Stromal CXCR4 and CXCL12 Expression is Associated with Distant Recurrence and Poor Prognosis in Rectal Cancer After Chemoradiotherapy

Abstract

Distant recurrence remains the major cause of mortality in rectal cancer patients with preoperative chemoradiotherapy (CRT). Recently, cancer stroma has been implicated in influencing proliferation, invasion, and metastasis of cancer cells. It has been reported that expression of CXCR4 and its ligand CXCL12 are associated with migration, invasion, and proliferation of colorectal cancer. A total of 53 patients with rectal cancer underwent preoperative CRT. Total RNAs of residual rectal cancer stromal cells after CRT were obtained from formalin-fixed paraffin-embedded (FFPE) specimens using microdissection. The expression levels of CXCR4 and CXCL12 genes were measured using real-time reverse transcription polymerase chain reaction (RT-PCR). Immunohistochemical staining of these markers after CRT was also investigated. Of the 53 patients, 16 (30.1%) and 14 (26.4%) showed detectable CXCR4 and CXCL12 levels, respectively. We found a significant positive correlation between expression levels of CXCR4 and CXCL12. Patients who developed distant recurrence had twofold higher expression levels of both CXCR4 and CXCL12 compared with those without recurrence after CRT (P < 0.01). Elevated expression levels were also associated with poor probability of recurrence-free survival in both genes (P < 0.01). Additionally, positive CXCL12 expression, but not CXCR4, was significantly correlated with poorer overall survival (P < 0.01). CXCR4 and CXCL12 expression determined using immunohistochemistry was observed in not only cancer but also stromal cells. Our results suggest that evaluation of the expression of both genes may be useful for predicting distant recurrence and poor prognosis in rectal cancer patients treated with preoperative CRT followed by surgery.