Platelet-derived growth factor (PDGF) cross-signaling via non-corresponding receptors indicates bypassed signaling in colorectal cancer

Abstract

// Romana Moench 1 , 2 , Martin Gasser 3 , Karol Nawalaniec 1 , Tanja Grimmig 2 , Amrendra K. Ajay 1 , Larissa Camila Ribeiro de Souza 1 , Minghua Cao 1 , Yueming Luo 1 , 4 , Petra Hoegger 5 , Carmen M. Ribas 6 , Jurandir M. Ribas-Filho 6 , Osvaldo Malafaia 6 , Reinhard Lissner 2 , Li-Li Hsiao 1 , * and Ana Maria Waaga-Gasser 1 , 2 , * 1 Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA 2 Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Wuerzburg 97080, Bavaria, Germany 3 Department of Surgery I, University of Wuerzburg, Wuerzburg 97080, Bavaria, Germany 4 Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China 5 Institute for Pharmacy and Food Chemistry, University of Wuerzburg, Wuerzburg 97074, Bavaria, Germany 6 Mackenzie Evangelical Faculty of Paraná, Curitiba 80730-000, Parana, Brazil * Co-senior investigators Correspondence to: Ana Maria Waaga-Gasser, email: [email protected] Keywords: PDGF; VEGFR; EGFR; bypassed signaling; colorectal cancer Received: August 15, 2022     Accepted: September 27, 2022     Published: October 19, 2022 Copyright: © 2022 Moench et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Platelet-derived growth factor (PDGF) signaling, besides other growth factor-mediated signaling pathways like vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), seems to play a crucial role in tumor development and progression. We have recently provided evidence for upregulation of PDGF expression in UICC stage I–IV primary colorectal cancer (CRC) and demonstrated PDGF-mediated induction of PI3K/Akt/mTOR signaling in CRC cell lines. The present study sought to follow up on our previous findings and explore the alternative receptor cross-binding potential of PDGF in CRC. Our analysis of primary human colon tumor samples demonstrated upregulation of the PDGFRβ, VEGFR1, and VEGFR2 genes in UICC stage I-III tumors. Immunohistological analysis revealed co-expression of PDGF and its putative cross-binding partners, VEGFR2 and EGFR. We then analyzed several CRC cell lines for PDGFRα, PDGFRβ, VEGFR1, and VEGFR2 protein expression and found these receptors to be variably expressed amongst the investigated cell lines. Interestingly, whereas Caco-2 and SW480 cells showed expression of all analyzed receptors, HT29 cells expressed only VEGFR1 and VEGFR2. However, stimulation of HT29 cells with PDGF resulted in upregulation of VEGFR1 and VEGFR2 expression despite the absence of PDGFR expression and mimicked the effect of VEGF stimulation. Moreover, PDGF recovered HT29 cell proliferation under simultaneous treatment with a VEGFR or EGFR inhibitor. Our results provide some of the first evidence for PDGF cross-signaling through alternative receptors in colorectal cancer and support anti-PDGF therapy as a combination strategy alongside VEGF and EGF targeting even in tumors lacking PDGFR expression.

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