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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 4  |  Page : 811-815

Association of cytokines levels with epidermal growth factor receptor mutation in lung cancer patients


1 Department of Physiology, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of Respiratory Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India
3 Department of Biotechnology, Kunwar Satya Vira College of Engineering and Management, Bijnor, Uttar Pradesh, India

Date of Submission27-Sep-2018
Date of Decision25-Dec-2018
Date of Acceptance11-May-2019
Date of Web Publication13-May-2020

Correspondence Address:
Sandeep Bhattacharya
Department of Physiology, King George's Medical University, Lucknow - 226 010, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_632_18

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 > Abstract 


Background: Lung cancer is one of the most frequent types of cancer and the leading cause of cancer-related deaths. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (TK) being highly expressed in lung cancers. Activation of EGFR through oncogenic mutations leads to upregulation of gene expression that may heighten the inflammatory response in certain situations. EGFR acts as a key regulator and a cellular hub for inflammatory cytokine signaling, thereby promoting tumor cell proliferation, invasion, migration, metastases, and survival. The aim of the present study is to determine the serum cytokines levels and EGFR mutation status in lung cancer patients to investigate the association between the EGFR mutation status and cytokines levels with lung cancer patients.
Materials and Methods: Blood and tissue samples of lung cancer patients were collected. The EGFR mutations of lung cancer patients were determined by the immunohistochemistry (IHC) and serum cytokines levels of lung cancer patients were determined using ELISA.
Results: Statistically significant association of EGFR mutations with adenocarcinoma subtypes and non-smokers were found (P < 0.05). Lung cancer patients with EGFR mutations had significantly higher tumor necrosis factor-alpha levels when compared to lung cancer patients without EGFR mutations (P < 0.01), and EGFR mutation status was not significantly associated with interleukin-6 levels (P = 0.24).
Conclusion: EGFR mutation detection by the IHC method is a potentially useful tool to guide clinicians for personalized treatment of lung cancer patients of adenocarcinoma subtype, and cytokines are good biomarkers for the diagnosis, prognosis, and prediction of treatment responses in lung cancer patients as well as act as therapeutic targets. This study will provide biomarkers for lung cancer diagnosis and treatments.

Keywords: Biomarker, cytokines, epidermal growth factor receptor, lung cancer, smoker


How to cite this article:
Gaur P, Bhattacharya S, Kant S, Kushwaha R A, Singh G, Pandey S. Association of cytokines levels with epidermal growth factor receptor mutation in lung cancer patients. J Can Res Ther 2020;16:811-5

How to cite this URL:
Gaur P, Bhattacharya S, Kant S, Kushwaha R A, Singh G, Pandey S. Association of cytokines levels with epidermal growth factor receptor mutation in lung cancer patients. J Can Res Ther [serial online] 2020 [cited 2020 Sep 30];16:811-5. Available from: http://www.cancerjournal.net/text.asp?2020/16/4/811/284264




 > Introduction Top


Lung cancer is the most common type of cancer worldwide and is the leading cause of cancer-related deaths.[1] Lung cancers are mainly classified into two major types, including small-cell lung cancer (SCLC) and nonSCLC (NSCLC) and mainly consists of adenocarcinoma and squamous cell carcinoma.[2] It has been shown that approximately 80–85 percent cases are non-small-cell lung cancer (NSCLC).[3] In recent decades, targeted therapies which have been represented by epidermal growth factor receptor (EGFR) inhibitors have gained attention for their ability to significantly improving the clinical outcomes and also reducing the side effects of the chemotherapy.[4] It has been shown that the EGFR mutations were the first targetable mutations to be identified in NSCLC.[5] Lung cancer Patients with these mutations show higher response rates with EGFR TK inhibitors such as gefitinib, erlotinib, and afatinib and thus have a better prognosis than patients without an EGFR mutation.[6],[7],[8] The discovery of oncogenic driver mutations in the EGFR gene of exons 18–21 and approval of agents which target against these molecular drivers have been revolutionized the management of NSCLC.[9] Activation of EGFR through oncogenic mutations leads to upregulation of gene expression that may heighten the infiammatory response in certain situations.[10],[11] EGFR signaling also leads to downstream production of interleukin-6 (IL-6) in human lung cancer cells.[12] A substantial portion of the tumor microenvironment is infiammatory,[13] and pro-infiammatory cytokines and growth factors exacerbate cellular processes such as tumor proliferation and inhibit immune responses.[14] In turn, chronic inflammation contributes to the development of malignancies and metastases.[15],[16] Integral in these processes, EGFR acts as a key regulator and a cellular hub for inflammatory cytokine signaling, thereby promoting tumor cell proliferation, invasion, migration, metastases, and survival.[6],[7],[8]

