title: Tumor stromal architecture can define the intrinsic tumor response to VEGF-targeted therapy.
abstract: OBJECTIVE
  The aim of the study was to investigate the vascular and stromal architecture of preclinical tumor models and patient tumor specimens from malignancies with known clinical outcomes to VEGFi treatment, to gain insight into potential determinants of intrinsic sensitivity and resistance.
  
  
  METHODS
  The tumor stroma architecture of preclinical and clinical tumor samples were analyzed by staining for CD31 and α-smooth muscle actin (α-SMA). Tumor models representative of each phenotype were then tested for sensitivity to the VEGFR2-blocking antibody DC101.
  
  
  RESULTS
  Human tumor types with high response rates to VEGF inhibitors (e.g., renal cell carcinoma) have vessels distributed amongst the tumor cells (a "tumor vessel" phenotype, TV). In contrast, those malignancies where single-agent responses are lower, such as non-small cell lung cancer (NSCLC), display a complex morphology involving the encapsulation of tumor cells within stroma that also supports the majority of vessels (a "stromal vessel" phenotype). Only 1 of 31 tumor xenograft models displayed the stromal vessel phenotype. Tumor vessel models were sensitive to VEGFR2-blocking antibody DC101, whereas the stromal vessel models were exclusively refractory. The tumor vessel phenotype was also associated with a better Response Evaluation Criteria in Solid Tumors (RECIST) response to bevacizumab + chemotherapy in metastatic colorectal cancer (CRC).
  
  
  CONCLUSIONS
  The tumor stromal architecture can differentiate between human tumor types that respond to a VEGF signaling inhibitor as single-agent therapy. In addition to reconciling the clinical experience with these agents versus their broad activity in preclinical models, these findings may help to select solid tumor types with intrinsic sensitivity to a VEGFi or other vascular-directed therapies.
authors.affiliation: Authors' Affiliations: Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire; and Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Smith
authors.forename: Dawn
authors.initials: D
authors.lastname: Baker
authors.forename: Matthew
authors.initials: M
authors.lastname: Farren
authors.forename: Aurelien
authors.initials: A
authors.lastname: Pommier
authors.forename: Ruth
authors.initials: R
authors.lastname: Swann
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Sunita
authors.initials: S
authors.lastname: Mistry
authors.forename: Karen
authors.initials: K
authors.lastname: McDaid
authors.forename: Jane
authors.initials: J
authors.lastname: Kendrew
authors.forename: Chris
authors.initials: C
authors.lastname: Womack
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Wedge
authors.forename: Simon T
authors.initials: ST
authors.lastname: Barry
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C511761:DC101 monoclonal antibody; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2