PEG-3, a nontransforming cancer progression gene, is a positive regulator of cancer aggressiveness and angiogenesis

Cancer is a progressive disease culminating in acquisition of metastatic po tential by a subset of evolving tumor cells. Generation of an adequate bloo d supply in tumors by production of new blood vessels, angiogenesis, is a d efining element in this process. Although extensively investigated, the pre cise molecular events underlying tumor development, cancer progression, and angiogenesis remain unclear. Subtraction hybridization identified a geneti c element, progression elevated gene-3 (PEG-3), whose expression directly c orrelates with cancer progression and acquisition of oncogenic potential by transformed rodent cells. We presently demonstrate that forced expression of PEG-3 in tumorigenic rodent cells, and in human cancer cells, increases their oncogenic potential in nude mice as reflected by a shorter tumor late ncy time and the production of larger tumors with increased vascularization . Moreover, inhibiting endogenous PEG-3 expression in progressed rodent can cer cells by stable expression of an antisense expression vector extinguish es the progressed cancer phenotype, Cancer aggressiveness of PEG-3 expressi ng rodent cells correlates directly with increased RNA transcription, eleva ted mRNA levels, and augmented secretion of vascular endothelial growth fac tor (VEGF). Furthermore, transient ectopic expression of PEG-3 transcriptio nally activates VEGF in transformed rodent and human cancer cells. Taken to gether these data demonstrate that PEG-3 is a positive regulator of cancer aggressiveness, a process regulated by augmented VEGF production. These stu dies also support an association between expression of a single nontransfor ming cancer progression-inducing gene, PEG-3, and the processes of cancer a ggressiveness and angiogenesis, In these contexts, PEG-3 may represent an i mportant target molecule for developing cancer therapeutics and inhibitors of angiogenesis.