PDGFRB Promotes Liver Metastasis Formation of Mesenchymal-Like Colorectal Tumor Cells

Abstract

In epithelial tumors, the platelet-derived growth factor receptor B (PDGFRB) is mainly expressed by stromal cells of mesenchymal origin. Tumor cells may also acquire PDGFRB expression following epithelial-to-mesenchymal transition (EMT), which occurs during metastasis formation. Little is known about PDGFRB signaling in colorectal tumor cells. We studied the relationship between PDGFRB expression, EMT, and metastasis in human colorectal cancer (CRC) cohorts by analysis of gene expression profiles. PDGFRB expression in primary CRC was correlated with short disease-free and overall survival. PDGFRB was co-expressed with genes involved in platelet activation, transforming growth factor beta (TGFB) signaling, and EMT in three CRC cohorts. PDGFRB was expressed in mesenchymal-like tumor cell lines in vitro and stimulated invasion and liver metastasis formation in mice. Platelets, a major source of PDGF, preferentially bound to tumor cells in a non-activated state. Platelet activation caused robust PDGFRB tyrosine phosphorylation on tumor cells in vitro and in liver sinusoids in vivo. Platelets also release TGFB, which is a potent inducer of EMT. Inhibition of TGFB signaling in tumor cells caused partial reversion of the mesenchymal phenotype and strongly reduced PDGFRB expression and PDGF-stimulated tumor cell invasion. These results suggest that PDGFRB may contribute to the aggressive phenotype of colorectal tumors with mesenchymal properties, most likely downstream of platelet activation and TGFB signaling.

Characteristics of the expression of KAI1/CD82 and PDGFRβ and their impact on glioma progression

“…Specific chemotactic signaling pathways are involved in the regulation of tumor cell motility [22]. In agreement with earlier data [14,16,21,31], we found the PDGFRβ expression more frequently in grade III and IV than in grade I and II gliomas.…”

“…Based on previous reports and our data we postulate that a high PDGFRβ expression in low grade gliomas might characterize the subset of gliomas with biological aggressive behavior and suggest that depending on the PDGFRβ signaling pathway, activation is possible in an early oncogenic event in gliomas [14]. Similarly to other tumors such as breast or liver tumors, a high PDGFRβ expression in gliomas might contribute to the decreased cell-cell adhesion and promote metastatic capacity of tumor cells [22]. Some data indicate that PDGFRβ overexpression is associated with epithelial-to-mesenchymal transition (EMT) [22].…”

“…Similarly to other tumors such as breast or liver tumors, a high PDGFRβ expression in gliomas might contribute to the decreased cell-cell adhesion and promote metastatic capacity of tumor cells [22]. Some data indicate that PDGFRβ overexpression is associated with epithelial-to-mesenchymal transition (EMT) [22]. Moreover, the PDGFRβ expression following EMT transient state may induce the metastatic process [27].…”

Platelet-derived Growth Factor β-Receptor, Transforming Growth Factor β Type I Receptor, and CD44 Protein Modulate Each Other's Signaling and Stability

“…PDGFR expression is induced in breast epithelial cells during TGF␤-induced EMT (32,33), and PDGF signaling maintains EMT and promotes breast cancer metastasis (34). TGF␤-mediated tumor progression in hepatocytes is also dependent on PDGF signaling (35).…”

“…TGF␤-mediated tumor progression in hepatocytes is also dependent on PDGF signaling (35). In a bioinformatics screen, expression of PDGFR␤ was strongly associated with genes involved in TGF␤ signaling and EMT in all the cohorts analyzed (33). Because CD44 interacts with both PDGFR␤ and ⌻␤RI, we explored the possibility that CD44 simultaneously interacts with the receptors for PDGF and ⌻GF␤, and facilitates crosstalk between them.…”