Neoadjuvant chemoradiation changes podoplanin expression in esophageal cancer patients

Abstract

BACKGROUND Locally advanced adenocarcinoma of the esophagus (EAC) and squamous cell carcinoma (ESCC) result in a worse prognosis. Neoadjuvant treatment improves survival, however, only for responders. The transmembrane glycoprotein podoplanin is overexpressed in squamous cell carcinomas, miRNA-363 is associated to its regulation in head and neck cancer. AIM To predict therapy response and prognosis markers, and targets for novel therapies would individualize treatments leading to more favourable outcomes. METHODS Expression of podoplanin protein has been visualized by immunohistochemistry in surgical specimens of 195 esophageal cancer patients who underwent transthoracic esophagectomy: 90 ESCC and 105 EAC with clinical T2-3, Nx, M0. One hundred and six patients received neoadjuvant chemoradiation. RNA was extracted from paraffin-embedded tissue, and miRNA-363 quantified by real-time TaqMan-real-time-PCR. D2-40 mab staining of > 5% was scored as high podoplanin expression (HPE). We related podoplanin and miRNA-363 expression to histopathologic response after neoadjuvant treatment and clinicopathological characteristics, such as histological tumor type, survival rate or clinical tumor category. RESULTS We confirmed expression of membrane-bound podoplanin in 90 ESCC patients. 26% showed HPE of > 5%. In addition, absence in EAC patients (only 2% with HPE) was shown. Lower podoplanin expression has been detected in resection-specimen of 58 ESCC patients after neoadjuvant (RTx/CTx) treatment, only 11% with HPE, compared to 50% HPE of 32 non-pretreated primary surgery patients, P = 0.0001. This difference of podoplanin expression was confirmed comparing pre-treatment biopsies with matching post-treatment surgical specimens, P < 0.001. Podoplanin has been identified as a prognostic marker in 32 patients that underwent primary surgery without neoadjuvant treatment. Low (0-5%) podoplanin expression was associated with better prognosis compared to patients with HPE, P = 0.013. Podoplanin expression has been associated with post-transcriptional regulation by miRNA-363. At a cut-off value of miR-363 < 7, lower miR-363 expression correlated with HPE in surgical tissue specimens of primary surgery patients, P = 0.013. Therefore, ESCC patients with miRNA-363 expression < 7 had a worse prognosis than patients expressing miRNA-363 ≥ 7, P = 0.049. CONCLUSION Analysis of the molecular process that leads to decrease in podoplanin expression during neoadjuvant treatment and its regulation may provide novel markers and targets to improve targeted therapy of ESCC.