Hypoxia often occurs in some regions of solid tumors and has also been suggested to be associated with aggressive tumor behavior, treatment resistance to chemotherapy and radiotherapy, and poor outcome. CA9, an endogenous marker for hypoxia, is induced by HIF-1a transcriptionally, but more stable than HIF-1a as the marker of hypoxia. CA9 is upregulated and has been described with prognostic and predictive value as well as a compelling therapeutic target in diverse tumor types due to its role in promoting tumor cell survival, invasiveness and metastasis. In the current study, we first observed CA9 expression in SNSCC and demonstrated that CA9 overexpression in cancer cells was associated with tumor recurrence postoperatively. Furthermore, we found CA9 could serve as an independent adverse prognostic factor for SNSCC.
In a meta-analysis published in 2016, 147 studies and more than 24 thousand patients with solid tumors were included to evaluate the prognostic value of CA9 expression[9]. The authors demonstrated strong significant associations between CA9 expression in cancer cells assessed by immunohistochemistry and all endpoints including overall survival, disease-free, locoregional control, disease-specific, metastasis-free survival, and progression-free survival. In the subgroup analyses, similar associations in the majority of tumor sites and types including breast, bladder, lung, liver and head and neck cancer were observed. Additionally, previous studies shown that overexpression of CA9 was associated with more advanced T stage and lymphatic spread to the cervical region[10-12]. In line with previous meta-analysis, we also observed a significant correlation between CA9 overexpression and local recurrence, shorter OS as well as DFS of patients with SNSCC. However, we did not observe a correlation between CAXI overexpression and advanced T stage or lymph node metastases. This may be related to the occult growth pattern of SNSCC which leads to high percentage of patients with advanced T stage and low incidence of neck nodal metastases. In combination with previous reports, our findings demonstrated that CA9 may serve as a universal prognostic marker which indicates higher risk of disease progression in patients with higher expression of CA9 independent of tumor type or site. Furthermore, numerous studies showed that CA9 positivity could predict the treatment resistance to chemotherapy and radiotherapy[13-15]. Therefore, the prognostic value of CA9 in treatment response of SNSCC patients after chemotherapy or radiotherapy is deserved to further evaluated.
In our analysis, advanced pT stage or advanced age was significantly associated with worse OS and DFS. This is in agreement with a recent study by Jain et al[4] who demonstrated increased age at diagnosis and higher stage as prognostic factors associated with poor survival by analyzing data from the Surveillance, Epidemiology and End Results (SEER) database. Similarly, Michel et al[16] reported that patients with stage T3 or T4 disease had significantly worse OS than patients with stage T1 or T2 disease. However, in the multivariate regression analysis, we only found that advanced age was an independent prognostic factor for worse OS and DFS.
Accumulating experimental evidences suggested that increased expression of CA9 under hypoxic conditions play pivotal roles in tumor development. A majority of studies reported the expression of CA9 was significantly increased in head and neck carcinoma, breast carcinoma, brain tumors, lung, and colorectal carcinoma. CA9 was functionally implicated in adaptation to metabolism generating excess of acidic products, thus allowing for cancer cell survival and proliferation. Moreover, CA IX may promote the tumor growth and progression by exacerbating extracellular acidosis that can activate proteases to degrade extracellular matrix, affect cell adhesion, facilitate epithelial-mesenchymal transition and invasion, and support angiogenesis. Overexpression of CA9 was shown to be a potential hypoxic biomarker for head and neck squamous cell carcinoma, and correlated with advanced stage and poor survival[9, 17]. Hoogsteen further et al[18] reported that CA9 positive expression in cancer cells of HNSCC was also indicative of proliferative capacity. In the present study, we observed that CA9 expression in the SNSCC group was significantly higher than that in the normal control group. In spite of only 33.3% (21/63) of patients with positive CA9 expression in our cohort, the mechanisms that upregulate CA9 expression in SNSCC are unclear. We also found that patients with positive CA9 expression was more likely to have postoperative recurrence and poor survival than patients without CA9 expression. Our findings implied that CA9 was associated with tumor progression of SNSCC, but further studies are required to investigate the molecular mechanism controlling CA9 expression as well as its role in regulating the survival and growth of SNSCC cancer cells.
In recent years, new treatment options such as tumor immunotherapy and targeted therapy have made great breakthroughs for various malignancies including lung cancer, breast cancer, liver cancer and HNSCC. However, these new treatment strategies were rarely explored in SNSCC and the entity is always not incorporated into the research of HNSCC due to the extremely low incidence of sinonasal SCC. CA9 has been investigated as a potential therapeutic target by utilization of specific monoclonal antibodies to detect and cause selective killing of CA9-positive cancer cells or synthetic compounds to inhibit CA9 enzymatic activity in preclinical and early clinical stages of various cancers[19, 20]. Our study firstly showed the positive expression of CA9 in a subset of SNSCC patients and its predictive value for patient survival. Therefore, CA9 expression is a potentially useful biomarker for therapeutic targeting using monoclonal antibodies or synthetic inhibitors for SNSCC.
In conclusion, our findings showed that CA9 is an independent prognostic marker for SNSCC patients who have undergone surgical treatment. To our knowledge, this is the first study demonstrating CA9 expression as a strong predictor for tumor recurrence and poor prognosis in patients with SNSCC after curative resection. These findings suggest that CA9 may serve as a novel therapeutic target for SNSCC.