and formation of lung metastases. TBI-promoted metastasis can also be reduced by targeting of the small GTPase Rac1 using the small molecule inhibitor NSC23766 and/or the Sialyl-Lewis X mimetic glycyrrhizic acid, which acts as E-selectin antagonist. CAF, cell adhesion factors; FPP, farnesylpyrophosphate; GGPP, geranylgeranylpyrophosphate; GL, Glycyrrhizic acid.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198428&req=5

pone-0026413-g006: Model of IR-induced tumor cell extravasation and metastasis and pharmacological strategies to prevent this adverse radiation effect.Ionizing radiation (IR) triggers the expression of different types of cell adhesion molecules on tumor (TC) and endothelial (EC) cells, which augment TC-EC adhesion and subsequent extravasation of tumor cells. By inhibiting Rac1-regulated activation of NF-κB, HMG-CoA reductase inhibitors (statins) specifically attenuate IR-induced expression of endothelial cell adhesion molecules, thereby antagonizing radiation-promoted adhesion of circulating tumor cells as well as subsequent extravasation and formation of lung metastases. TBI-promoted metastasis can also be reduced by targeting of the small GTPase Rac1 using the small molecule inhibitor NSC23766 and/or the Sialyl-Lewis X mimetic glycyrrhizic acid, which acts as E-selectin antagonist. CAF, cell adhesion factors; FPP, farnesylpyrophosphate; GGPP, geranylgeranylpyrophosphate; GL, Glycyrrhizic acid.
Mentions: In summary, we provide evidence that IR largely stimulates EC-TC adhesion in vitro and that whole body irradiation of mice increases the probability of extravasation and subsequent formation of lung metastases of transplanted circulating tumorigenic cells of rodent and human origin. The pro-metastatic radiation effect appears to rest on the upregulation of both endothelial and tumor cell-specific adhesion factors (see Fig. 6). Importantly, the radiation response is a trans-effect since irradiation of mice prior to transplantation of non-irradiated tumor cells also stimulated metastasis. From this we infer that irradiation of the normal tissue is sufficient to trigger metastasis. Searching for pharmacological strategies counteracting the adverse radiation effect, we show that pre-administration of lovastatin, which is nowadays widely used as lipid-lowering drug, can antagonize pro-adhesive radiation effects in vitro and the pro-metastatic effects of TBI in vivo. The anti-metastatic statin effect is very likely due to inhibition of IR-induced normal tissue responses, in particular the IR-stimulated Rac-1-regulated increase in the expression of endothelial cell adhesion molecules (see Fig. 6). Thus, the proposed pharmacological strategy suitable to counteract pro-metastatic effects of RT is based on the inhibition of Rac1 signaling, either by statins (e.g. lovastatin) or Rac1-specific inhibitors, such as NSC23766 (see Fig. 6). Alternatively, radiation-stimulated binding of tumor cells to the endothelium can be blocked by Sialyl-LewisX mimetic drugs, which act as E-selectin antagonists (see Fig. 6). However, neither Sialyl-LewisX mimetics nor Rac1 inhibitors have thus far been established for clinical use. Therefore, we propose to focus on statins that are clinically well established, very well tolerated and widely used for lipid lowering purpose. We consider them as first choice drugs for short-term clinical application.

Bottom Line: IR-stimulated TC-EC adhesion was blocked by the HMG-CoA reductase inhibitor lovastatin.Glycyrrhizic acid from liquorice root, which acts as a Sialyl-Lewis X mimetic drug, and the Rac1 inhibitor NSC23766 also reduced TC-EC adhesion.To examine the in vivo relevance of these findings, tumorigenic cells were injected into the tail vein of immunodeficient mice followed by total body irradiation (TBI).

View Article: PubMed Central - PubMed

Affiliation: Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

ABSTRACT
Radiotherapy (RT) plays a key role in cancer treatment. Although the benefit of ionizing radiation (IR) is well established, some findings raise the possibility that irradiation of the primary tumor not only triggers a killing response but also increases the metastatic potential of surviving tumor cells. Here we addressed the question of whether irradiation of normal cells outside of the primary tumor augments metastasis by stimulating the extravasation of circulating tumor cells. We show that IR exposure of human endothelial cells (EC), tumor cells (TC) or both increases TC-EC adhesion in vitro. IR-stimulated TC-EC adhesion was blocked by the HMG-CoA reductase inhibitor lovastatin. Glycyrrhizic acid from liquorice root, which acts as a Sialyl-Lewis X mimetic drug, and the Rac1 inhibitor NSC23766 also reduced TC-EC adhesion. To examine the in vivo relevance of these findings, tumorigenic cells were injected into the tail vein of immunodeficient mice followed by total body irradiation (TBI). The data obtained show that TBI dramatically enhances tumor cell extravasation and lung metastasis. This pro-metastatic radiation effect was blocked by pre-treating mice with lovastatin, glycyrrhizic acid or NSC23766. TBI of mice prior to tumor cell transplantation also stimulated metastasis, which was again blocked by lovastatin. The data point to a pro-metastatic trans-effect of RT, which likely rests on the endothelial radiation response promoting the extravasation of circulating tumor cells. Administration of the widely used lipid-lowering drug lovastatin prior to irradiation counteracts this process, likely by suppressing Rac1-regulated E-selectin expression following irradiation. The data support the concern that radiation exposure might increase the extravasation of circulating tumor cells and recommend co-administration of lipid-lowering drugs to avoid this adverse effect of ionizing radiation.

Show MeSH
Related in: MedlinePlus