|Year : 2019 | Volume
| Issue : 1 | Page : 40-43
Proinflammatory cytokine profile in head and neck squamous cell carcinoma patients: Preliminary report
Victor I Akinmoladun1, Clara A Akinyamoju1, Fabian Edem2, Eniola J Ezeyi3, Olatubosun G Arinola2
1 Department of Oral and Maxillofacial Surgery, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria
2 Department of Chemical Pathology, College of Medicine, University of Ibadan, Ibadan, Nigeria
3 Department of Otorhinolaringology, College of Health Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria
|Date of Web Publication||14-May-2019|
Dr. Victor I Akinmoladun
Department of Oral and Maxillofacial Surgery, College of Medicine, University of Ibadan, University College Hospital, Ibadan
Source of Support: None, Conflict of Interest: None
Background: Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant neoplasms globally. Tobacco and alcohol use are predominant risk factors. Inflammation plays a major role in the etiopathogenesis of cancers and cytokines influence activation, growth, and differentiation of several target cells. This study aimed at profiling head and neck cancer patients with regards to the serum level of proinflammatory cytokines and disease stage. Materials and Methods: This study involved thirty newly diagnosed cases of HNSCC and thirty apparently healthy comparable group. Five milliliter of venous blood was collected from the antecubital vein of each individual. The blood samples dispensed in plain bottles were allowed to clot and retract; serum was stored at −20°C until analysis. Cytokine assay was carried out by enzyme-linked immunosorbent assay technique using a commercial kit. Results: The study group was made up of 19 (63.3%) males and 11 (36.7%) females. The ages ranged from 19 to 92 years with a mean of 59.1 ± 19.1 years. The comparative group was made up of 14 (46.7%) males and 16 (53.3%) females with a mean age of 63.2 ± 7.5 years. The oral cavity was the most common site of SCC [6 (20.0%)]. The cases were mostly advanced in 28 (93.3%, Stages III and IV). Serum interleukin-1 IL-1 (β), IL-6, IL-8, TNF – α, and IFN – γ were elevated in the test cases relative to the controls. This however, was only statistically significantly so with IL-6 and IL-8. The mean values for both cytokines for all tumor sites were exceeded in nasopharyngeal carcinoma. Conclusion: Serum IL-6 and IL-8 appear to be significant in the pathology of head and neck cancer and could be explored for possible roles in the management of HNSCC.
Keywords: Carcinoma, proinflammatory, cytokines head neck
|How to cite this article:|
Akinmoladun VI, Akinyamoju CA, Edem F, Ezeyi EJ, Arinola OG. Proinflammatory cytokine profile in head and neck squamous cell carcinoma patients: Preliminary report. Ann Trop Pathol 2019;10:40-3
|How to cite this URL:|
Akinmoladun VI, Akinyamoju CA, Edem F, Ezeyi EJ, Arinola OG. Proinflammatory cytokine profile in head and neck squamous cell carcinoma patients: Preliminary report. Ann Trop Pathol [serial online] 2019 [cited 2019 Jul 21];10:40-3. Available from: http://www.atpjournal.org/text.asp?2019/10/1/40/258163
| Introduction|| |
Head and neck cancers represent the sixth most common cancer worldwide, with approximately 630,000 new patients diagnosed annually resulting in >350,000 deaths every year. More than 90% of head and neck cancers are squamous cell carcinomas (HNSCCs) that arise from the mucosal surfaces of the oral cavity (ICD-10 code: C00-08), oropharynx (ICD-10 code: C09-10 and C12-14), and larynx (ICD-10 code: C32-9). There is wide geographical variation in the incidence and anatomic distribution of HNSCC worldwide; this is predominately attributable to demographic differences in the habits of tobacco and alcohol use. Although the mechanisms driving tissue transformation that result in malignant transformation are incompletely understood, these etiologic factors contribute to carcinogenesis in several ways including genotoxicity and increased proinflammation and proangiogenesis cytokine expression and aberrant pathway signaling.,, Cytokines are typically divided into two categories: proinflammatory (e.g., IL-1 (β), IL-6, IL-8, TNF-α [IFN-γ]) and anti-inflammatory (e.g., IL-4, IL-10, and TGF-(β), and VEGF). These factors modulate tissue remodeling and angiogenesis and actively promote tumor cell survival and chemoresistance through autocrine and paracrine mechanisms. Altered expression of cytokines and growth factors plays a major role in the malignant transformation of many cancers including HNSCC., The aim of this study was to carry out a cytokine profiling of patients with head and neck cancer and relate the same with the disease stage.
