Proliferation and invasion: Plasticity in tumor cells

TLDR

Invasive and proliferative phenotypes are key features of malignant disease, but it is unclear whether tumor cells can simultaneously express both, and suitable in vitro models are limited because proliferation is required for cell maintenance. The study describes glioblastoma cells that become highly invasive in response to hepatocyte growth factor/scatter factor (HGF/SF). From this invasive population, subclones were selected that were either highly proliferative or exhibited both invasive and proliferative phenotypes. Highly invasive subclones displayed invasion, migration, urokinase‑type plasminogen activation, and branching morphogenesis, whereas highly proliferative subclones showed anchorage‑independent growth and tumorigenicity; MAPK signaling mediated invasion, Myc signaling drove proliferation, and dual‑phenotype cells activated both pathways, illustrating that MAPK and Myc cooperate to confer invasive and proliferative traits and providing a system to study transitions between these phenotypes.

Abstract

Invasive and proliferative phenotypes are fundamental components of malignant disease, yet basic questions persist about whether tumor cells can express both phenotypes simultaneously and, if so, what are their properties. Suitable in vitro models that allow characterization of cells that are purely invasive are limited because proliferation is required for cell maintenance. Here, we describe glioblastoma cells that are highly invasive in response to hepatocyte growth factor/scatter factor (HGF/SF). From this cell population, we selected subclones that were highly proliferative or displayed both invasive and proliferative phenotypes. The biological activities of invasion, migration, urokinase-type plasminogen activation, and branching morphogenesis exclusively partitioned with the highly invasive cells, whereas the highly proliferative subcloned cells uniquely displayed anchorage independent growth in soft agar and were highly tumorigenic as xenografts in immune-compromised mice. In response to HGF/SF, the highly invasive cells signal through the MAPK pathway, whereas the selection of the highly proliferative cells coselected for signaling through Myc. Moreover, in subcloned cells displaying both invasive and proliferative phenotypes, both signaling pathways are activated by HGF/SF. These results show how the mitogen-activated protein kinase and Myc pathways can cooperate to confer both invasive and proliferative phenotypes on tumor cells and provide a system for studying how transitions between invasion and proliferation can contribute to malignant progression.