Tumor cell crosstalk with platelets and, subsequently, their activation are key steps in hematogenous
tumor metastasis. MACC1 is an oncogene involved in molecular pathogenesis of
colorectal cancer (CRC) and other solid
tumor entities, mediating motility and
metastasis, making MACC1 an accepted prognostic
biomarker. However, the impact of MACC1 on platelet activation has not yet been addressed. Here, we investigated the activation of platelets by human CRC cells upon MACC1 modulation, indicated by platelet aggregation and granule release. These approaches led to the identification of
insulin-like growth factor binding protein-2 (IGFBP2) as a functional downstream molecule of MACC1, affecting communication with platelets. This was confirmed by an
shRNA-mediated IGFBP2 knockdown, while maintaining MACC1 activity. Although IGFBP2 displayed an attenuated platelet activation potential, obviously by scavenging
IGF-I as a platelet costimulatory mediator, the MACC1/IGFBP2 axis did not affect the
thrombin formation potential of the cells. Furthermore, the IGFBP2/MACC1-driven cell migration and invasiveness was further accelerated by platelets. The key role of IGFBP2 for the metastatic spread in vivo was confirmed in a xenograft mouse model. Data provide evidence for IGFBP2 as a downstream functional component of MACC1-driven
metastasis, linking these two accepted oncogenic
biomarkers for the first time in a platelet context.