|
Angiogenesis is required for tumor formation. Several studies have
demonstrated that tumor angiogenesis is regulated by a balance
between proangiogenesis and antiangiogenesis factors and that
this balance varies in different organ environments. To investigate
if expression of an angiogenesis inhibitor by cancer cells could
alter this balance and prevent tumor formation in different organ
environments, we engineered stable transfectants from RenCa mouse
renal carcinoma cells and SW620 human colon carcinoma cells to
constitutively secrete a mouse endostatin protein with c-myc
and polyhistidine (His) tags. Conditioned medium from endostatin-transfected
cells inhibit human umbilical vein endothelial cell (HUVEC) proliferation
compared to conditioned medium from control cells. Following
inoculation into mice, flank tumors from endostatin-transfected
cells are growth-inhibited compared to flank tumors from control cells after
3 weeks. Inoculation of a cell mixture containing 25% endostatin-transfected
cells and 75% control cells results in inhibition of flank tumor formation
as effective as following inoculation of 100% endostatin-transfected cells.
Formation of lung metastases by RenCa endostatin-transfected cells and formation
of liver metastases by SW620 endostatin-transfected cells are dramatically
inhibited compared to formation of metastases by control cells. These findings
demonstrate that endostatin can inhibit tumor formation in different organ
environments and that gene delivery of endostatin into even a minority of
tumor cells may be an effective strategy to prevent progression of micrometastases
to macroscopic disease. To develop oncolytic vectors with multiple mechanisms
of anti-neoplastic activity, we have constructed both HSV and adenoviral
vectors to express mouse endostatin. The interaction between endostatin expression
and viral oncolysis is currently under examination.
Viral Oncolysis and Antiangiogenesis
Principal Investigator: Kenneth K. Tanabe, MD
Group Members: James M. Donahue, MD; John T. Mullen, MD
|
