Elevated CXCL12 in the plasma membrane of locally advanced rectal cancer after neoadjuvant chemoradiotherapy: a potential prognostic marker

Background: Neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC) has been shown to improve sphincter preservation and local pelvic control, but the efficacy of nCRT plateaus due to metastasis. CXC chemokine ligand 12 (CXCL12) has a critical impact on cancer development and metastasis. Methods: By investigating public databases containing LARC patient data, CXCL12, CXCR4 and FAPα expression was analyzed via the Tumor Immune Estimation Resource (TIMER) and GSEA. Immunohistochemistry was applied to a total of 121 surgically resected specimens consisting of 61 LARCs after nCRT and 60 LARCs with no nCRT and 16 cases with endoscopic resection of high-grade colorectal adenoma. Results: By investigating public databases containing LARC patient data, CXCL12 expression is correlated with poor prognosis, immune cell infiltration, epithelial- mesenchymal transition, and angiogenesis in LARC. Furthermore, radiation selectively induced CXCL12, CXCR4 and FAPα expression in tumor tissues. Immunohistochemistry results showed that the levels of CXCL12, CXCR4, and FAPα in LARC cells after nCRT were higher than in LARC cells untreated with nCRT (p < 0.001 for each). Elevated levels of CXCL12 in the plasma membrane of LARC cells after nCRT demonstrated an association with the period of freedom from recurrence (FFR) in univariate and multivariate survival analyses (p = 0.005 and p = 0.031, respectively). Conclusions: The expression of CXCL12 may influence the survival and invasive properties of LARC cells during nCRT and promote cancer recurrence. We suggest that CXCL12 expression in the plasma membrane of radioresistant LARC cells may be a predictive factor of recurrence and a viable therapeutic strategy to control radioresistant LARC recurrence.