The release of reactive oxygen species (ROS) from the mitochondria of inflammatory cells under chronic inflammatory conditions could directly cause a genotoxic effect and damage to tissues, thereby initiating and promoting tumor development, invasion, and migration [7]. As a response, the expression of SOD released from mitochondria to the peripheral blood is increased [8, 9]. Increased SOD expression was found to be related to the upregulation of matrix metalloprotein (MMP), hence blocking SOD could partly reverse epithelial-mesenchymal transition (EMT) and migration of A549 cells [10 ]. Other studies found that the content of SOD in tissues of adenocarcinoma of the lung was significantly higher than that in adjacent normal tissues [11]. We found that SOD levels in the IL-6 elevated level group were significantly higher than those in the normal IL-6 level group. In addition, GGN in the group with elevated levels of IL-6 exhibited more malignant signs on imaging, suggesting that lung GGN with SOD elevation may have a more malignant transformation potential [12].
IgE can provide a protective effect on the mucosal epithelium exposed to carcinogenic environments. It was found that exposure of the mouse skin to benzopyrene could produce a local IgE response, which induced the basophilic granulocyte-mediated anti-tumor effect to clear cancerous cells following DNA damage by cancerogenic substances. When the IgE response was blocked, the cancerous tissue induced by the carcinogenic substances grew even faster [13, 14]. It was found in our study that the IgE level in the GGN patients of the IL-6 elevated group was increased significantly. IgE could promote the transformation of the activated macrophages to the proinflammatory phenotype [15], and enhance the anti-tumor proinflammatory signal and promote the killing effect of human mononuclear cells on tumor cells [16]. Therefore, a reactive elevation of IgE may be a tumor protective mechanism in early canceration of lung GGN. However, this postulate could on the other hand imply that GGN lesions with an elevation of IL-6 and IgE could be associated with an increased risk of malignancy.
We found from the sample of GGN patients with elevated levels of IL-6 that, while the levels of Ts cells were increased, that of Th cells was decreased significantly. IL-6 has a role in promoting tumor formation [17, 18]. Myeloid-derived suppressor cells (MDSC) are a group of cells generated in the process of tumor progression, that function to inhibit T cells and natural killer (NK) cells, promoting tumor progression. IL-6 is an important regulatory factor aggregated and activated by MDSC, resulting in the inhibition of adaptive immunity [19]. Studies demonstrated that CD40 of upregulated MDSC could induce T cell tolerance in tumor-bearing mice. In addition, MDSC could stimulate M2-like macrophages to produce large amounts of IL-1 to promote tumor progression and induce Treg cell-mediated immune suppression. Under the stimulation of tumor-derived transforming growth factor TGF-β, MDSC upregulates the expression of peripheral ATP hydrolase-1 and nucleotidase and catalyzes the degradation of ATP into adenosine [20], which has an immunosuppressive effect on T and NK cells, thus reducing their killing effect on tumor cells. Other studies [21] also found that IL-6 could inhibit T cell activation in tumors, suggesting that IL-6 may be an important factor in inhibiting anti-tumor immunity of T cells.
Chronic inflammation and decreased immune function are common phenomena of immunosenescence [22]. Most GGN patients in our study were between 50 and 60 years of age, which is a period of quick immunosenescence. Therefore, complications in GGN patients with IL-6 elevation should not be ignored. Clinicians should first assess whether complications of the patients would produce a negative impact on their lung GGN, such as chronic intestinal diseases. Recent studies have demonstrated a close relationship between the gut and lung [23]. For instance, patients with chronic pulmonary diseases do not only present microecological changes in the respiratory tract but their gut microbiota as well. Gut microbiota metabolites such as short-chain fatty acids (SCFAs) have systemic anti-inflammatory effects. Destruction of intestinal microecology will lead to GI dysfunction and imbalance between anti- and pro-inflammatory cells of the human body [24]. Gut microbiota also undergoes abnormal changes in patients with anxiety. In addition, metabolites from intestinal flora have important impacts on human inflammatory responses [25]. Both IL-6 and TNF-α mediators of pro-inflammation in the inflammatory mechanism of the gut-lung axis as well as gut-brain axis [24, 26]. Coronary stenting is quite common in lung GGN patients with elevated levels of IL-6, which may reflect that inflammatory mediators could be implicated in aggravating coronary arterial damage. Higher levels of IL-6 and TNF-α participate in coronary arterial damage, as well as in the development and progression of tumors [27, 28]. Besides, IL-6 also mediates the systemic inflammatory response of cancer patients [29, 30]. For this reason, lung GGN is to some extent a systemic disease accompanied by other complications. Regulating gut microbiota and controlling inflammation are important critical ways to prevent GGN canceration [31, 32].
It was found in our study that tumor markers were elevated in GGN patients with elevated levels of IL-6. IL-6 promoted {had a role in promoting} the transformation of lung tumor stem cells to foci of early canceration. In addition, combined use of the anti-IL-6 antibody and cisplatin could destroy lung cancer-like organs, while use of cisplatin alone did not produce such an effect. A study detected the presence of positive expression of IL-6mRNA in lung cancer cells [33]. Tumor cell-derived IL-6 promotes tumor cell proliferation by promoting glycolytic metabolism of tumor cells and activating the MEK/Erk1/2 hypoxia-inducible factor 1α (HIF-1α) pathway [34, 35]. IL-6 can also confer stem cell-like properties on cancer cells by activating IL-6/STAT3 signaling [36, 37]. Elevation of NSE and CY21-1 in GGN patients of IL-6 elevated group suggests that inflammation has a promoting effect on tumor development and progression [38–42]. IL-6 promotes angiogenesis of early cancer tissues. It was found that the vascular endothelial growth factor receptor (VEGFR) level in non-small cell lung cancer (NSCLC) patients with elevated levels of IL-6 were even higher than that in those with normal IL-6 levels, and IL-6 and VEGFR were independent prognostic factors [43]. Inflammation and angiogenesis are two important features in tumorigenesis. Tumor microvascular density (MVD) was found to correlate positively with the expression of IL-6 and VEGFR in human lung adenocarcinoma tissues [44]. IL-6 and VEGFR were found to play a key role in tumor angiogenesis [45]; when IL-6 formation was inhibited, tumor infiltration and metastasis were decreased [46]. Lung GGN with VCS may most probably represent lung cancer in its early stage. This could be evident on CT imaging as gathering or displacement of a single or multiple pulmonary microvessels to the GGN lesion due to traction, disrupting the GGN lesion, or penetrating through it [47]. It is reported in the literature that the canceration rate of mixed GGN (mGGN) is more than 50% [48, 49]. Such canceration rate is even higher in GGN patients with IL-6 elevation and VCS, and in mGGN patients.
Highlights and limitations
To the best of our knowledge, this is the most comprehensive clinical study on factors affecting the biological behavior of lung GG by summarizing the occurrence and progression of lung GGN from the perspective of how IL-6 mediates inflammation-induced canceration. We also found that lung GGN patients with IL-6 levels elevated were more likely to be inflicted with anxiety and GI dysfunction. By inhibiting the anti-tumor immune function, tumor markers became even higher and CT imaging revealed more malignant signs in such patients. These findings may provide clinicians with more clues to identifying high-risk GGN at an earlier stage and preventing them from cancerous transformation.
The main limitation of the study is that the level of evidence is relatively low due to the lack of surgical-pathologic results and postoperative follow-up observations. Future research will seek to observe changes in GGN after treatment by inhibiting the inflammatory factors. This will help gain knowledge about the impact, of which inhibiting inflammatory mediators will have on cancer prevention.