Prognostic Implications of ALDH1 and Notch1 in Different Subtypes of Oral Cancer

Abstract

Background. The present study aimed to investigate the clinical significance and prognostic value of the immunoexpression of cancer stem cell markers, ALDH1 and Notch1, in subtypes of oral squamous cell carcinoma. Materials and Methods. The expression of ALDH1 and Notch1 in 63 patients with well and poorly differentiated oral squamous cell carcinomas and their subtypes, verrucous carcinoma and basaloid squamous cell carcinoma, was evaluated by immunohistochemistry. The semi-quantitative analysis of the ALDH1 and Notch immunoexpression levels, based on the capture of 10 microscopic fields, at 400X magnification, at the invasive tumor front was performed and associated with clinicopathological variables using the chi-square test or Fisher’s exact test. The overall and disease-free survival rates were estimated according to the Kaplan–Meier method and the curves were compared using the log-rank test. The independent effects of variables were calculated using Cox’s proportional hazards regression model. Results. Strong ALDH1 and Notch1 expression was observed in 16 (25.4%) and 27 (42.9%) oral squamous cell carcinomas including their subtypes, respectively. Most tumors with strong immunoexpression of ALDH1 were basaloid squamous cell carcinoma (56.3%). Statistically significant associations were observed between the strong immunoexpression of Notch1 in poorly differentiated oral squamous cell carcinoma with perineural infiltration ( p = 0.011) and lymph node involvement (pN+) ( p = 0.034). The strong immunoexpression of ALDH1 was a prognostic factor associated with worse overall survival ( p = 0.040) for patients with oral cancer. Conclusion. The strong immunoexpression of Notch1 can contribute to identification of patients with poorly differentiated oral squamous cell carcinoma, who have perineural infiltration or lymph node metastasis. In addition, the strong immunoexpression of ALDH1 may help to identify a worse prognosis in patients with oral squamous cell carcinoma and their subtypes.

Notch1-Jagged1 Signaling Pathway in Oral Squamous Cell Carcinoma: Relation to Tumor Recurrence and Patient Survival

“…Several studies on head-and-neck cancer, ovarian, breast cancer, gastric cancer, and prostate cancer reported similar findings [32], [39], [40], [41], [42], [43]. In contrary to our findings, De Freitas Filho et al concluded that immunoexpression of Notch1 has no influence on the prognosis of patients with oral cancer [44], a result similar to those obtained by Joo et al and Ravindran and Devaraj [16], [44].…”

The Multiple Roles of CD147 in the Development and Progression of Oral Squamous Cell Carcinoma: An Overview

“…This phenomenon is associated with the emergence of OSCC lesions of cells which are so dedifferentiated that they resemble stem cells ( Figure 2 ) [ 189 ]. These cells are found next to the cells that have undergone EMT and indeed express stem markers including CD133, Notch, and aldehyde dehydrogenase 1 [ 189 , 215 , 216 , 217 , 218 , 219 ]. Many of the stem-like cells populating OSCC tissues are cancerous (cancer stem cells) [ 41 ], and their number is negatively correlated with OSCC differentiation grade [ 215 ].…”

“…At variance with normal basal stem cells, the stem-like cells present in OSCCs display low E-cadherin/β-catenin and high CD147/CD44 levels [ 41 ]. The concomitant overexpression of CD147 and CD44 makes the cancer stem cells present in OSCCs very viable and invasive [ 141 , 215 , 216 , 217 , 218 , 219 , 220 , 221 ]. In fact, while CD147 triggers MMP-9 expression, CD44 anchors MMP-9 in the invadopodia, thus enforcing and orienting cellular invasion [ 41 ].…”

“…Furthermore, CD44 stimulation upregulates the expression of multidrug transporters and multidrug resistance-associated proteins [ 41 ]. Accordingly, OSCCs rich in cancer stem cells are characterized by a high rate of relapse and metastasis and poor sensitivity to antitumor therapies [ 215 , 216 , 217 , 218 , 219 , 220 , 221 ].…”

“…A further effect resulting from CD147-promoted AKT phosphorylation is an increase in glucose uptake and lactate secretion by OSCC cells ( Figure 2 ) [ 234 ]. The increase in glucose uptake is very likely to be involved in the tumor growth effect promoted by the stimulation of the CD147/AKT axis [ 235 ], while the acidification of the tumor microenvironment, which results from lactate secretion, favors HIF-1 activation that, in turn, triggers angiogenesis [ 63 , 206 ] and contributes to the induction of cell dedifferentiation ( Figure 2 ) [ 189 , 214 , 215 , 216 , 217 , 218 , 219 ]. The development of angiogenesis is accelerated by the fact that CD147-promoted AKT phosphorylation directly stimulates VEGF synthesis ( Figure 2 ) [ 53 ].…”