ANXA11 recruits tumor-associated neutrophils to promote the progression of colorectal cancer.

BACKGROUND

Tumor-associated neutrophils (TANs) play a crucial role in the tumor microenvironment of colorectal cancer (CRC). Although Annexin A11 (ANXA11) is highly expressed in CRC tissues, its prognostic value and its mechanism in mediating tumor-neutrophil crosstalk to drive CRC progression require further investigation.

METHODS

The expression and prognostic value of ANXA11 were analyzed using bioinformatics databases, clinical CRC cohorts, and multiplex immunohistochemistry (mIHC). In vitro functional assays and in vivo subcutaneous xenograft mouse models were employed to evaluate its impact on tumor progression. Neutrophil recruitment and activation were assessed using in vivo orthotopic mouse models and in vitro co-culture systems comprising CRC cells and differentiated neutrophil-like cells (dHL-60). Potential molecular pathways and effector molecules were investigated through RT-qPCR, Western blotting, ELISA, and immunohistochemistry, combined with specific inhibitors and neutralizing antibodies.

RESULTS

ANXA11 was significantly upregulated in CRC and served as an independent prognostic factor associated with poor patient survival. Functionally, ANXA11 promoted CRC cell proliferation, migration, invasion, and in vivo tumor growth. Notably, ANXA11 expression positively correlated with the abundance of infiltrating tumor-associated neutrophils in both clinical specimens and orthotopic mouse models. Mechanistically, ANXA11 activated the NF-κB signaling pathway in CRC cells to upregulate CXCL5 expression, which was effectively blocked by the NF-κB inhibitor BAY11-7082. Tumor-derived CXCL5 recruited neutrophils via the CXCR2 receptor and stimulated their secretion of matrix metalloproteinase-9 (MMP9). Subsequently, neutrophil-derived MMP9 triggered a malignant positive feedback loop by promoting epithelial-mesenchymal transition (EMT) and exacerbating tumor invasiveness. In vivo, blockade of this signaling axis using the CXCR2 antagonist SB225002 effectively reduced neutrophil infiltration, restored E-cadherin expression, and significantly inhibited ANXA11-driven tumor growth.

CONCLUSIONS

ANXA11 establishes a pro-tumorigenic positive feedback loop in the CRC microenvironment by regulating the NF-κB/CXCL5/CXCR2 signaling axis. Targeting the ANXA11/CXCR2 axis represents a potential therapeutic strategy for CRC intervention.