Tumor vessel phenotype in colorectal cancer microenvironment according to age at diagnosis

Abstract Background Given the global issue of the rising incidence of early-onset colorectal cancer (CRC), we tested the hypothesis that tumor vasculature phenotypes might vary with age at CRC diagnosis. Method We used in situ multispectral immunofluorescence combined with digital image analysis and machine learning to measure expression of endothelial cell markers [ACKR1 (DARC), CD34, CD36, KDR (VEGFR2), LAMB1 (laminin β1), MADCAM1] and KRT (keratin) in 843 tumors derived from 4476 CRC cases in U.S.-wide prospective cohorts under the prospective cohort incident-tumor biobank method. Results Overall CD34 + vessel and CD34 + LAMB1 + vessel densities inversely correlated with younger age at CRC diagnosis (both P trend < 0.0001). In the inverse probability-weighted multivariable-adjusted logistic regression analyses, compared to age ≥70, odds ratios (with 95% confidence interval) for high (vs. low) overall vessel density were 0.85 (0.74–0.99) for age 55–69 and 0.63 (0.48–0.81) for age <55, and those for high (vs. low/negative) CD34 + LAMB1 + vessel density were 0.56 (0.47–0.65) for age 55–69 and 0.28 (0.20–0.40) for age <55. Conclusions Hypovascularities of overall and CD34 + LAMB1 + vessels may be microenvironmental characteristics of early-onset CRC if validated by independent studies. Our findings highlight age-related tumor pathobiological differences. Identifying specific biomarkers of early-onset CRC can provide pathogenetic and etiological clues.