PLXDC1

PLXDC1 (TEM7) is a single-pass transmembrane cell-surface receptor that functions in tumor and angiogenic endothelium to promote angiogenesis and tumor progression (PMID:25535841, PMID:29890852). Together with PLXDC2, it serves as a receptor for the secreted factor PEDF: the receptors form homooligomers under basal conditions that PEDF binding dissociates to activate downstream signaling, and mutations in the intracellular domain alter receptor activity (PMID:25535841). Its extracellular region binds cortactin through a discrete nine-amino-acid segment in the cortactin plexin-like domain (PMID:15574754). PLXDC1 is selectively displayed on the luminal surface of tumor and pathological vascular endothelium and on endothelial progenitor cells, being absent from normal mature endothelium (PMID:15574754, PMID:21958527, PMID:18316703); this restricted expression is exploited by anti-TEM7 antibodies that drive antibody-dependent cellular cytotoxicity and phagocytosis of TEM7-positive cells (PMID:21958527). Expression is driven transcriptionally by direct promoter binding of the gain-of-function transcription factor TGLI1, with PLXDC1 acting as a required downstream effector of TGLI1-induced endothelial tubule formation (PMID:26093087). Functionally, PLXDC1 is required for tumor angiogenesis and growth—its silencing reduces tumor growth, proliferation, and microvessel density while increasing apoptosis (PMID:29890852)—and it is induced by anti-VEGF (bevacizumab) therapy via epithelial-to-mesenchymal transition to drive perivascular brain tumor infiltration, with PLXDC1 inhibition preventing infiltration and prolonging survival (PMID:30414187).

1. 2004 Medium

   Established the first molecular interaction partner of PLXDC1, linking its extracellular domain to the actin-regulatory adaptor cortactin and confirming tumor-endothelial expression.

   Evidence Affinity purification, domain mapping, and antibody-based cell-surface detection in tumor endothelium

   PMID:15574754

   Open questions at the time

   • Functional consequence of the cortactin interaction not established
   • No reciprocal validation or signaling readout
   • Mechanism connecting extracellular receptor to intracellular cortactin unresolved
2. 2008 Medium

   Localized PLXDC1 protein to the luminal endothelial surface in pathological neovasculature, defining where the receptor acts in disease.

   Evidence Immunoelectron microscopy, immunohistochemistry, in situ hybridization, and RT-PCR in proliferative diabetic retinopathy membranes

   PMID:18316703

   Open questions at the time

   • Descriptive localization without functional perturbation
   • Does not establish signaling role at this site
3. 2011 Medium

   Demonstrated PLXDC1 is restricted to tumor/progenitor endothelium and absent from normal vasculature, validating it as a targetable tumor-vascular marker.

   Evidence Flow cytometry, RT-PCR, PMA induction in endothelial precursors, and ADCC/phagocytosis assays with anti-TEM7 antibody

   PMID:21958527

   Open questions at the time

   • Mechanism of expression induction by PMA not defined
   • Antibody efficacy not tested in vivo here
4. 2014 High

   Defined PLXDC1 as a ligand-activated PEDF receptor with a homooligomer-dissociation activation mechanism and an intracellular signaling domain, answering how the receptor transduces a signal.

   Evidence Reciprocal gain- and loss-of-function cellular assays, receptor binding, and intracellular-domain mutagenesis

   PMID:25535841

   Open questions at the time

   • Downstream signaling effectors not identified
   • Structural basis of homooligomer dissociation unresolved
   • Cell-type-specific receptor activities not mechanistically explained
5. 2015 Medium

   Placed PLXDC1 within a transcriptional axis as a direct TGLI1 target required for tumor-induced angiogenesis, connecting upstream regulation to functional output.

   Evidence Promoter binding assay, expression profiling, siRNA knockdown, and endothelial tubule formation assay in glioblastoma models

   PMID:26093087

   Open questions at the time

   • Direct promoter occupancy by ChIP only implied
   • Does not connect TGLI1-driven expression to PEDF receptor signaling
6. 2018 Medium

   Demonstrated PLXDC1 is functionally required for tumor angiogenesis and growth in vivo, moving beyond correlation to causal requirement.

   Evidence In vivo siRNA silencing via CD44-targeted nanoparticles in ovarian tumor xenografts with tumor growth, microvessel, and apoptosis readouts

   PMID:29890852

   Open questions at the time

   • Single tumor model
   • Molecular mechanism downstream of knockdown not dissected
7. 2018 Medium

   Linked PLXDC1 to therapy resistance, showing anti-VEGF treatment induces PLXDC1 via EMT to drive perivascular tumor infiltration and that inhibition improves survival.

   Evidence In vivo xenograft models with lentiviral overexpression, PLXDC1 inhibition, and survival analysis in bevacizumab-treated rats

   PMID:30414187

   Open questions at the time

   • Mechanism coupling PLXDC1 to invasive phenotype not defined
   • EMT-to-PLXDC1 regulatory link not molecularly mapped

• The intracellular signaling cascade triggered by PEDF-induced PLXDC1 activation and how it mechanistically drives angiogenesis and tumor infiltration remain undefined.
• No downstream signaling effectors identified
• Relationship between PEDF receptor signaling and cortactin binding unknown
• No structural model of the receptor or its activation