Several cytokines have been identified which play an important role in lung cancer. The cytokines are considered as good biomarkers for the diagnosis, prognosis, and prediction of treatment responses in lung cancer patients. Lung cancer is characterized by the poor prognosis with a 5-year survival rate of 15%, which is mainly due to the initial diagnosis of lung cancer is at advanced stages of the disease. For this reason, in addition to advances in treatment, the search for diagnostic strategies of early lung cancer detection is very important. Hence, the use of biomarkers is essential for early detection. The activation of EGFR by its gene mutations such as exon 19 in-frame deletions and exon 21 L858R substitution is currently recognized as the most potent biological predictors of EGFR TKI sensitivity. Surgical intervention, platinum-based chemotherapy and radiotherapy were the principal available therapeutic options for the treatment of lung cancer in the past decade. However, with the description of EGFR mutations in lung adenocarcinoma and the response of these tumors to TKI, a new hope in making a significant difference in the survival of such patients has arisen.[17],[18],[19] This study determines the EGFR mutation status and serum cytokines levels in lung cancer patients to investigate the association of EGFR mutation status and cytokines levels with the clinicopathological characters of lung cancer patients.


 > Materials and Methods Top


Recruitment of subjects

The present study was conducted in the Department of Respiratory King George's Medical University, Lucknow, India. The study was approved by the Ethics Committee of the corresponding institute and all the participants gave their written consent. This study included only lung cancer patients and participants having other disorders such as chronic obstructive pulmonary disease (COPD), asthma, tuberculosis, interstitial lung disease, and other malignancies were excluded from the study.

Epidermal growth factor receptor mutation detection

Tissue samples of lung cancer participants were collected bronchoscopically for the detection of EGFR mutations. The EGFR mutation was detected by immunohistochemistry (IHC) method. Formalin-fixed, paraffin-embedded tissue sections were cut into 4 μm-thick sequential sections. After deparaffinization and rehydration, sections were boiled in citrate buffer (0.01 M, pH 6.0) for antigen retrieval. The sections were incubated with 3% H2O2 and 5% serum to block endogenous peroxidase activity and nonspecific binding. Two primary antibodies (delE746-A750 mutation-specific monoclonal antibody [6B6] and L858R mutation-specific monoclonal antibody [43B2]; Cell Signaling Technology, Danvers, MA, USA) were used for the detection of EGFR mutation. The sections were then incubated with biotinylated secondary antibodies and visualized by 3,3′-Diaminobenzidine (DAB). Counterstaining was carried out with hematoxylin. The sections were then dehydrated in alcohol and mounted with DPX.

The IHC staining score was based on the staining intensity and percentage positivity (0%–100%) of cells in the membrane and/or cytoplasm of tumor cells. Four grades were employed as follows: 0, 1+, 2+, 3+. 0 = no staining; 1+ = faint membrane and/or cytoplasmic staining in <10% positive cells; 2+ = moderate membrane and/or cytoplasmic staining in greater than 10% and <50% cells; 3+ = strong membrane and/or cytoplasmic staining >50% cells positive; 0 and 1 + score was considered as negative; whereas 2+ and 3+ were considered as positive cases.

Estimation of serum cytokines levels

Peripheral blood samples of lung cancer patients and controls were collected into the plain vial by venipuncture on the first admission before chemotherapy. Serum samples were obtained by centrifugation at 3000 rpm for 10 min and stored at − 80°C until use. Serum levels of IL-6 and tumor necrosis factor-alpha (TNF-α) levels were determined using a commercially available ELISA kit according to the manufacturer's instructions.

Statistical analysis

Data were analyzed using the Graph Pad Prism version 5 (Graph Pad software Inc.; La, Jolla, CA, USA). Descriptive data are presented as mean, standard deviation, or as percentages. The Chi-square test was used for categorical data and groups were compared by unpaired t-test or one-way analysis of variance. P < 0.05 was considered as statistically significant.


 > Results Top


In this study, 121 lung cancer patients were recruited. The demographic and clinical characteristics of lung cancer patients are shown in [Table 1]. The mean age of lung cancer patients was 53.95 years. The proportion of male patients was higher as compared to females. In the present study, 56.2% of the lung cancer patient was smokers/ex-smokers and 43.8% was nonsmokers. Most of the lung cancer patients were of Stage III/IV, which consists of 93.39%.
Table 1: Demographic characterstics of lung cancer patients

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EGFR mutations were found in 34.29% of lung cancer patients.

