C-reactive protein reduces the relative number of tumor-associated M2 macrophages and intratumoral angiogenesis in mice.

Tumor-associated macrophages play a key role in cancer metastasis. On the other hand, C-reactive protein (CRP), a widely used biomarker of inflammation, has been shown to have inhibitory effects on tumor proliferation and metastasis. Here we used an implanted tumor mouse model to assess the effect of CRP on tumor-associated macrophage numbers and on their phenotype, as well as on intratumoral angiogenesis. NR-S1M murine oral squamous cell carcinoma cells were implanted subcutaneously in the backs of anesthetized C3H/HeN mice. Some of the mice were also subcutaneously administered 1 µg of recombinant mouse CRP in 100 µL of phosphate-buffered saline (PBS) (CRP group, n = 10) near the neck every 2 days for 30 days (15 injections in all). Control mice received PBS without CRP. The mice were then sacrificed and the excised tumors were analyzed. Tumor weight and size did not differ between the two groups, but immunohistochemical analysis showed the F4/80(+) macrophage (total macrophages) count to be significantly larger in the CRP group (P = 0.0028), while the relative number of CD206(+) anti-inflammatory M2 macrophages was significantly reduced (P = 0.0091). In addition, expression of colony stimulating factor 1 mRNA, which is associated with the M2 macrophage phenotype, was significantly lower in the CRP group. Intratumoral angiogenesis, indicated by the presence of CD31(+) vessels within the tumor, was reduced in the CRP group (P = 0.0028). These findings suggest that CRP has therapeutic potential against cancer through decreasing the accumulation of M2 macrophages and angiogenesis within tumors.

REG1A expression status suggests chemosensitivity among advanced thoracic esophageal squamous cell carcinoma patients treated with esophagectomy followed by adjuvant chemotherapy.

BACKGROUND: Regenerating gene 1A (REG1A) plays an important role in tissue regeneration and in cell proliferation in the mucous membrane of the gastrointestinal tract. We previously reported that the positive expression status of REG1A was predictive of chemoradiosensitivity in patients treated with preoperative chemoradiotherapy before esophagectomy or with definitive chemoradiotherapy. To further confirm the utility of REG1A as a chemosensitivity marker, we carried out an additional retrospective clinical study aimed at determining whether REG1A is a reliable chemosensitivity marker in patients treated with esophagectomy followed by adjuvant chemotherapy. METHOD: A total of 177 patients with T2-4 thoracic esophageal squamous cell carcinoma received curative surgery without preoperative treatment at Akita University Hospital between 2001 and 2011. A tissue microarray was constructed, and REG1A expression status was analyzed immunohistochemically. We then statistically analyzed the relationships between REG1A expression status and 5-year overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). RESULTS: In the adjuvant group (n=105), REG1A-positive patients showed significantly better prognoses than REG1A-negative patients. (5-year OS, p=.0022; DSS, p=.0004; and DFS, p=.0040). However, there were no significant differences between REG1A-positive and REG1A-negative patients in the surgery group (n=72). Univariate and multivariate analyses showed REG1A expression status to be a significant prognostic factor affecting 5-year DSS, comparable to lymph node metastatic status. CONCLUSION: The present study suggests REG1A expression status has the potential to be a highly reliable and clinically useful chemosensitivity marker in patients treated with advanced thoracic esophageal squamous cell carcinoma. REG1A expression status will provide a good indication of treatment strategy and enable more individualized treatment for patients.