Pregnancy-associated plasma protein-A (
PAPP-A) is an important regulatory component of the IGF system. Through proteolysis of inhibitory
IGF binding proteins (IGFBPs),
PAPP-A acts as a positive modulator of local IGF signaling in a variety of
biological systems. A role of IGF in the progression of several common forms of human
cancer is now emerging, and therapeutic intervention of IGF receptor signaling is currently being explored. However, little is known about the activities of other components of the IGF system in relation to
cancer. We hypothesized that
PAPP-A acts to enhance
tumor growth in vivo. To test this hypothesis, we overexpressed wild-type
PAPP-A or a mutant
PAPP-A with markedly reduced
IGFBP protease activity in SKOV3 cells, a human ovarian
carcinoma cell line with low tumorigenic potential. In vitro, SKOV3 clones with elevated
PAPP-A expression (PAPP-A-1, PAPP-A-28) showed accelerated anchorage-independent growth in soft
agar assays compared to clones overexpressing mutant
PAPP-A (E483Q-1, E483Q-5) and vector controls. PAPP-A-28, with the highest
PAPP-A expression and
IGFBP proteolytic activity, also had markedly increased cell invasion through
Matrigel. In vivo, we found significantly accelerated
tumor growth rates of
PAPP-A-overexpressing SKOV3 clones compared with mutant
PAPP-A and controls. Investigation of angiogenesis indicated that overexpression of
PAPP-A favored development of mature
tumor vasculature and that
tumor precursors of PAPP-A-28 in particular had a significantly higher degree of vascularization months before obvious
tumor development. In conclusion, our data show that
PAPP-A proteolytic activity enhances the tumorigenic potential of
ovarian cancer cells and establish a novel
tumor growth-promoting role of
PAPP-A.