ACADEMIC RESEARCH ENHANCEMENT AWARD

点击翻译按钮获取中文摘要

DESCRIPTION: The broad, long-term objectives of this work are a) to identify specific cellular and molecular mechanisms by which antiosteolytic therapy prevents the skeletal metastasis of some neoplasms and b) to identify specific properties that allow other bone-metastatic tumor cells to escape this inhibitory effect. Biophosphonates such as risedronate strongly inhibit osteoclastic bone resorption and can be used to treat osteolytic bone metastasis. In addition to decreased lesion size, bisphosphonate treatment sometimes results in a decreased incidence of bone metastases. Specific mechanisms responsible for this protective effect on incidence of bone metastases have not been determined. Using a rat model of bone-metastatic breast cancer, the first specific aim of this application is to evaluate early morphologic events in the establishment of lesions in untreated or risedronate-treated rats. Risedronate treatment decreases the incidence of bone metastases of one of the tumor clones to be used in the study, but has little effect on lesion size or incidence in the other. The objective will be accomplished by performing a time-point experiment and monitoring lesion development of lacZ-transfected tumor cells localized in tissue sections by histochemical staining. This approach may allow identification of specific steps in the development of bone metastatic lesions that are altered by bisphosphonate treatment and suggest possible mechanisms for the treatment effect. The second specific aim of the study is to evaluate the capacity of different ENU1564 tumor clones to directly lyse untreated and risedronate-treated bone and secondly, to determine whether there are differences in the chemotactic or mitogenic responses of the tumor cells to products released from resorbing treated or untreated bone. While bisphosphonate treatment efficiently inhibits bone destruction by osteoclasts, histologic sections of bone metastatic lesions clearly indicate that some degree of direct lysis of bone by tumor cells frequently continues to occur in this model system. The capacity to directly lyse bone may vary from tumor to tumor and could account for the residual bone destruction and unsatisfactory treatment responses to biophosphonates that occur with some bone-metastatic tumors. While products released from resorbing bone have been shown to stimulate chemotaxis and proliferation of some tumor cells, it is not known whether release of these factors or their influence on tumor cells is altered in bisphosphonate treated bone. The eventual ability to identify tumor cell properties responsible for unsatisfactory responses to antiosteolytic therapies will enable selection of patients that may benefit from alternative treatments.