Metastatic rectal cancer patients could benefit from novel therapeutic approaches. The signaling network
formed by chemokines and their receptors can promote metastasis and resistance to current anticancer treatments.
This study assessed the expression of chemokine receptor 4 (CXCR4) and its ligand CXCL12 immuhistochemically
in stage IV rectal tumors. Paraffin-embedded primary tumor collected before and after local radiotherapy
and systemic treatment with bevacizumab, oxaliplatin and capecitabine was analyzed. Receptor and ligand expression
was assessed in the cytoplasm and nucleus of tumor, stromal and normal rectal crypt cells. Baseline expression
of CXCR4 and CXCL12 was correlated with patients' pathologic response to treatment. At diagnosis
(n=46), 89% of the rectal tumors expressed cytoplasmic CXCR4 and 81% CXCL12. Nuclear CXCR4 expression in tumor cells was present
in 30% and nuclear CXCL12 expression in 35% of the tumors. After radiochemotherapy and administration of bevacizumab, nuclear
CXCL12 expression was observed in 79% of residual tumors, as compared to 31% of the paired tumor samples expressing nuclear
CXCL12 before treatment (P=0.001). There were no differences in CXCR4 or CXCL12 expression at baseline between the patients who
had (n=9) and did not have (n=30) a pathologic complete response. Our results show that CXCR4 and CXCL12 are extensively expressed
in primary rectal tumors of patients presenting with metastatic disease, while radiochemotherapy and bevacizumab further upregulate
CXCL12 expression. These data indicate the importance of the CXCR4/CXCL12 axis in rectal tumor biology, and may suggest the
CXCR4/CXCL12 receptor-ligand pair as a potential therapeutic target in metastatic rectal cancer.
Keywords: Chemokine receptor 4 (CXCR4), chemokine ligand 12 (CXCL12), (metastatic) rectal cancer, radiotherapy, bevacizumab, chemotherapy.
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