Abstract 4157: Heterogeneity of vascular endothelial growth factor receptors 1, 2, and 3 in human non-small cell lung carcinomas
Authors: Holzer Timothy R. , Fulford Angie D. , O'Neill Reising Leslie , Nedderman Drew M. , Benjamin Laura E. , Schade Andrew E. , Nasir Aejaz 
Published: August 2015

The Vascular Endothelial Growth Factor (VEGF) pathway plays a prominent role in the growth and progression of human cancers, including non-small cell lung carcinoma (NSCLC). The key mediators of VEGF signaling are a family of related receptor tyrosine kinases that include VEGFR1, VEGFR2, and VEGFR3. The relative expression levels, activity and cross-talk among these receptors may contribute to clinical response of NSCLC patients to anti-angiogenic therapies. Using a well-annotated tissue microarray (TMA) and robust immunohistochemical (IHC) assays developed, standardized and implemented in our laboratory, we comparatively evaluated expression of the three VEGFRs in archival primary NSCLC tissues (n = 97). VEGFR1 and VEGFR2 were localized both in tumor vessels and cells, while VEGFR3 was only localized in tumor vessels. VEGFR1 immunoreactivity was reported as negative/low, medium, or high, based on intensity and proportion of stained tumor cell by an experienced solid tumor immunopathologist (AN), who was blinded to clinico-pathologic details. VEGFR2 and VEGFR3 positive vessels were counted by manual assessment of each core by the same immunopathologist. For systematic comparative analysis of VEGFR data, IHC expression thresholds were selected based on the 25% and 75% quartiles around the median of the range of counts for VEGFR2 and VEGFR3: 0-2, 3-10 and &gt;10 (VEGFR2+ vascular count) respectively; and 0-1, 2-9 and &gt;9 (VEGFR3+ vascular count) respectively. Based on VEGFR (1,2 and3) expression levels defined above, a set of eight VEGFR staining profiles were identified: Triple VEGFR positive (n = 11, 11.3%), VEGFR1 predominant (22, 22.7%), VEGFR2 predominant (9, 9.3%), VEGFR3 predominant (3, 3.1%), VEGFR1/2 predominant (13, 13.4%), VEGFR1/3 predominant (2, 2.1%), VEGFR2/3 predominant (9, 9.3%), and triple VEGFR negative (28, 28.9%). These new data provide original insights on the tissue distribution, subcellular localization and heterogeneity of expression of VEGFRs in human NSCLC cells and stromal vessels. The proposed human NSCLC sub-classification, based on the observed differential VEGFR 1, 2, 3 expression profiles, has identified various subsets of human NSCLC, especially triple VEGFR +, triple VEGFR -, VEGFR1 predominant and VEGFR 1 / 2 predominant. These profiles are distinct from the VEGF receptor profiles that we reported in a prior study on colorectal carcinomas (Holzer, Nasir et al., AACR 2014), of which VEGFR1/2 predominant subset was 50% and triple VEGFR-negative subset was only 4%. This work suggests distinct patterns of heterogeneity of VEGF receptor profiles in human NSCLC and CRCs. These data also support further evaluation of whether the reported VEGFR profiles correlate with differential sensitivity to therapeutic VEGF/VEGFR pathway inhibition.

Citation Format: Timothy R. Holzer, Angie D. Fulford, Leslie O'Neill Reising, Drew M. Nedderman, Laura E. Benjamin, Andrew E. Schade, Aejaz Nasir. Heterogeneity of vascular endothelial growth factor receptors 1, 2, and 3 in human non-small cell lung carcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4157. doi:10.1158/1538-7445.AM2015-4157