| Materials and Methods|| |
This was a cross-sectional study conducted at a tertiary center in Southwest, Nigeria. It involved thirty newly diagnosed cases of HNSCC and thirty apparently healthy volunteers who served as a comparative group. Patients with ongoing infection received appropriate treatment, while others with comorbidities were referred for management before commencement of the study. Five milliliter of venous blood was collected from the antecubital vein without venous stasis from each individual. The blood sample dispensed in a plain bottle was allowed to clot and retract after which the serum was separated into a plain cryovial bottle for storage and subsequent analysis. The specimen was stored at −20°C until time of analysis.
Analysis for cytokines
Concentrations of IL-1(β), IL-6, IL-8, TNF-a, and IFN-γ in serum were analyzed with the enzyme-linked immunosorbent assay (ELISA)-based technique using a commercially available ELISA kit by indirect sandwich technique (RayBiotech R and D Systems, GA) according to the manufacturer's instruction. Cytokine concentrations were obtained by interpolation of the standard curve. Standard curves were generated for each analyte and sample concentrations were calculated from the standard curve. Select samples were done in duplicates, thereby serving as intraassay controls. Data were analyzed using descriptive statistic with level of significance set at P < 0.05.
| Results|| |
The study group was made up of thirty recently diagnosed cases of HNSCC, consisting of 19 (63.3%) males and 11 (36.7%) females aged between 19 and 92 years. Thirty apparently healthy individuals aged between 21 and 76 years, made up of 14 (46.7%) males and 16 (53.3%) females, served as comparative group. The mean ages of the cases and controls were, however, 59 (standard deviation [SD] ± 19.1) and 63 (SD ± 7.5) years, respectively. There was a male dominance in the incidence of the cancers at a male-to-female ratio of 1.7: 1 [Table 1]. The oral cavity was the most common site for HNSCC, making up 20% of all cases [Table 2]. Majority 28 (93.3%) of cases were advanced disease; Stages III and IV. No Stage I disease was recorded. The serum levels of all cytokines were higher in cases compared to comparative group; however, it was only significantly so with IL-6 and IL-8 [Table 3]. Among the studied risk factors, only tobacco–alcohol combination showed significant association with cancer (P = 0.00) [Table 4]. Nasopharyngeal tumors had serum values of IL-6 and IL-8 higher than mean for all tumor sites.
| Discussion|| |
In addition to the genetic changes that are recognized as the hallmarks of cancer, other processes involving cells within the tumor microenvironment that are not necessarily cancerous themselves are significant. Cancer-related inflammation is considered the “seventh hallmark of cancer;” several studies have demonstrated that tumors develop and progress as inflammatory diseases. Molecules including cytokines play key roles in both inflammation and cancer by promoting proliferation, angiogenesis, and carcinogenesis and by recruiting immune cells. HNSCC cells have been shown to express both IL-6 and its receptors. Our results showing elevated serum levels of IL-6 in SCC patients are in accordance with the previous studies., Current evidence suggests that IL-6 can promote tumor cell proliferation in several tumor cell lines including HNSCC, and patients with higher IL-6 serum levels have been shown with more advanced tumor.
