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INTERLEUKIN-8 AND LARYNGEAL SQUAMOUS CELL CARCINOMA

may be used as additional diagnostic markers in the sera of patients because of their excessive production by the tumor cells. This could be of great value since there are currently no reliable markers to predict either tumor development or relapse. Interleukin-8 (IL-8), a chemokine (C-X-C motif) ligand 8 (CXCL8), is now reported to play an important role in cancer invasion, angiogenesis and metastasis. Recent studies have shown an increased concentration of IL-8 in patients with LSCC and a positive association


INTRODUCTION
Laryngeal squamous cell cancer (LSCC) is the second most common neoplasm of the upper aerodigestive tract after cancer of the oral cavity (1). Over the past two decades, even though surgical techniques, chemotherapy and radiation therapy, the In 2016, an estimated 13,430 new cases of laryngeal cancer have been diagnosed, with approximately 3620 patients dying from the disease. Laryngeal squamous cell cancer occurs more commonly in men than in women (5.8 cases per 100.000 vs 1.2 per 100.000, respectively). In addition, there are racial disparities observed in laryngeal cancer, with African Americans presenting at a younger age and having a higher incidence and mortality compared with Caucasians (2).
Several risk factors have been implicated in the pathogenesis alcohol consumption (4). Tobacco use has been shown to have a linear association with the development of laryngeal cancer, with a risk for smokers that is 10 to 15 times higher than the risk for nonsmokers, and the heaviest smokers have as much as a 30 times greater risk. Research has also demonstrated a linear relationship between the amount of alcohol consumed and the risk of laryngeal cancer. In a study that examined the role of alcohol and tobacco in laryngeal cancer, the multivariate as > 8 drinks per day) and 9.38 for nondrinking smokers (5)(6)(7)(8)(9)(10)(11). It has also been shown that alcohol and tobacco have a multiplicative effect on the risk of laryngeal cancer. Exposure to other environmental factors is thought to potentially increase the risk of LSCC, such as asbestos, polycyclic aromatic hydrocarbons, and textile dust (12). Dietary factors have also been noted, with red meat increasing the risk of laryngeal cancer, while a diet varied in fruit and vegetables potentially has a protective effect. The role that both disease process is still controversial and under investigation.
Although the human papillomavirus (HPV) is a proven driver of the majority cancers of the oropharynx, it was initially thought that the virus did not play a role in laryngeal cancer (13)(14)(15)(16)(17)(18). However, new research demonstrates the presence of HPV and/or the surrogate marker p16 (cyclindependent kinase inhibitor 2A/multiple tumor suppressor 1) in a minority of laryngeal tumors, although the biologic and that the prevalence of HPV ranges from 20% to 30% in laryngeal cancer; however, this percentage varies widely between studies and depends on the detection method used. More work is needed to determine the clinical relevance of HPV/p16-positive status in laryngeal cancer, as this remains controversial (13)(14)(15)(16)(17)(18)(19)(20)(21).
Approximately 60% of patients present with advanced (stage III or IV) disease at diagnosis. Unfortunately, laryngeal cancer is one of the few oncologic diseases in which the 5-year survival rate has decreased over the past 40 years, from 66% to 63%, although the overall incidence is declining. This highlights the need for further research and innovation rate are the lack of screening methods (clinical examination remains the single solution to early detection) and the late presentation of patients to the specialist as a result of little worrying symptoms (hoarseness). The lack of suspicion of second consultation among patients who were not diagnosed with cancer initially (1,25).

