HtrA3 stromal expression is correlated with tumor budding in stage II colorectal cancer

Tumor budding is a well-established adverse prognostic factor in colorectal carcinoma (CRC). It may represent a form of epithelial-to-mesenchymal transition (EMT), although the underlying mechanisms remain unclear. High-temperature requirement A3 (HtrA3) is an inhibitor of the bone morphogenetic protein pathway, the suppression of which has been linked to EMT. Since HtrA3 is highly expressed in the desmoplastic stroma at the CRC invasive front, we sought to evaluate the relationship between tumor budding and HtrA3 expression in 172 stage II CRC resection specimens. All tumors were evaluated for tumor budding, with the highest budding slide selected for pan-keratin (CK) and HtrA3 immunohistochemistry. Representative areas of tumor core and invasive front, including budding and non-budding areas, were marked on CK stained slides, and then evaluated on HtrA3 stained slides. HtrA3 expression in tumor cells (tHtrA3) and peritumoral stroma (sHtrA3) was assessed for staining percentage and intensity (the product yielding a final score). Tumors with high-grade tumor budding (HGTB) showed increased expression of sHtrA3 in budding areas compared to non-budding areas at the invasive front (P < 0.001). In addition, sHtrA3 expression at the invasive front was significantly higher in HGTB tumors compared to minimally budding tumors (P < 0.05). tHtrA3 expression at the invasive front was significantly associated with high histological grade (P < 0.05). Higher sHtrA3 expression in the tumor core (but not invasive front) was significantly associated with decreased 5-year overall survival on univariate analysis (P < 0.05), but not multivariate analysis. HtrA3 expression in the peritumoral stroma of patients with stage II CRC is associated with HGTB and may be a novel marker of poor outcome.