# Electronic Cigarettes' Toxicity: From Periodontal Disease to Oral Cancer
## 2 Effects of Electronic Cigarettes on the Oral Cavity
### Inflammatory Response  
The concept of inflammation-associated tumorigenesis has attracted the interest of several research teams in recent years. A complex inflammatory cascade and a high production of cytokines can be linked to several oral cavity diseases, from periodontal disease to oral cancer. Cytokines are important regulators of the immune processes, involved in inducing growth, proliferation, and differentiation of normal cells, in inflammation and tumorigenesis. Increased inflammatory reactions can lead to the alteration of the mucosal epithelium, which can respond to external aggression through morphological adaptations (keratinization, metaplasia) [34]. The cytokines that are most commonly assessed in saliva are IL-6, IL-8, IL-18, and TNF-\(\alpha\). Their salivary levels are also linked to predicting the prognosis and progression of precancerous lesions [34]. High IL-8 levels may promote carcinogenesis due to its ability to induce cell proliferation and promote DNA damage, but also by upregulating gene transcription and activity of metalloproteinase-2. By stimulating the activity of collagenases, IL8 is also associated with metastasis and enhanced tumor cells invasion in healthy tissues [24].  
In inducing oncogenic inflammatory conditions, STAT3 signaling is a major intrinsic pathway, involved in the initiation and progression of malignant transformation. It is frequently activated in cancer cells and capable of inducing a large number of genes encoding for inflammation. STAT3 hyperactivation may be due to two molecular events, one is constitutive activation by cytokine stimulation and the other is loss of SOCS (suppressor of cytokine signaling) proteins expression [35].  
To better understand the effect of electronic cigarettes on oral tissues, [PERSON] et al. showed that exposure to e-vapors with flavorings caused increased carbonyl stress and inflammatory cytokine release in human periodontal ligament fibroblasts, human gingival epithelium progenitors pooled, and epi-gingival 3D epithelium. Increased levels of prostaglandin-E2, cyclooxygenase-2, and IL-8 were observed [2].  
TNF-\(\alpha\) is another promoter in the process of carcinogenesis, and [PERSON] analyzed in a pilot study the salivary levels of TNF-\(\alpha\) in the group of electronic cigarette smokers were significantly higher than in the control group, despite the lack of tobacco combustion [34].  
To gain insights into the mechanism by which smoking could affect oral cancer cells, and tumor invasion and metastasis, [PERSON] et al. examined the collagen degrading ability and MMP (matrix metalloproteinase) production of two lines of oral carcinoma cells (metastatic and non-metastatic) exposed to cigarette smoke condensate. There is clear evidence of the connection between tumor progression and metastases and the expression and activity of MMP-2 and MMP-9 because one of the key elements in the metastatic cascade is the degradation of collagen, which disrupts the extracellular matrix  
Figure 3: Oxidative stress implications.  
and basement membranes. The conclusion of the study was that continued smoking in oral cancer patients can enhance the metastatic potential of cancer cells, reducing the survival rates [12].