PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling

Abstract

Cancer cell proliferation and insufficient blood supply can lead to the development of hypoxic areas in the tumor tissue. The adaptation to the hypoxic environment is mediated by a transcriptional complex called hypoxia-inducible factor (HIF). HIF protein levels are tightly controlled by oxygen-dependent prolyl hydroxylase domain proteins (PHDs). However, the precise roles of these enzymes in tumor progression and their downstream signaling pathways are not fully characterized. Here, we study PHD3 function in murine experimental osteosarcoma. Unexpectedly, PHD3 silencing in LM8 cells affects neither HIF-1α protein levels, nor the expression of various HIF-1 target genes. Subcutaneous injection of PHD3-silenced tumor cells accelerated tumor progression and was accompanied by dramatic phenotypic changes in the tumor vasculature. Blood vessels in advanced PHD3-silenced tumors were enlarged whereas their density was greatly reduced. Examination of the molecular pathways underlying these alterations revealed that platelet-derived growth factor (PDGF)-C signaling is activated in the vasculature of PHD3-deficient tumors. Silencing of PDGF-C depleted tumor growth, increased vessel density and reduced vessel size. Our data show that PHD3 controls tumor growth and vessel architecture in LM8 osteosarcoma by regulating the PDGF-C pathway, and support the hypothesis that different members of the PHD family exert unique functions in tumors.

Current research progress in targeted anti‐angiogenesis therapy for osteosarcoma

“…Possible targets for anti‐angiogenesis therapies include transcription factors or signal pathways that directly or indirectly affect VEGF, PDGF, fibroblast growth factor (FGF), hepatocyte growth factor, integrin, cyclooxygenase (COX‐2), metalloproteinases (MMP‐2, MMP‐9) and HIF‐1. 19 , 20 , 21 VEGF and its receptors (VEGFRs) are key mediators of angiogenesis in cancer.…”

Comprehensive analysis of potential cellular communication networks in advanced osteosarcoma using single-cell RNA sequencing data

“…The details of all signaling pathway networks identified were also shown in Figures 6A-C (A: numbers of ligand receptors among all cell types; B: weights of ligand receptors among all cell types; C: chordal graph of ligand-receptor interactions among all cell types). Among the total of 57 signaling pathways, the following signaling pathways were related to osteosarcoma: COLLAGEN ( Baumann and Hennet, 2016 ; Elenjord et al, 2009 ; Levinson et al, 2002 ; Yamaguchi et al, 2005 ), CD99 ( Manara et al, 2006 ; Sciandra et al, 2014 ; Zucchini et al, 2014 ), PTN ( He et al, 2019 ; Qin et al, 2022 ; Sun et al, 2020 ), MIF( Liu et al, 2014 ), SPP1( Dalla-Torre et al, 2006 ; Li et al, 2017 ), FN1( Saba et al, 2019 ; Zhou et al, 2019 ), LAMININ( Heino and Massague, 1989 ), FGF ( Kurogi et al, 1996 ; Laulederkind et al, 2000 ; Li et al, 2019 ; Xu et al, 2010 ), VEGF ( Ji et al, 2020 ; Lei et al, 2018 ; Oda et al, 2006 ; Tsai et al, 2017 ; Zhang et al, 2019 ), GALECTIN( Gomez-Brouchet et al, 2010 ; Miao et al, 2014 ; Park et al, 2015 ; Zhou et al, 2014 ), PERIOSTIN( Ma et al, 2020 ; Xu et al, 2022 ), VISFATIN( Cheng et al, 2015 ; Wang et al, 2019 , 2016 ), ITGB2 ( Dai et al, 2018 ), NOTCH( Jin et al, 2017 ; Mu et al, 2013 ; Ongaro et al, 2016 ; Tanaka et al, 2009 ; Zhang et al, 2010 ), IGF ( Armakolas et al, 2016 ; Giatagana et al, 2022 ; Gvozdenovic et al, 2017 ; Molina et al, 2019 ; Tan et al, 2015 ), VWF( Wang et al, 2020 ), and PDGF ( Chen et al, 2009 ; Egners et al, 2018 ; Heldin et al, 1986 ). The ligand-receptor interact...…”

Hif-Prolyl Hydroxylase Domain Proteins (Phds) in Cancer – Potential Targets for Anti-Tumor Therapy?

“…In gastric cancer, cell migration and invasion were significantly higher in PHD3-silenced tumor cells than controls, and both HIF1 and VEGF showed greater expression [141]. In mouse LM8 osteosarcoma, we showed that PHD3 is a tumor suppressor as silencing of this oxygen sensor led to enhanced tumor growth and dramatically changed vessel morphology that was directly related to significantly activated platelet-derived growth factor (PDGF)-C signaling in the vasculature of PHD3 knockdown tumors [142]. Thus, the impact of the PHDs in tumor progression is diverse and cell-dependent, i.e., tumor cell vs. TME.…”