|Year : 2018 | Volume
| Issue : 10 | Page : 758-760
Clinical significance of interleukin-6 in diagnosis of lung, oral, esophageal, and gall bladder carcinomas
Anjali Vinocha, Rajesh K Grover, Rani Deepak
Department of Lab Medicine, Delhi State Cancer Institute, New Delhi, India
|Date of Web Publication||24-Sep-2018|
Department of Lab Medicine, Delhi State Cancer Institute, Dilshad Garden, New Delhi - 110 095
Source of Support: None, Conflict of Interest: None
Introduction: Chronic inflammation predisposes to cancer. Cytokines play an essential role in cancer pathogenesis. Interleukin-6 (IL-6) is a pleiotropic cytokine that enables growth and differentiation of tumors. The effects of IL-6 are mediated by signal transducers and activators of transcription 3 (STAT3). STAT3 deficiency reduced tumor incidence and growth while STAT3 hyperactivation has an opposite effect; also it negatively regulates p53 gene. IL-6/STAT3 signaling is crucial in carcinogenesis linked to inflammation. Increased IL-6 levels are observed in cancer. Studies investigating the role of IL-6 is limited.
Aim: This study aims at determining IL-6 levels in lung, oral, esophageal, and gallbladder cancer patients.
Materials and Methods: Subjects consisted of 175 patients with lung, oral, gall bladder, and esophageal cancers. The patients included 68 females and 107 males with an average age of 52 years. Fifty healthy individuals served as controls. IL-6 was detected by electrochemiluminescent immunoassay principle.
Results: IL-6 values were determined in 175 (21 lung, 55 oral, 17 esophageal and 82 gallbladder) cancer patients. Of these, 147/175 (18 lung, 43 oral, 13 esophageal and 73 gallbladder) cancer patients (84%) showed higher IL-6 levels as compared to control group (normal range: <7 pg/ml).
Conclusion: This indicates a significant correlation between IL-6 overexpression and cancer development, highlighting the significance of IL-6 in oral, lung, esophageal, and gallbladder carcinomas. IL-6 may be used as a tumor marker for cancer diagnosis. It may be a clinically significant predictor and may represent a target for cancer treatment. However, to definitely conclude this, further extensive studies would be required.
Keywords: Cancer, cytokines, electrochemiluminescent immunoassay, esophageal, gallbladder, inflammation, lung, oral, tumors
|How to cite this article:|
Vinocha A, Grover RK, Deepak R. Clinical significance of interleukin-6 in diagnosis of lung, oral, esophageal, and gall bladder carcinomas. J Can Res Ther 2018;14, Suppl S3:758-60
|How to cite this URL:|
Vinocha A, Grover RK, Deepak R. Clinical significance of interleukin-6 in diagnosis of lung, oral, esophageal, and gall bladder carcinomas. J Can Res Ther [serial online] 2018 [cited 2020 Oct 27];14:758-60. Available from: https://www.cancerjournal.net/text.asp?2018/14/10/758/183217
| > Introduction|| |
The presence of leukocytes within tumors provided the first indication of a possible link between inflammation and cancer. However, a role for inflammation in tumorigenesis is now widely accepted. It is evident that an inflammatory microenvironment is an essential component of all tumors. Only a minority of all cancers are caused by germline mutations, whereas vast majority (90%) are linked to somatic mutations and environmental factors.
Many environmental causes of cancer and risk factors are associated with some form of chronic inflammation. Up to 20% of cancers are linked to chronic infections, 30% may be attributed to cigarette smoking, tobacco smoking, and inhaled pollutants (such as silica and asbestos), and 35% are attributed to dietary factors.
The connection between inflammation and cancer can be thought of as consisting of two pathways: An extrinsic mechanism, where a constant inflammatory state contributes to increased cancer risk (such as inflammatory bowel disease); and an intrinsic mechanism, where acquired genetic alterations (such as activation of oncogenes) trigger tumor development. Both precancerous inflammation and inflammation stemming from genetic alteration can cause cell transformation and promote tumor progression. The former can increase the risk to cancer development while the latter is necessary to maintain and promote cancer progression. The roles and the relationship between the two pathways in the cancer development process depend on their specific interactions between genetic/epigenetic factors and environmental factors.
Chronic inflammation and cytokine dysregulation
Lung and oral cancers are mainly caused due to chronic inflammation caused by high carcinogen content in cigarette smoke and tobacco, respectively.
In esophageal carcinoma, chronic inflammation is triggered by repeated exposure to components of refluxate (gastric acid). Esophageal mucosa damaged by refluxate is commonly infiltrated by inflammatory cells of different lineages. First, the damaged site is infiltrated by neutrophils and monocytes (acute inflammation) followed by lymphocytes and plasma cells primarily at the site of metaplasia (chronic inflammation).
