Histamine hinders radiation-induced mesenchymal transition in epithelial tumor cells.

MOHAMAD N, CRICCO G, PORRETTI J, VENTURA C, NÚÑEZ M, COCCA C, RIVERA E, MARTÍN G.

Congreso; IRPA 13. Living with Radiation - Engaging with Society; 2012

Epithelial-mesenchymal transition (EMT) is a physiologic process during which epithelial cells acquire mesenchymal features. Up to 90 % of human neoplasias are carcinomas fromepithelial tissues. During malignant progression the EMT process is necessary to the conversion of tumors to aggressive and highly invasive cancers. Due to complex interactions between cancer cells and their microenvironment, changes in cell adhesion, apositive regulation of metaloproteinases 2 and 9 (MMP2 and MMP9) and activation of cell motility are observed together with an increase in mesenchymal markers like N-cadherin, vimentin and smooth muscle alpha-actin. Intrinsic radiosensitivity of tumor cell is only one of the factors that affect effectiveness of radiotherapy existing evidence that proliferative, invasive and metastatic capacities can be increased in the surviving tumor cells of irradiated neoplasias.In previous works on pancreatic adenocarcinoma (PANC-1) and breast cancer (MDA-MB-231) cell lines we demonstrated that histamine exerts an antiproliferative effect over 10 uM. The aim of this work was to study the effect of histamine on ionizingradiation-induced EMT.Histamine treatment produced a concentration dependent effect on EMT in PANC-1 and MDA-MB-231 cells. At high concentrations (over 10 uM) a reduction in MMP2 and MMP9 activity (evaluated by zymography) and cell migration (evaluated by migration chambers) was observed in both cell lines. Moreover an enhancement of E-cadherin expression (epithelial marker) and diminution of smooth muscle alpha-actin, vimentin and N-catherin (mesenchymal markers) were determined by immunocytochemistry or immunoblot.When tumor cells were 2 gray gamma irradiated an increase in gelatinolytic activity, migration and expression of mesenchymal markers was detected in both cell lines evidencing some degree of mesenchymal transition. Notably, treatment with highconcentrations of histamine before irradiation counteracted those effects.The mechanisms that control the efficacy of radiotherapy have classically focused on the ability of ionizing radiation to kill cancer cells while sparing normal tissues. However, the identification of pharmacological agents that target oncogenic pathways which may regulate tumor cell proliferation and simultaneously control metastatic ability will help to delineate more effective strategies to improve overall and disease free-survival and health-related quality of life in patients undergoing radiotherapy.