The role of MMPs in Drosophila tumor metastasis.

摘要

Metastasis is a complex process that involves the integration of many molecular pathways. Lethal giant larvae (lgl) and brain tumor (brat) are tumor suppressor genes in Drosophila that cause neoplastic overgrowth of larval brain lobes when either is mutant. Brain tissue transplanted into an adult host will proliferate and travel to distant sites of the body eventually killing the host. This thesis presents the analysis of metastatic capabilities of these brain tumors. I utilized a transplantation assay in which fragments of tumorous brains were injected into the abdomen of adult female hosts and allowed to proliferate for a set number of days. The host ovaries were harvested and the ovarioles, individual subunits that constitute the ovary, were examined for micrometastases by immunofluorescence. I quantified metastatic frequency as the percentage of ovarioles with micrometastases. By this method, I found that lgl- and brat- brain tumors have equal metastatic frequencies. Serial transplantation of tumor cells into multiple hosts allowed for analysis of changes in metastatic frequency over time. Lgl- tumor metastatic frequency significantly increased over time while brat- tumor metastatic frequency remained constant. Lgl- and brat - micrometastases also had different expression of cell type markers. I examined the role of matrix metalloproteinases (MMPs) in lgl - and brat- metastasis. Tumors alter their microenvironment to facilitate metastasis by releasing proteases or inducing surrounding normal cells to release proteases. MMPs have been strongly implicated in mammalian tumor progression and metastasis. Drosophila has two MMPs, the soluble MMP1 and the membrane bound MMP2. I found that both MMPs are required in lgl- tumor cells for metastasis, while brat- tumor cells induce mmp expression in host ovaries to facilitate metastasis.