Dados do Trabalho

Título

Growth factor signaling drives colon cancer growth – what comes after VEGF/EGFR inhibition?

Introdução

In the last two decades anti-Epithelial Growth Factor Receptor and Vascular Endothelial Growth Factor (EGFR/VEGF) antibodies became integrated in multimodal therapies for patients with advanced stage colorectal cancer (CRC). Despite overall impressive clinical data not all patients respond to these therapies with tumor regression, suggestive to be related to different tumor biology. This demands a further analysis of underlying growth factor and angiogenetic signaling pathways. Recent studies pointed to alternative receptor/ligand signaling beside VEGF/EGFR which may explain failure of single growth factor monoclonal antibody (mAb) therapy. Platelet-derived Growth Factor (PDGF) and particularly its isoform PDGF-BB have been shown recently to be ligands mediating angiogenesis which implies that constitutive paracrine and/or autocrine PDGF activation in colon cancer cells boosts tumor growth.

Objetivo

To analyze Platelet derived Growth Factor (PDGF) signaling in colon cancer.

Método

UICC stage I-IV tumors from a cohort of patients (n=46) and additionally HT29 cells were studied for their PDGF/PDGFR, VEGF/VEGFR and EGFR expression.

Resultados

Investigated UICC stage I-IV tumors (n=46) demonstrated increased PDGFRβ and VEGFR1/2 gene expression (p<0.01/p<0.001). Further in vitro studies using human HT29 colon cancer cells showed upregulated VEGFR1/2 expression upon VEGF stimulation that was exceeded by PDGF in comparison. Inhibition of VEGFR2 and EGFR resulted in decreased cancer cell proliferation, while additional treatment with VEGF and particularly PDGF attenuated the inhibiting effect and resulted in altered downstream signaling events. Treatment solely with the tyrosine kinase inhibitor Regorafenib, that inhibits VEGFR/EGFR+PDGFR signaling, but not anti-VEGFR2 mAb treatment with Ramucirumab nor anti-EGFR mAb therapy with Cetuximab alone prevented PDGF and VEGF-induced proliferation

Conclusão

To conclude, PDGF-induced human colon cancer cell proliferation in the absence of its receptor and concurrently inhibited VEGFR2 and EGFR expression in HT29 colon cancer cells strongly suggest bypassed alternative PDGF receptors for receptor-ligand binding on the tumor cell surface and subsequent intracellular growth signaling. This may explain failure of anti-VEGF/EGFR-targeted monoclonal antibody therapies alone in individual colorectal cancer patients and underlines the urgent need for additional and effective PDGF-mediated signaling inhibition as additional or second-line immune therapy in such patients.