CYTOKINES IN HEAD AND NECK CANCER
It has been reported that changes in the expression of cytokines and growth factors may have implications in the malignant transformation of many cancers including head and neck squamous cell carcinoma (HNSCC) and, more recently, LSCC (2,26). Cytokines are a group of soluble, low-molecular-weight proteins that mediate immune and groups: T-helper 1 (Th1), T-helper 2 (Th2) and T-helper 17 (Th17), as determined by their biological properties (27). Th1 cytokines stimulate cellular immune responses, while Th2 cytokines predominantly regulate humoral responses. and plays several roles in autoimmunity (27). Cytokines are (28). As for nerve growth factor (NGF), several studies led distribution pattern within the tissues and its implication in induction as well as progression of carcinogenesis. However, other recent studies have shown that NGF may have direct clinical relevance in certain tumor cell prevention (29)(30)(31)(32).
Involvement of cytokines in the pathogenesis of cancer, and especially HNSCC, has been investigated in a number Interleukin-8 and laryngeal squamous cell carcinoma of recent studies (33)(34)(35)(36). These studies have categorized cytokines as (a) factors that affect tumor growth, (b) factors that can be used as prognostic markers and (c) those that are possible immunotherapeutic targets (37). Although the main source of cytokines are immune cells, many tumor cells have been shown to make autocrine mediators to support their own growth thus evading the immune response (38); they include HNSCC that produce IL-4, IL-6, IL-8, IL-10, granulocyte macrophage-colony-stimulating factor (GM-CSF), VEGF, factor (bFGF).
It has been hypothesized that some of these cytokines may be used as additional diagnostic markers in the sera of patients because of their excessive production by the tumor cells (39). This could be of great value since there are currently no reliable markers to predict either tumor development or relapse in treated HNSCC patients. Recent studies have demonstrated that HNSCC is associated to a decrease in Th1 and an increase in Th2 cytokine levels, which is thought to be used as a mechanism to evade anti-tumor immune response. In fact, this shift towards the Th2 cytokine response is a common event in HNSCC and many other solid tumors, such as colorectal cancer, renal cell carcinoma, prostate cancer, and melanoma. Therefore, current studies in search of immunotherapeutic approaches to cancer aim to shift the balance in favor of Th1 response.

NEUTROPHIL-TO-LYMPHOCYTE RATIO
An increased neutrophil-to-lymphocyte ratio (NLR) is associated with poorer prognostic outcomes in numerous types of cancer, including HNSCC (40)(41)(42)(43). However, a small number of studies have demonstrated the prognostic role of NLR in patients with laryngeal cancer (44). The association between NLR and survival outcomes in 654 patients with LSCC was evaluated (45) and the authors reported that blood and biochemical parameters, including NLR, plateletto-lymphocyte ratio and albumin-to-globulin ratio were associated with clinical characteristics of the patients, with the exception of histologic grade. Survival analysis demonstrated that NLR at cutoff values subdivided patients into different survival outcomes; subsequent to adjustments for age and other prognostic factor for overall survival and progression-free survival. Increased levels of cytokines, including IL-6 and IL-8 in tumor tissues were associated with NLR values. In summary, pre-treatment NLR was associated with the prognostic outcomes for patients with laryngeal cancer and may assist to establish prognostic factors for these patients.

INTERLEUKIN-8
chemoattractant, is now reported to play an important role in cancer invasion, angiogenesis and metastasis (46)(47)(48)(49)(50)(51). The cancer cells themselves can also secret IL-8 in an autocrine or paracrine manner, such as in breast cancer, gastric cancer, colon cancer, cervical cancer, pancreatic cancer and leukemia (52). Moreover, in human colon cancer cell lines, constitutive expression of IL-8 has been linked to metastatic potential and has been suggested to play a role in the development of distant metastases. In vivo analysis also showed that IL-8 would be a sensitive marker in predicting prognosis and monitoring disease progression of the pancreatic cancer patients (52).

