Biological Mechanisms of Metastasis Suppression: Which Steps in the Metastatic Cascade are Inhabited by the Metastasis Suppressor Gene BRMS1

摘要

The purpose of this research is to determine which steps in the metastatic process are affected by the metastasis suppressor gene, BRMS1. Stable b-Gal expressing MDA-MB-231 and MDA-MB-231/BRMS1 cell lines were used to identify 2 steps in the metastatic process inhibited by BRMS1. It was found that BRMS1-expression (I) reduced the numbers of solitary cells that survive initial arrest in the lung (4 hours) and (2) reduced the numbers of cells that initiate form microscopic lung metastases (4 weeks) (both p < 0.05). Both these decreases account for the 80% reduction in lung metastases seen after 8 weeks. In vitro work has shown that anchorage dependence may account of the reduction seen after 4 hours and work is underway to determine factors that may be responsible for the growth inhibition. To determine if BRMS1 suppresses metastatic growth in liver, BRMS1 over-expressing cells and controls were injected via the mesenteric vein to target the liver. No suppression of liver metastases was seen by BRMS1 expression in MDA-MB-435 breast cancer cells. To date these studies have shown no significant difference between the growth rates and vascularity (assessed by H&E and CD31) of MDA-MB-435 +/- BRMS1 primary tumors in nude mice. However, a significant lag in initial tumor detection in BRMS1-expressing MDA-MB-435 cells was observed. Furthermore, a significant reduction in the numbers of functional vessels in BRMS1-expressing primary tumors has been shown and work in progress will determine the extent of this reduction.