In this study we investigated the blood group antigens SLeX, SLeA and LeY in endometrial cancer, a disease with increasing incidence. A high expression of SleX and SLeA correlated to better survival rates, while high expression of LeY went along with poorer prognosis. SLeX expression also correlated to low tumor stage: low pT-stage, low grade and low FIGO, resulting in better overall- and progression free survival. Interestingly previous studies in other malignancies (for example lung (Iwanari et al. 1990) and breast cancer (Jeschke et al. 2005)), suggested that high levels of SLex are associated with advanced disease, so researchers suggested it to be a tumor marker. High levels of SLeX were associated with worse prognosis in liver cancer (Nakagoe et al. 2002).
SLeX can promote metastasis by inducing overexpression of E-selectin, resulting in haematogenous metastasis (Okuno et al. 2003; Shah et al. 2009; Jin and Wang 2020). Also in cervical carcinoma in situ, the expression of SLex is higher compared to healthy cervical tissue (Engelstaedter et al. 2012). In contrast, in invasive carcinoma a loss of SLeX was reported (Moro-Rodríguez and Álvarez-Fernández 2008), leading to the opposite effect of SLeX: It can also improve the anti-tumor immune response: Its derivate 6-sulfo SLex is involved in the recruitment of T-lymphocytes, which was shown in urothelial carcinomas (Taga et al. 2015). High SLeX levels can also support natural killer cells attacking tumor cells (Ohyama et al. 2002). This might result in lower tumor stages and better survival rates, matching our results. Based on the paradoxical observations, Ohyama et al suggest that the results of SLeX expression depend on its different expression levels (Ohyama et al. 2002). Jin et al found out, that in early tumor stages, the abnormal SLeX synthesis leads to an immune imbalance, while in advanced stages, it promotes tumor vascularisation and metastasis (Jin and Wang 2020). In summary, the exact role of SleX and the underlying mechanisms are not clearly understood yet. Nevertheless, it seems clear, that abnormal glycolisation plays an important role and data supporting a suppressing and a promoting role in tumorigenesis exist, make more investigations necessary.
Like SLeX, also its isomer SLeA serves as a tumor marker: as epitope of the Ca 19-9 antigen, it is overexpressed in pancreatic, colorectal and breast cancer (Ugorski and Laskowska 2002; Trinchera, Aronica, and Dall'Olio 2017; Jeschke et al. 2005). Analogous to SLeX, also SLeA is a ligand for E-selectin and an overexpression of both – E-selectin and SLeA or SLeA alone is associated with distant haematogenous metastasis (Kannagi 2004, 2007; Tozawa et al. 2005). In contrast to these described results, we detected a high expression of SleA being associated with low pT-stage, low grade and better overall survival rates. Until now, only little data about SLeA in EC exist: Inoue et all described an increased expression of SLeA in EC compared to healthy endometrial tissue (Inoue et al. 1987). As with SLeX, the cellular mechanisms of SLeA expression are not completely understood. In cervical cancer for example, it was shown, that the effect of SLeA depends on the tumor stage: In CIN II a high expression was correlated to a progressive state (Kolben et al. 2017), while in invasive carcinomas, a loss of SLeA was shown (Moro-Rodríguez and Álvarez-Fernández 2008), resulting in a poorere prognosis with low SLeA expression.
Similar to SLeX and SleA, also LeY is overexpressed in several tumors, like breast cancer, ovarian cancer, prostate- and colon cancer (Arai and Nishida 2003; Madjd et al. 2005). At the same time, the expression of LeY has been described to be associated with poorer prognosis (Madjd et al. 2005; Liu et al. 2018). In EC high expression of LeY went along with positive lymph node status – a predictor for poorer prognosis. It also correlated significantly to poorer progression free survival, but not to overall survival in EC. Different theories about the underlying mechanism exist: Liu et al suggest a connection to chemo-resistance, as in chemo-resistant ovarian cancer cells, LeY was significantly elevated (Liu et al. 2018). Additionally, ovarian cancer cells with high LeY expression developed more often chemo-resistance (Liu et al. 2018). Both observations resulted in progression and highlight the role of LeY in invasion and metastasis of ovarian cancer (Liu et al. 2019; Liu et al. 2009; Iwamori et al. 2005; Yan et al. 2010). Additionally, the proliferation of cancer, e.g. ovarian cancer, can be influenced by LeY through the PIK3/Akt pathway (Liu et al. 2009). Also in colon cancer LeY is examined: its expression led to a decrease of apoptosis (Baldus et al. 2006), also resulting in progression and thus poorer survival rates. In cervical cancer and its pre-cancer-lesions LeY has a prognostic impact: significant differences were found between normal samples compared to CIN I / CIN II / CIN III and invasive cancer (Engelstaedter et al. 2012).
Our results show significant correlations of SLeX, SLeA and LeY to clinicopathological variables and survival rates independent of molecular subtypes. Lewis Y turned out to be independent variables regarding progression free survival, SLeX and SLeA showed a significance regarding survival rates, but they were not independent factors. Beside Lewis Y, also SLeA turned out to be a possible marker for progression free survival: in the group with better progression-free survial rates we had almost no events. As we used immunohistochemical methods, we cannot say if these results are consequence or cause of the cancer phenotype. Further experiments are, therefore, needed and could lead to a deeper understanding of the molecular mechanisms. Finally, this could result in the identification of new therapeutic targets for endometrial cancer treatment.