INTERLEUKIN-8 IN HEAD AND NECK CANCER
One of the factors that is known to positively drive metastasis is angiogenesis, which has been reported to be associated with decreased survival of HNSCC patients (2, 53-55). IL-8, along with other factors produced either by normal or malignant cells such as VEGF and bFGF has been shown to contribute to angiogenesis, tumorigenesis, and metastasis in patients with HNSCC (2,33,56).
Serum levels of IL-8 are consistently elevated in patients with recurrent or metastatic SCCHN and elevated levels may correlate with advanced or aggressive disease (34,36,57); in general, IL-8 production is linked with tumor vascularization, metastatic phenotype, tumor growth, and overall poor prognosis. A clear switch from cytokine Th1 to cytokine Th2 in HNSCC patients, low levels of IL-2 and increased levels of both IL-2 and IL-12 with the early stages of laryngo-pharyngeal cancer were reported (58). Loco-regional metastases were correlated with increased levels of IL-8 and correlated with increased levels of Th2 cytokines, supporting the hypothesis that the ratio between different Th1 and Th2 cytokines could represent a useful marker for clinical and pathological evaluation of cancer patients.
CXCR4 interaction in HNSCC and its secretion is regulated by Akt phosphorylation after SDF-1 stimulation (59). These Grasso et al results point out the importance of SDF-1/CXCR4 interaction in HNSCC angiogenesis and provides a new targeting therapy utility, disrupting SDF-1/CXCR4 interaction combined with downstream-induced angiogenic factors in HNSCC would be According to Swenson and colleagues IL-8 and VEGF expression is based on interactions between NF-kB, AP-1, and induction of AP-1, VEGF, and IL-8 promoter/reporter gene activity after 24-hour exposure to cigarette smoke condensate (CSC) reporting that tobacco carcinogens up-regulate AP-1 activity and AP-1 dependent IL-8 and VEGF gene expression in head and neck cancer (60). This up-regulation may promote an angiogenic phenotype that favors invasion in both premalignant and squamous cancer cells of the head activation of both genes, resulting in increased IL-8 and VEGF secretion, and these processes could be down-regulated with introduction of a dominant negative A-Fos gene. These data demonstrate a role for tobacco carcinogen stimulation of proangiogenic cytokines, thus promoting an environment suitable for development and metastatic spread of head and neck cancer cells.

INTERLEUKIN-8 IN LARYNGEAL CANCER
The role of IL-8 in the development and progression of LSCC has been recently investigated (61). In the last decade, four studies focused on the role of IL-8 in LSCC, enrolling a total of 214 patients with laryngeal cancer, and 6 patients with laryngeal dysplasia (52,58,62,63). IL-8 sample was taken by peripheral venous blood, while the types of assays for IL-8 measurement were ELISA kits. The main results of these studies are summarized in Table 1.
Eyigor et al investigated the relationship between the size of tumors, lymph node metastases, stage, differentiation and these variables. IL-8 level in patients affected by laryngeal cancer ranged from 24.9 pg\ml (52) to 227.15 pg\ml (62). Patients with laryngeal dysplasia presented 24.02 pg\ml. IL-8 cytokine level in controls reached the maximum of 34.33 (62). These results are in line with two previous studies (33,38), although they focused on HNSCC and did not specify how many patients had laryngeal cancer compared with other sites in head and neck (38). Similarly, Druzgal et al (34) and Hathaway et al (36) also demonstrated some elevation in IL-et al, Gokhale (57) reported that IL-8 was not elevated in newly diagnosed patients but in patients with recurrence and metastasis of HNSCC. Likewise, Hathaway et al (36) also reported that, although IL-8 is not markedly increased in cancer patients, it is associated with the tumor size. Serum IL-8 level of patients with LSCC was associated overall survival and progression-free survival. Univariate and multivariate analyses showed that high IL-6 serum level, contrarily to IL-8, was an independent adverse prognostic variable for progression free and overall survival (52).
Patients with T2 pharyngeal cancer showed that the average value of IL-8 was much higher than in patients with T2 stage laryngeal cancer (58). In exchange, in T3 group, nearly 25% of patients exhibiting high or detectable levels of IL-8 had laryngeal cancer. Concerning the Th1/Th2 levels levels of IL-8 and IL-10. Serum level of IL-8 was high in patients with loco-regional metastases and was low, although noticeable, in patients with reactive nodes. Loco-regional consisting of increased levels of IL-8 and IL-10 and a drastic immunological balance in these patients with the activation of processes. The switch towards a Th2-type response in advanced cancer patients and the high levels of IL-8 and IL-10 could be responsible of promoting the tumor growth through contiguity. The higher level of IL-8 in patients with loco-regional metastases demonstrates the importance of this cytokine as an indicator of the presence of local metastases, potentially contributing to the correct evaluation of patients and an adequate therapy selection.
TNF-receptor-associated-factor (TRAF)-6 mRNA expression and IL-8 secretion when stimulated with phytohaemagglutinin (PHA) in patients with laryngeal carcinomas (63). These authors found that patients with carcinomas characterized by the highest TRAF6 mRNA expression had higher IL-8 concentration. They also noted the positive relationship between toll-like receptor-4 (TLR-4) mRNA status and IL-8 concentration, but this association had borderline statistical Interleukin-8 and laryngeal squamous cell carcinoma