Glottic carcinomas present with a favorable prognosis comparing to supraglottic. This fact is mainly attributed to differences in anatomical, histological and embryological aspects. It is possible that differential molecular anatomy between the two distinct anatomical entities contributes to this clinical observation as well. The current study intended to evaluate, by immunohistochemistry in paraffin-embedded tissue samples from 97 invasive squamous laryngeal carcinomas, the possible differential expression of crucial molecules for malignant cell's function such as integrin-linked kinase, phosphorylated Akt, E-cadherin, beta-catenin, androgen receptor, estrogen receptor-beta and vimentin between glottic and supraglottic laryngeal carcinomas. We documented a correlation of supraglottic laryngeal carcinomas with high grade (p = 0.001) and enhanced tumor TNM stage (p < 0.001). The supraglottic location was correlated with the abolishment of beta-catenin from the membrane (p = 0.025). However, the diverse anatomical locations are not characterized by statistically significant differential expression of ILK, p-Akt, AR, ER-beta, E-cadherin and vimentin. Our results show that it is possible that molecular factors, such as beta-catenin, are differently expressed in glottic and supraglottic carcinomas, leading to the distinct clinical behavior of those tumors.
Integrin-linked kinase (ILK) has been implicated in the development and progression of several human malignancies. Previous in vitro studies also implicate ILK in the activation of Akt and beta-catenin as well as in the regulation of E-cadherin expression. However, the role of ILK in human laryngeal cancer and its possible in vivo downstream effectors in the disease are currently unknown. We examined by immunohistochemistry the protein expression of ILK, phosphorylated-Akt (p-Akt), E-cadherin, and beta-catenin in 97 invasive squamous laryngeal carcinomas. Increased cytoplasmic and nuclear expression of ILK and p-Akt decreased membranous expression of E-cadherin and nuclear accumulation of beta-catenin was found in 87.6%, 85.6%, 71.1%, and 43.3% of cases, respectively. Our results suggest that ILK expression may be implicated in human laryngeal carcinoma and its localization in the nucleus possibly proposes novel nuclear functions of this molecule. In addition, enhanced ILK expression correlates with activation of Akt but not with downregulation of E-cadherin and activation of beta-catenin. Finally, in our material while activated Akt seems to characterize well-differentiated tumors, loss of E-cadherin and activation of beta-catenin correlated with high grade carcinomas.
Androgen receptors (ARs) which are implicated in the pathogenesis of several malignancies can also be a possible downstream effector in laryngeal cancer. In the present study, 97 invasive squamous laryngeal carcinomas were studied by immunohistochemistry for protein expression of AR. Androgen receptors were expressed in 52.6% of tumor specimens, suggesting their implication in the pathogenesis of this tumor. Our study's aim was to investigate the hypothetical scenario of an androgen refractory laryngeal carcinoma where androgen receptors can be activated by nodal molecules in the course of an Epithelial-to-mesenchymal transition (EMT) phenomenon. In line with this we correlated AR expression with the expression of ILK, p-Akt, E-cadherin, β-catenin in our sample as well as with tumor grade and TNM stage. A reverse correlation between nuclear AR and cytoplasmic ILK expression was evidenced, indicating an interaction of those molecules in laryngeal carcinoma. Finally in our material, in those carcinomas that were expressing ARs, stronger nuclear expression of the receptor was characterized by poorer cell differentiation and correlated with the acquisition of EMT features like E-cadherin loss and β-catenin translocation raising a question whether activated ARs can drive an EMT procedure.
In epithelial neoplasms, such as laryngeal carcinoma, the survival indexes deteriorate abruptly when the tumor becomes metastatic. A molecular phenomenon that normally appears during embryogenesis, epithelial-to-mesenchymal transition (EMT), is reactivated at the initial stage of metastasis when tumor cells invade the adjacent stroma. The hallmarks of this phenomenon are the abolishment of the epithelial and acquisition of mesenchymal traits by tumor cells which enhance their migratory capacity. EMT signaling is mediated by complex molecular pathways that regulate the expression of crucial molecules contributing to the tumor’s metastatic potential. Effectors of EMT include loss of adhesion, cytoskeleton remodeling, evasion of apoptosis and immune surveillance, upregulation of metalloproteinases, neovascularization, acquisition of stem-cell properties, and the activation of tumor stroma. However, the current approach to EMT involves a holistic model that incorporates the acquisition of potentials beyond mesenchymal transition. As EMT is inevitably associated with a reverse mesenchymal-to-epithelial transition (MET), a model of partial EMT is currently accepted, signifying the cell plasticity associated with invasion and metastasis. In this review, we identify the cumulative evidence which suggests that various aspects of EMT theory apply to laryngeal carcinoma, a tumor of significant morbidity and mortality, introducing novel molecular targets with prognostic and therapeutic potential.
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