The interaction between lipid imbalance and cancer microenvironment is complex [20]. Abnormal lipid metabolism is related to the formation and development of tumor and possible to become a new target of anti-cancer [21]. Many studies have suggested that lipid molecules and their derivatives are associated with the morbidity and mortality of some cancers, such as the cancer of breast, stomach, colorectal and prostate [9, 15]. However, few studies have investigated the significance of dyslipidemia and lipoprotein metabolism in the prognosis of NSCLC.
In the present study, we found that statistically significant differences of serum lipids and lipoproteins levels were observed between NSCLC patients and healthy controls. Moreover, preoperative serum TG and HDL-C can be identified as independent prognostic factors for OS and DFS in patients with NSCLC. Besides, patients with relatively high preoperative TG levels (> 1.21 mmol/L) and low preoperative HDL-C levels (≤ 1.26 mmol/L) were associated with shorter OS and DFS. We confirmed a significant association of decreased preoperative serum TG levels and increased preoperative serum HDL-C levels with favorable prognosis in NSCLC patients.
Our findings are consistent with some previous studies. A meta-analysis of Lin et al. [22] showed that the levels of serum HDL-C in patients with lung cancer were significantly lower than that of the healthy controls, but serum TG levels were significantly higher in patients with lung cancer. Additionally, some previous studies have indicated that abnormalities in serum lipids and lipoproteins, such as preoperative low levels of TC, HDL-C, apolipoprotein A-1 or high levels of TG, were associated with poor prognosis in cancer patients [9, 16, 23, 24]. The present study showed that increased preoperative serum HDL-C levels were a favorable prognostic factor for NSCLC patients, which was consistent with the study of Chi et al. [25] in NSCLC. Of note, compared with previous studies, our study suggested for the first time that relatively high preoperative TG levels were associated with poor outcomes in patients with stages I-IIIA NSCLC. Furthermore, Khurana et al. [26] reported that statins with anti-lipidemic effects used more than 6 months were associated with a 55% reduction in lung cancer risk. This further indicates that a correlation between serum lipids and lung cancer.
The present study suggested that TG and HDL-C are effective pre-treatment biomarkers for predicting prognosis of NSCLC. However, as new indicators for evaluating OS and DFS, the potential mechanism of preoperative serum TG and HDL-C to reflect the survival outcomes of NSCLC is unclear. We can only attempt to give a preliminary interpretation through considering previous studies. Observations to date have shown that oxidative stress and inflammation are closely related to cancer [27]. The mechanism of TG in cancer is that high levels of serum TG can upregulate cell signal pathways (such as MEK/ERK and AKT pathways), which promote the development of oxidative stress and reactive oxygen species (ROS), thereby leading to the proliferation and progression of cancer cells [12, 28, 29]. Zuber et al. [30] found that one genetic locus at 6p22.1 (rs6904596, ZNF184) in humans was associated with both NSCLC and TG. This suggested that genes that affect lipid metabolism may also affect the development and outcome of cancer.
Moreover, abnormal serum cholesterol levels cause immune system disorders, protein dysfunction, and redox disorders [17]. These factors may increase tumor angiogenesis and tumor cell proliferation, and reduce tumor cell apoptosis [31, 32]. HDL-C can reverse cholesterol transport and has antioxidant, anti-inflammatory, and anti-proliferative effects [33]. Therefore, low serum HDL-C levels may weaken its protective agent in the development of cancer, and the disorder of cholesterol metabolism caused by the decreased HDL-C levels may contribute to the cancer progression [7, 34–37]. Besides, tissue growth, including tumor tissue, uses extra cholesterol to support membrane biosynthesis [31]. During the rapid growth of a tumor, the decreased HDL-C levels in the tumor may be due to the increased demand for cholesterol by tumor cells and the decrease of cholesterol efflux [25, 38]. In addition, under a condition of high TG levels, the net movement of TG to HDL-C molecules could increase, and triglycerides-enriched HDL-cholesterol was more easily cleared from the blood, resulting in a decrease in serum HDL-C levels [39]. The low levels of HDL-C not only weakened anti-inflammatory and antioxidant effects, but also reduced the effect of EGFR-TKI treatment, thereby leading to poorer survival outcomes [40, 41]. Collectively, the mechanisms described above seem to partly explain why preoperative serum TG and HDL-C may be the potential indicator to predict prognosis for NSCLC.
Certainly, some limitations also exist in this study. First, as a retrospective design, our research is vulnerable to bias in data selection and analysis. Second, the sample size is relatively small, especially concerning the patients at stage IIIA or with large-cell lung cancer histological subtypes, and the data may not be representative of all patients at these status. Last, our findings still need large-scale prospective studies and clinical trials to verify.