Evaluation of rock kinases and their interaction with microRNAs in bone sarcomas of childhood: implications for tumor progression and invasion

Abstract

The treatment of childhood cancer has evolved significantly in recent decades. However, the cure rates obtained for certain histological subtypes, such as malignant high-grade brain tumors, aggressive subtypes of leukemias and sarcomas are mostly lagging behind. Ewing's sarcoma and osteosarcoma represent the most frequent malignant bone tumors , representing 5-7 % of all cancers affecting children. Both tumor types are initially considered curable, though they present a great propensity for metastasis and relapses due to the inherent chemoresistance and invasiveness of cells. Recently, ROCK kinases have been identified as important contributors in the pathophysiology and progression of different tumors due to their role in cell migration. In fact, different studies suggest that blocking elements involved in the control of cell migration can reduce the opportunistic ability of tumor cells to invade and metastasize to distant organs, a step considered critical in goal-directed intervention. Thus, we propose to evaluate the expression of ROCK1 and ROCK2 genes and associated microRNAs in samples of pediatric patients affected with osteosarcoma and Ewing's sarcoma and to evaluate the in vitro effects of ROCK kinases inhibition in cell lines from these bone tumors, emphasizing on the processes of proliferation, migration and invasion. Moreover, we also aim to assess the influence of ROCK inhibition on resistance and sensitization to treatments currently available for each tumor type. In parallel, in vivo experiments in immunodeficient mice will be conducted in order to study the therapeutic potential of the inhibition of the kinases targeted towards tumor dissemination. (AU)