Exon 19 mutation was the most common and seen in 79.17% of the lung cancer patients and L858R point mutations of exon 21 was found in 20.83% of lung cancer patients [Figure 1].
Figure 1: Exon 21 (L858R) and Exon 19 (E746-A750) EGFR mutation positive lung cancer patients

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Lung cancer patients with EGFR mutations had significantly higher TNF-α levels when compared to lung cancer patients without EGFR mutations (P < 0.01) and EGFR mutation status was not significantly associated with IL-6 levels (P= 0.24) [Figure 2].
Figure 2: Levels of IL6 and TNF-α in lung cancer patients with EGFR mutation and without EGFR mutation

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The level TNF α and IL 6 in lung cancer patients of Stage III/IV was significantly higher than Stage I/II (P< 0.01) [Figure 3].
Figure 3: Levels of TNF-α and IL-6 in different stages of lung cancer patients

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Significantly higher levels of TNF-α and IL-6 were observed in smokers/ ex-smokers as compared to non-smokers lung cancer patients (P< 0.001) [Figure 4].
Figure 4: Levels of TNF-α and IL-6 in Smokers/Exsmokers and Nonsmokers lung cancer patients

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 > Discussion Top


EGFR gained pharmaceutical significance with the discovery of its involvement in a number of cancers, including NSCLC and head-and-neck cancers. It has been found that the EGFR is upregulated in several types of cancers.[20] Higher prevalence of EGFR mutations is reported in females, non-smokers and lung cancer patients with adenocarcinoma.[21]

It has been reported that EGFR mutations are found in 40%–55% of adenocarcinoma in various studies.[22],[23] EGFR mutation is found in 34.29% of NSCLC patients in our study. Previous studies shows that in frame deletions mutations in exon 19 were found in 26–79 percent, whereas the point mutations in exon 21 (L858R) was observed in 13–47 percent.[24],[25],[26] It has been reported that tumors with exon 19 deletions were more susceptible to gefitinib than exon 21 point mutations.[27] Lung cancer patients showing mutations in the EGFR gene have been associated with better response to TKI such as gefitinib.[28] Although the recent advances are applicable for the management of advanced NSCLC, the cure rate remains still low. Hence, further molecular investigations are required for the development of the new treatment strategies to improve the prognosis of lung cancer patients. It has been shown by several studies that the EGFR mutations are predictive factors of response to EGFR-TKI treatment. Activation of EGFR through oncogenic mutations leads to upregulation of gene expression that may heighten the inflammatory response in certain situations. EGFR acts as a key regulator and a cellular hub for inflammatory cytokine signaling, thereby promoting tumor cell proliferation, invasion, migration, metastases, and survival.

Inflammatory cells may provide growth and survival factors which contribute to various hallmarks of cancer. It has been reported that chronic inflammation due to pulmonary disorders such as COPD significantly increases the patients' risk of developing lung cancer.[29],[30] It has been found that the main mediators of inflammation are cytokines proteins which can be classified as pro-inflammatory and anti-inflammatory molecules such as chemokines and growth factors.[31],[32],[33] These proteins can modulate different cellular responses, including inflammation, the immune response, apoptosis as well as chemoattractant processes.[34],[35],[36],[37] Characteristic cytokine patterns have been associated with different cancer patients and are related to their prognosis also. Therefore, some cytokines are the good prognostic biomarkers of cancer.[10],[11],[38] The cytokines that are good biomarkers for the diagnosis, prognosis, and the prediction of treatment responses in lung cancer patients. The cytokines could act as therapeutic targets and describe the therapeutic strategies based on these targets. The results of the previous study suggest that therapy with TNF-α would be effective in some cases of nonsmall-cell lung cancer that have acquired resistance to gefitinib. Recent insights into genetic aberrations and the role of the immune system in NSCLC have used in a new era of rapidly evolving targeted therapy and immune-based treatments.[39],[40],[41] It has been shown that the blocking of EGFR activation by TKI consequently generates the downregulation of IL-6. The biological rationale for therapeutic anti-IL-6 activity and preliminary clinical evidence which target anti-IL-6 antibodies are well tolerated in cancer patients, these findings provide the insight into a potential strategy for improving gefitinib anticancer efficacy and prolonging PFS by combining the anti-IL-6 agent with gefitinib.[42],[43] It has been reported that the serum TNF-α levels and IL-6 were found increased with the advanced stages of lung cancer suggesting a possible local production of inflammatory cytokines which is also in accordance with some previous studies.[44] The higher levels TNF-α and IL-6 were observed in smokers/ex-smokers as compared with nonsmokers lung cancer patient. Serum TNF-α and IL-6 levels are the promising biomarkers in the identification of lung cancer patients. The study is also supporting the association of inflammatory markers to lung cancer risk. Hence these findings suggest the levels of these biomarkers could be a useful tool for guiding the diagnosis of lung cancer.


 > Conclusion Top


EGFR mutation detection is a potentially useful tool to guide clinicians for personalized treatment of NSCLC patients. EGFR mutation status is the most valuable indicator for the screening of NSCLC patients for TKI therapy. The detection of EGFR mutation in NSCLC patients is helpful in the selection of targeted therapy. Serum TNF-α and IL-6 levels are the promising biomarkers in the identification of lung cancer patients. The study is also supporting the association of inflammatory markers to lung cancer risk. Hence, these findings suggest the levels of these biomarkers could be a useful tool for guiding the diagnosis of lung cancer.

Acknowledgment

We would like to thank the faculty and staff of the Department of Respiratory medicine, King George's Medical University, Lucknow for providing samples. The authors also would like to thank all the patients and their families for their cooperation and participation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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