C-reactive protein inhibits lymphangiogenesis and resultant lymph node metastasis of squamous cell carcinoma in mice

Background: Lymph node involvement is the most important prognostic factor in many solid cancers. Recently, we found that patients with esophageal and lung cancer carrying the C-reactive protein (CRP) 1846T/T genotype, which is associated with lower serum CRP levels, are more likely to have lymph node metastasis. We hypothesized that host CRP directly inhibits lymph node metastasis.

Methods: We inoculated NR-S1M metastatic cells subcutaneously into the backs of C3H/HeN mice. Concurrently, 1 μg of recombinant mouse CRP or phosphate-buffered saline was injected subcutaneously every 3 days for 5 weeks, after which the mice were killed for evaluation. We evaluated lymph node metastasis and lymphangiogenesis in the implanted tumor by using immunohistochemical analysis with anti-pancytokeratin and antilymphatic vessel endothelial hyaluronan receptor-1 antibodies.

Results: There was no substantial difference in tumor size between the 2 groups but the lymph nodes were smaller in the CRP group than the control group (P < .044). Immunohistochemical analysis confirmed inguinal lymph node metastasis in 70% (14/20) of control mice, but in only 30% (3/10) of mice in the CRP group. Moreover, the metastatic area within lymph nodes was less in the CRP group (P < .042) and tumoral lymphangiogenesis was decreased in the CRP group (P < .037).

Conclusion: CRP appears to inhibit tumoral lymphangiogenesis and lymph node metastasis in mice. These findings suggest that by inhibiting lymph node metastasis, CPR may have therapeutic potential for use against cancer.