10780432ccr131637-sup-fig3.pdf (260.23 kB)
Supplementary Figure 3 from Tumor Stromal Architecture Can Define the Intrinsic Tumor Response to VEGF-Targeted Therapy
journal contributionposted on 2023-03-31, 17:03 authored by Neil R. Smith, Dawn Baker, Matthew Farren, Aurelien Pommier, Ruth Swann, Xin Wang, Sunita Mistry, Karen McDaid, Jane Kendrew, Chris Womack, Stephen R. Wedge, Simon T. Barry
PDF file - 260K, H+E comparison of typical morphologies of pancreatic neuroendocrine cancer and pancreatic adenocarcinoma and additional biomarker analyses of the two phenotypes.
ARTICLE ABSTRACTPurpose: 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.Experimental Design: 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).Conclusion: 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. Clin Cancer Res; 19(24); 6943–56. ©2013 AACR.
AngiogenesisAngiogenesis inhibitors & stimulatorsAngiogenesis mechanismsComputational MethodsGene expression profilingDrug MechanismsCellular responses to anticancer drugsDrug ResistanceClinical drug resistanceDrug TargetsCell surface receptor drug targetsPreclinical ModelsAnimal models of cancerXenograft modelsTumor MicroenvironmentHost-tumor interactions