Persistent elevation of plasma Neuropilin-1, a tumorigenic protein, during the first month after minimally invasive colorectal cancer resection

Introduction: Neuropilin-1 (NRP1), also known as CD304, is a transmembrane glycoprotein that functions as a co-receptor for VEGF, PLGF, TGF-B1 and other ligands. NRP1 is expressed in various tissues and in endothelial cells (EC), tumor and immune cells. NRP1 upregulation is closely associated with enhanced angiogenesis in tumors and can promote EC proliferation, migration, and neovascularization. NRP-1 also plays a role in the tumor microenvironment by stabilizing regulatory T cells, which suppress the immune response. NRP1 is overexpressed in various tumors including colorectal cancer (CRC) and elevated plasma levels are linked to tumor progression, higher tumor grades, and poor clinical outcomes. NRP-1 also plays a role in the tumor microenvironment by stabilizing regulatory T cells,that suppress the immune ability. NRP1 regulates VEGF-driven wound angiogenesis, with peak vascular growth followed by regression that restores normal capillary density. Surgery's impact on blood levels of NRP1 levels is poorly studied. This study's purpose was to measure plasma NRP1 levels before and during the first month after minimally invasive colorectal resection (MICR) for CRC. Method: This study included CRC patients from an IRB-approved data/plasma bank who underwent MICR for whom sufficient plasma samples were available. Clinical data were reviewed, and blood was collected preoperatively (preop) and at defined postoperative (postop) intervals. Plasma was stored at -80°C and late samples were grouped into 7-day bundles intervals. NRP1 levels were measured in duplicate using ELISA (ng/ml) and reported as mean± SD mean ± SD. The paired t-test was used for statistical analysis (significance p<0.05). Results: Preop and 1 or more late postop plasma sample were available for 92 MICR patients (colon 71%; rectal 29%; 47 male /45 female, mean age 64.3± 14.1years). The mean incision length was 8.3± 3.6 cm and mean length of stay was 6.8 ± 4.2 days. The final cancer stage breakdown was; Stage I, 30%, Stage II, 30%, stage III, 35% and stage IV, 5%. The mean Preop NRP1 level was 296.0± 68.8 ng/m; in comparison, mean postop levels were significantly elevated (p<0.0001) on postop day (POD) 3 (384.3±96.6, n=88), POD7-13 (405.4±111.9, n=73), and POD14-20 (380.4±101.7, n=28) , POD 21-27(346.8±87.9, n=16,p-0.01) and on POD 28-41 (342.8± 84.3, n=18; p<0.001). Conclusion: Following MICR for CRC, plasma NRP1 levels were significantly increased from POD3 through POD 28-41. The rise in NRP1 levels may reflect enhanced shedding from EC and circulating tumor cells, potentially driven by angiogenesis related processes associated with wound repair and regeneration. Surgery-induced inflammatory signaling likely contributes to increased NRP1 expression and release. Elevated levels of NRP1 may promote angiogenesis in residual tumor deposits after surgery. Further investigation is warranted.