In general, a tumor-promoting role for IL-8 has been identified in a wide variety of human solid tumors including malignant melanoma; non-small cell lung cancer; malignant mesothelioma; head and neck squamous carcinoma; cervical and endometrial carcinoma; epithelial ovarian carcinoma; gastric, pancreatic, and colorectal carcinomas; hepatocellular carcinoma; androgen-independent prostate adenocarcinoma; renal cell carcinoma; breast cancer; and Kaposi's sarcomas.,,,,,,,,,,,,, IL-8 production is linked with tumor vascularization, metastatic phenotype, tumor growth, and overall poor prognosis. Our results showing elevated IL-8 levels in HNSCC patients are in concordance with previous studies demonstrating elevated serum concentrations of IL-8 in HNSCC patients., Our findings also support the fact that HNSCCs are highly inflammatory in nature as previously reported, and this may contribute to the rather relatively aggressive nature of the disease. It is also plausible to say that nasopharyngeal tumors may be more inflammatory, in view of the serum values of IL-6 and IL-8 being higher in these patients than the mean in all tumor sites.
| Conclusion|| |
We conclude that IL-6 and IL-8 may play an important role in HNSCC tumorigenesis. However, further studies on a larger patient population will be needed to evaluate the association between serum cytokine levels and disease stage as well as the potential use of these cytokines as biomarkers in head and neck cancer. It also has to be noted that serum cytokine profiles might be influenced by processes independent of head and neck cancer; therefore, it might be necessary to combine serum cytokine profiles with other markers, for more sensitive and specific interpretations. Furthermore, the observed increases in IL-6 and IL-8 could not be correlated with disease stage, as cases were mainly advanced at presentation. Although Kim et al. have demonstrated that serum levels of cytokines do not differ significantly between healthy young adults and elderly individuals, appropriate matching of test and control is desirable. In addition, values obtained from the cases and the comparative group could also not be related to a reference range because of the reported huge variations, although values could be extrapolated.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.
Vigneswaran N, Williams MD. Epidemiologic trends in head and neck cancer and aids in diagnosis. Oral Maxillofac Surg Clin North Am 2014;26:123-41.
Kumar S, Weaver VM. Mechanics, malignancy, and metastasis: The force journey of a tumor cell. Cancer Metastasis Rev 2009;28:113-27.
Ragin CC, Modugno F, Gollin SM. The epidemiology and risk factors of head and neck cancer: A focus on human papillomavirus. J Dent Res 2007;86:104-14.
Klein JD, Grandis JR. The molecular pathogenesis of head and neck cancer. Cancer Biol Ther 2010;9:1-7.
Serefoglou Z, Yapijakis C, Nkenke E, Vairaktaris E. Genetic association of cytokine DNA polymorphisms with head and neck cancer. Oral Oncol 2008;44:1093-9.
Wang F, Arun P, Friedman J, Chen Z, Van Waes C. Current and potential inflammation targeted therapies in head and neck cancer. Curr Opin Pharmacol 2009;9:389-95.
Pries R, Nitsch S, Wollenberg B. Role of cytokines in head and neck squamous cell carcinoma. Expert Rev Anticancer Ther 2006;6:1195-203.
Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436-44.
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70.
Bonomi M, Patsias A, Posner M, Sikora A. The role of inflammation in head and neck cancer. Adv Exp Med Biol 2014;816:107-27.
Wang YF, Chang SY, Tai SK, Li WY, Wang LS. Clinical significance of interleukin-6 and interleukin-6 receptor expressions in oral squamous cell carcinoma. Head Neck 2002;24:850-8.
Sparano A, Lathers DM, Achille N, Petruzzelli GJ, Young MR. Modulation of Th1 and Th2 cytokine profiles and their association with advanced head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg 2004;131:573-6.
Riedel F, Zaiss I, Herzog D, Götte K, Naim R, Hörmann K.
Serum levels of interleukin-6 in patients with primary head and neck squamous cell carcinoma. Anticancer Res 2005;25:2761-5.
Huang S, Mills L, Mian B, Tellez C, McCarty M, Yang XD, et al.
Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol 2002;161:125-34.
Yuan A, Yu CJ, Luh KT, Kuo SH, Lee YC, Yang PC, et al.
Aberrant p53 expression correlates with expression of vascular endothelial growth factor mRNA and interleukin-8 mRNA and neoangiogenesis in non-small-cell lung cancer. J Clin Oncol 2002;20:900-10.
Galffy G, Mohammed KA, Dowling PA, Nasreen N, Ward MJ, Antony VB.
Interleukin 8: An autocrine growth factor for malignant mesothelioma. Cancer Res 1999;59:367-71.
Chen Z, Malhotra PS, Thomas GR, Ondrey FG, Duffey DC, Smith CW, et al.
Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res 1999;5:1369-79.
Fujimoto J, Sakaguchi H, Aoki I, Tamaya T. Clinical implications of expression of interleukin 8 related to angiogenesis in uterine cervical cancers. Cancer Res 2000;60:2632-5.
Fujimoto J, Aoki I, Khatun S, Toyoki H, Tamaya T. Clinical implications of expression of interleukin-8 related to myometrial invasion with angiogenesis in uterine endometrial cancers. Ann Oncol 2002;13:430-4.
Davidson B, Goldberg I, Kopolovic J, Gotlieb WH, Givant-Horwitz V, Nesland JM, et al.
Expression of angiogenesis-related genes in ovarian carcinoma – A clinicopathologic study. Clin Exp Metastasis 2000;18:501-7.
Kitadai Y, Haruma K, Sumii K, Yamamoto S, Ue T, Yokozaki H.
Expression of interleukin-8 correlates with vascularity in human gastric carcinomas. Am J Pathol 1998;152:93-100.
Haraguchi M, Komuta K, Akashi A, Matsuzaki S, Furui J, Kanematsu T, et al.
Elevated IL-8 levels in the drainage vein of resectable Dukes' C colorectal cancer indicate high risk for developing hepatic metastasis. Oncol Rep 2002;9:159-65.
Ren Y, Poon RT, Tsui HT, Chen WH, Li Z, Lau C.
Interleukin-8 serum levels in patients with hepatocellular carcinoma: Correlations with clinicopathological features and prognosis. Clin Cancer Res 2003;9:5996-6001.
Inoue K, Slaton JW, Eve BY, Kim SJ, Perrotte P, Balbay MD, et al.
Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer. Clin Cancer Res 2000;6:2104-19.
Slaton JW, Inoue K, Perrotte P, El-Naggar AK, Swanson DA, Fidler IJ, et al.
Expression levels of genes that regulate metastasis and angiogenesis correlate with advanced pathological stage of renal cell carcinoma. Am J Pathol 2001;158:735-43.
Green AR, Green VL, White MC, Speirs V. Expression of cytokine messenger RNA in normal and neoplastic human breast tissue: Identification of interleukin-8 as a potential regulatory factor in breast tumours. Int J Cancer 1997;72:937-41.
Masood R, Cai J, Tulpule A, Zheng T, Hamilton A, Sharma S, et al.
Interleukin 8 is an autocrine growth factor and a surrogate marker for Kaposi's sarcoma. Clin Cancer Res 2001;7:2693-702.
Gokhale AS, Haddad RI, Cavacini LA, Wirth L, Weeks L, Hallar M, et al.
Serum concentrations of interleukin-8, vascular endothelial growth factor, and epidermal growth factor receptor in patients with squamous cell cancer of the head and neck. Oral Oncol 2005;41:70-6.
Lathers DM, Young MR. Increased aberrance of cytokine expression in plasma of patients with more advanced squamous cell carcinoma of the head and neck. Cytokine 2004;25:220-8.
Kim HO, Kim HS, Youn JC, Shin EC, Park S. Serum cytokine profiles in healthy young and elderly population assessed using multiplexed bead-based immunoassays. J Transl Med 2011;9:113.
[Table 1], [Table 2], [Table 3], [Table 4]