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Simple Summary: Netrin-1 (NTN-1) regulates obesity-associated low-grade inflammation, being also involved in the control of cell migration and proliferation. We aim to study whether excess visceral adipose tissue in patients with obesity and colon cancer is associated with increased NTN1 and the expression levels of its main receptors, promoting an inflammatory microenvironment that favours colon cancer development. Increased expression levels of NTN1 and its receptor NEO1 in the visceral adipose tissue from patients with obesity and colon cancer together with elevated DCC and UNC5B mRNA levels in patients with colon cancer were found. Moreover, the treatment of colorectal cancer cells with NTN-1 and with the adipocyte-derived secretome obtained from patients with obesity increased the migration of colorectal cancer cells. These results suggest that NTN-1 plays an important role in obesity-associated colon cancer development. Netrin (NTN)-1, an extracellular matrix protein with a crucial role in inflammation, is dysregulated during obesity (OB) and influences colon cancer (CC) progression. To decipher the mechanisms underlying CC development during obesity, we examined the expression of NTN1 and its receptors in the visceral adipose tissue (VAT) of 74 (25 normal weight (NW)) (16 with CC) and 49 patients with OB (12 with CC). We also evaluated the effect of caloric restriction (CR) on the gene expression levels of Ntn1 and its receptors in the colon from a rat model fed a normal diet. The impact of adipocyte-conditioned media (ACM) from patients with OB and NTN-1 was assessed on the expression levels of neogenin 1(NEO1), deleted in colorectal carcinomas (DCC) and uncoordinated-5 homolog B (UNC5B) in Caco-2 and HT-29 human colorectal cell lines, as well as on Caco-2 cell migration. Increased NTN1 and NEO1 mRNA levels in VAT were due to OB (p < 0.05) and CC (p < 0.001). In addition, an upregulation in the expression levels of DCC and UNC5B in patients with CC (p < 0.01 and p < 0.05, respectively) was observed. Decreased (p < 0.01) Ntn1 levels in the colon from rats submitted to CR were found. In vitro experiments showed that ACM increased DCC (p < 0.05) and NEO1 (p < 0.01) mRNA levels in HT-29 and Caco-2 cell lines, respectively, while UNC5B decreased (p < 0.01) in HT-29. The treatment with NTN-1 increased (p < 0.05) NEO1 mRNA levels in HT-29 cells and DCC (p < 0.05) in both cell lines. Finally, we revealed a potent migratory effect of ACM and NTN-1 on Caco-2 cells. Collectively, these findings point to increased NTN-1 during OB and CC fuelling cancer progression and exerting a strong migratory effect on colon cancer cells. [ABSTRACT FROM AUTHOR]