Reduced E-Cadherin and Aberrant β-Catenin Expression are Associated With Advanced Disease in Signet-Ring Cell Carcinomas

Abstract

Signet-ring cell carcinomas (SRCCs) tend to present at higher stages and thus are generally associated with a worse prognosis. It has been postulated that a deficiency of E-cadherin may be causal in the pathogenesis of SRCC in animal models. In this study, we systemically analyzed the expression of E-cadherin and β-catenin, a key component of the cadherin complex, in 137 consecutive SRCCs of various organ systems to explore the significance of these molecules in the pathogenesis and progression of SRCCs. Seventy-six percent of SRCCs showed loss or reduced E-cadherin expression. Aberrant β-catenin expression, defined as loss of membranous expression and nuclear/cytoplasmic subcellular localization, was observed in 60% of these cases, with the altered β-catenin expression observed most commonly in the breast (93%) and least in the lung (38%) primaries. Further, the aberrant β-catenin was significantly associated with pathologic nodal stage (P=0.002) and clinical stage (P=0.02). Our findings demonstrated that reduced membranous E-cadherin and aberrant β-catenin expression were frequent events in SRCCs of various organs, and that the altered β-catenin expression was significantly associated with advanced disease. The observations further support the importance of these molecules in the pathogenesis of SRCCs, and indicate the fundamental role of the Wnt/β-catenin signaling pathway in the progression of these tumors. Further investigations of the downstream molecules in this cascade may provide potential novel therapeutic targets for this aggressive tumor type.

Reacquisition of E-cadherin expression in metastatic deposits of signet-ring cell carcinoma of the upper gastrointestinal system: a potential anchor for metastatic deposition

“…This phenomenon was exclusively seen in the signet ring cells but not non-signet ring cells, thus recapitulating our previous observations (table 1 and figure 1A–F) 15. Interestingly, this reduction was less frequently seen in the signet ring cells of the metastatic deposits when compared with their primary counterparts, and was only found in cells of 21 tumours (57%) in the lymph node metastasis or at distant sites of relapse (table 1 and figure 1G–L) (OR 0.36; χ 2 =3.95, 95% CI 0.13 to 1.0; p=0.047).…”

“…We previously found that loss of E-cadherin was a frequent event in SRCC of various organs, and this reduction was more prominent in signet ring cells than that in non-signet ring cells of the same tumours 15. In this study, we extended these observations and found that overall E-cadherin expression was significantly higher in the metastatic deposits of SRCC than in the primary sites, thus supporting the potential role of E-cadherin in the process of MET as speculated previously.…”

“…Immunohistochemistry was performed on the formalin-fixed, paraffin-embedded tissue as previously described 15. In brief, 5 μm sections were obtained from formalin-fixed, paraffin-embedded block preparations.…”

“…We previously demonstrated that reduced E-cadherin expression was a frequent event in SRCC of various organ systems, and that its expression levels were inversely associated with lymph node metastasis and clinical stage 15. In this study, the expression of E-cadherin was examined in paired primary tumours and metastatic deposits of SRCC to further explore the potential role of the molecule in metastatic spread of this unique tumour type.…”

Differentiating breast carcinoma with signet ring features from gastrointestinal signet ring carcinoma: assessment of immunohistochemical markers

“…Signet-ring cells are thought to derive from cellular alterations including abrogation of cell-to-cell adhesion, enhancement of mucin production, and disruption of mucin secretion. These mechanisms are thought to contribute to signet-ring morphology in carcinomas regardless of primary site [12, 13, 14]. While their morphology may be similar from organ-to-organ, they typically retain expression of markers from their site of origin [15].…”