1. Increased expression of the protein hemopexin in stroma of patients with pancreatic ductal adenocarcinoma may be associated with lymph node metastasis.
Evidence Rating Level: 2 (Good)
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of 7% and patients with lymph node metastases (≥4) have a 25% lower 5-year survival rate than those with no metastases. Proteomics has been increasingly used clinically to identify tumor biomarkers and increasing attention is being paid to the tumor microenvironment, including the stroma.In the first step of this experimental cohort study, proteomic profiling was used to determine if there was a difference in stromal protein expression (tissue ≤2mm away from cancer cells) in PDAC patients with lymph node metastasis (≥4 lymph nodes) (n=141) compared to those without (n=42). Included patients must have had resection of their pancreatic tumor, no neoadjuvant therapy, histologically classified as PDAC, tumor size ≥20 mm that extended beyond the pancreas, and sufficient stroma. Only five patients from each group were chosen for this step. Nine proteins were identified and two were chosen to be studied, hemopexin and ferritin light chain, as they had increased expression in tissues of patients with LN metastasis (as opposed to decreased expression in patients with LN metastasis) and this correlated well with validation by immunohistochemistry. When comparing both proteins to clinicopathological parameters, only hemopexin seemed to have an association and was further discussed.Characteristics of patients chosen for clinicopathological analysis (n=163) include 79% being lymph node positive, mean tumor size 31 mm, mean LN metastasis 2.5 (for all), 89% with R0 resection margins, and median overall survival 23 months. Univariate analysis showed that hemopexin did not relate to age, sex, tumor size, UICC T and M stages and histological grade but did relate to tumor location. The hemopexin-positive group also showed higher UICC N2 staging versus N0+N1 staging (26.3% versus 7.7%, p =0.0399), higher LN ratio of positive to dissected LNs (0.12 vs 0.05, p =0.0252), and increased chance of higher tumor invasion grades for venous and lymphatic invasion as per Classification of Pancreatic Carcinoma by the Japan Pancreas Society (high-grade venous invasion v3 50.1% vs. 23.1%, p=0.0096, high-grade lymphatic invasion ly3 23.4% vs. 3.9%, p=0.0232). Further in vitro studies of the effect on hemopexin on two pancreatic cell lines, MIA PaCa-2 and Panc-1, showed increased cell migration into wound areas and higher wound-repair rates with increasing hemopexin concentration. In addition, there was greater cell migration and increased number of invading cells with the presence of hemopexin. As PDAC is known to have abundant stroma, hemopexin may become a useful oncologic biomarker for predicting increased risk of lymph node metastases in these patients.
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