title: 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.
authors: Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Ernst J A
authors: EJ
authors: Steller
authors: Danielle A
authors: DA
authors: Raats
authors: Jan
authors: J
authors: Koster
authors: Bert
authors: B
authors: Rutten
authors: Klaas M
authors: KM
authors: Govaert
authors: Benjamin L
authors: BL
authors: Emmink
authors: Nikol
authors: N
authors: Snoeren
authors: Sander R
authors: SR
authors: van Hooff
authors: Frank C P
authors: FC
authors: Holstege
authors: Coen
authors: C
authors: Maas
authors: Inne H M
authors: IH
authors: Borel Rinkes
authors: Onno
authors: O
authors: Kranenburg
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D015539:Platelet Activation / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D020797:Receptor, Platelet-Derived Growth Factor beta