Table 1.

Predictors of limitations to antiangiogenic therapies and avenues for intervention

Limitation to therapyBiomarkerTumor compartment contributionMethod of detectionInterventional therapyReferences
Alternative proangiogenic factorsMSCStromaIHC/flow cytometry: CXCR4+Inhibition of VEGFR1+(47, 97, 100)
TAMStromaIHC/flow cytometry: M2 phenotypeInterfere with recruitment by anti-PlGF(47, 97, 100)
TEMStromaIHC/flow cytometry: Tie2+Neutralization of ANG2(101)
GR1+/CD11b+StromaIHC/flow cytometry: GR1+/CD11b+Interfere with recruitment by anti-Bv8(102)
FGF/PlGF/IL-8Tumor cells/stromaPlasma/urine detection by ELISAInhibition of FGF/FGFR, PlGF, etc.(36, 51, 95)
CSCTumor cellsFlow cytometry for specific markers (CD133, CD24, CD44, CD38, and CXCR4)Neutralization of CSCs by inhibition of specific targets (Notch, CXCR4, AKT-β-catenin pathway, etc.); ATRA(61–63)
Independence from VEGF/VEGFRVEGF/VEGFR2 (low levels)StromaPlasma/urine detection by ELISAInhibit alternative proangiogenic factors (new targets)(76, 103)
SNP in VEGFR1 locusStromaGenotype in bloodInhibition of VEGFR1(72, 104)
NeuropilinStromaNRP1 expressionInhibition of VEGF binding to NRP1(97, 105)
Vascular cooptionTumor cellsIHC: vWF-CD31(48)
Vascular mimicryTumor cellsIHC: vWF-CD31(48)
Maintained vessel protectionCAFStromaIHC: α-SMA; S100A4Neutralization of PDGF-C(46, 47, 97, 100)
CEC/CEPStromaFlow cytometry in bloodSimultaneous inhibition of VEGFR1 and VEGFR2(106, 107)
Pericyte coverageStromaIHC: NG2; α-SMATKI (inhibition of PDGFR)(8, 10, 90)
Expression of HIF downstream pathways (PDGF, PlGF, etc.)Tumor cells/stromaHIF expression/expression of HIF-target genes (PDGF, PlGF, etc.)Inhibition of HIF-1; specific inhibition of HIF downstream genes(47, 54, 72, 108)
Modification of EC featuresProangiogenic miRNAStromamiRNA expression in ECRegulation of miRNA expression(109)
Access and distribution of the drugHypoxia blood flow/permeability/IFPStromaTumor oxygen tension MRI/CT imaging/intratumoral needlePromote vascular normalization (inhibition of PHD2, administration of Sema3A, etc.) and new schedules.(20, 21, 47, 54, 65, 72, 79–81, 108, 110)
Resistance to glucose starvationGlycolytic phenotypeTumor cellsFDG uptake by PET imagingInhibition of AMPK(111–113)
Expression of HIF target genes (GLUT1, LDHA, etc.)Tumor cellsExpression of HIF target genes (GLUT1, LDHA, etc.); mutational profile (pVHL status)Inhibition of HIF-1; specific inhibition of HIF downstream genes(47, 54, 72, 86, 108)
AutophagyTumor cellsAutophagy markers (LC3, ATG16L, BNIP3, BNIP3L, and p62)Chemical inhibitors of autophagy; neutralization of p62(114, 115)
Resistant residual cellsEGFR/c-KIT, etc.Tumor cellsExpression of specific receptorSpecific inhibition of the receptor(96, 116)
CSCTumor cellsFlow cytometry for specific markers (CD133, CD24, CD44, CD38, and CXCR4)Neutralization of CSCs by inhibition of specific targets (Notch, CXCR4, AKT-β-catenin pathway, etc.); ATRA(61–63)
Metastatic potentialCEC/CEPStromaFlow cytometry in bloodSimultaneous inhibition of VEGFR1 and VEGFR2(106, 107)
CTCTumor cellsBlood CellSearch TechnologyTarget molecules specifically expressed by CTCs(117–119)
CSCTumor cellsFlow cytometry for specific markers (CD133, CD24, CD44, CD38, and CXCR4)Neutralization of CSCs by inhibition of specific targets (Notch, CXCR4, AKT-β-catenin pathway, etc.); ATRA(61–63)
c-MET/EGFRTumor cellsExpression of specific receptorSpecific inhibition of the receptor(72, 73)
Expression of HIF downstream pathways (CXCR4, SDF-1, MMP, etc.)Tumor cells/stromaExpression of HIF target genes (CXCR4, MMP, etc.); mutational profile (mTOR status)Inhibition of PHD2/HIF-1; specific inhibition of HIF downstream genes; inhibition of mTOR(47, 54, 72, 79, 108, 120)

NOTE: Basic mechanisms behind the limitations to antiangiogenic therapies with their predictive biomarkers and related methods of detection, together with opportunities for interventional therapy to overcome them.

Abbreviations: AMPK, AMP-activated protein kinase; ANG2, angiopoietin-2; ATRA, all-trans retinoic acid; CEC, circulating endothelial cell; CEP, circulating endothelial progenitor cell; CTC, circulating tumor cell; CT, computed tomographic scan; EC, endothelial cell; FDG, 2[18F]fluoro-2-deoxy-d-glucose; GLUT1, glucose transporter-1; IHC, immunohistochemistry; LDHA, lactate dehydrogenase A; miRNA, microRNA; MMP, matrix metalloproteinase; MSC, mesenchymal stem cell; NRP1, neuropilin-1; PlGF, placental growth factor; pVHL, VHL protein; SDF-1, stromal cell–derived factor-1; SNP, single-nucleotide polymorphism; TEM, Tie2-expressing monocyte; vWF, von Willebrand factor.