Insulin-like Growth Factor Binding Protein-2 (IGFBP2) Is a Key Molecule in the MACC1-Mediated Platelet Communication and Metastasis of Colorectal Cancer Cells.

Reza Haschemi,Gerd Bendas,Elisabeth Steinwarz,Ulrike Stein,Martin Schlesinger,Dennis Kobelt

doi:10.3390/ijms222212195

Abstract

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.

Highlights

Metastasis-associated in colon cancer (MACC) 1 has been identified as a key player in colorectal cancer (CRC) malignancy
We reveal insulin-like growth factor binding protein-2 (IGFBP2) as a downstream component of MACC1, affecting platelet activation potential and increasing cell mobility, invasiveness, and metastatic activity
MACC1 possesses various modes of action to foster tumor metastasis, a functional insight whether and how tumor cell communication with the cellular microenvironment is affected by MACC1 remains elusive

Summary

Introduction

Metastasis-associated in colon cancer (MACC) 1 has been identified as a key player in CRC malignancy. It is accepted as a prognostic and predictive biomarker for tumor progression and metastasis in a great variety of more than 20 solid cancers [1,2]. MACC1 transcriptionally activates the epithelial–mesenchymal transition (EMT) associated with modifications of the extracellular matrix, resulting in a higher invasiveness of cells [5]. This is reflected by an accumulation of MACC1 at the invasive front of tumor cells [6].

Objectives

Methods

Results

Discussion

Conclusion