The persistent local inflammatory reactions may contribute to the development of gallbladder carcinoma through inducing genetic alterations, and subsequently promoting survival and proliferation of mutated cells, inhibiting apoptosis, stimulating angiogenesis, and metastasis.
A major regulatory pathway linking inflammation and cancer are the activation of nuclear factor κB (NF-κB) signaling, which initiates the transcription of cytokines. It has been reported that NF-κB is constitutively activated in esophageal carcinoma, but is not detected in esophagitis or the adjacent normal esophageal mucosa.
Cytokines are multi-functional polypeptides synthesized from various cell types of the human body. They have important roles in many processes, such as the development of humoral and cellular responses, triggering of the inflammatory response, regulation of hematopoiesis, supervision of cellular differentiation and reproduction, and wound healing. Interleukin-6 (IL-6) is a cytokine that has an important role in cellular differentiation and growth.
Cytokines play an essential role in cancer pathogenesis. Cytokines can modulate expression of tumor antigens, adhesion molecules, and production of immunosuppressive factors by tumor cells. It is plausible that the local cytokine microenvironment, acting on the tumor cell or the adjacent cells, can either block or facilitate tumor growth.
It has been postulated that pro-inflammatory cytokines may contribute to tumor progression by stimulating angiogenesis, invasion, and metastasis. Among them, IL-6 can initiate the innate immune response by inducing the acute phase of inflammation. Cytokines such as IL-6 are essential for life, but its constitutive overproduction is often involved in various diseases, which accounts for a negative regulatory mechanism in the IL-6 signaling system. IL-6 appears to be involved in malignant transformation, tumor progression, and tumor-associated cachexia in a wide spectrum of malignancies.
Interleukin-6 and cancer
IL-6 is a potent, pleiotropic Th2 cytokine that regulates immune defence response. Its release is triggered by tissue damage, trauma, infection, or other stress. IL-6 acts as both pro-inflammatory and anti-inflammatory cytokine. IL-6 plays a central role in the transition from the acute to the chronic phase of the inflammatory process. IL-6 pathway is one of the most important mechanisms linking inflammation to cancer.
The mechanisms leading to IL-6 induction and IL-6 presence in high concentrations in the serum of cancer patients include malignancy-related chronic stress and direct IL-6 production and secretion by tumor-associated macrophages, or the tumor cells themselves. IL-6 appears to enhance tumorigenesis by a paracrine or autocrine mechanism and to have an inhibitory effect on the anti-tumor immune response.
IL-6 overexpression is implicated in various cancers. IL-6 signaling involves the activation of the growth factor tyrosine kinase receptors ErbB2/neu and ErbB3, the Ras/mitogen-activating protein kinase pathway, the phosphoinositide 3-kinases/AKT signaling pathway as well as signal transducers, and activators of transcription 3 (STAT3) pathway.
It has been reported that the ablation of IL-6 reduces tumor burden while the elevation of IL-6 levels accelerates tumor formation. The effects of IL-6 are mediated by STAT3. As expected, STAT3 deficiency reduced tumor incidence and growth while STAT3 hyperactivation has an opposite effect. Studies clearly indicate that IL-6/STAT3 signaling is crucial in the carcinogenesis that is linked to inflammation.
One strategy used by cancer cells to upregulate growth and survival pathways is through autocrine production of growth and survival factors. IL-6 is produced by different cells, including immune cells, and epithelial cells. Expression of IL-6 by cancer cells suggests that IL-6 acts as an autocrine growth factor to promote tumorigenesis.
IL-6 is a crucial factor in tumorigenesis though STAT3 could be activated by other cytokines. Tumors choose IL-6 to constitutively activate STAT3 because immune cells together with malignant cells are capable of producing massive amounts of start-up IL-6 (but not other family members) required for tumor progression.
It has been reported that the IL-6 pretreatment concentrations reflected disease status and were commonly associated with metastatic spread in various cancers.
Metastasis of cancer is a complicated process that involves coordinated cellular effect and the response of both cancer and normal cells. Metastasis has several steps: (1) Invasion of the stroma, (2) intravasation of blood vessels, (3) transportation in vasculature, (4) adhesion and implantation to target capillaries, (5) extravasations from blood vessels, and (6) proliferation of secondary tumors. IL-6 has a role in steps 1 through 3 of cancer metastasis.
In this study, we aim at determining IL-6 levels in lung, oral, esophageal, and gall bladder cancer patients and compare their levels in the control group.
| > Materials and Methods|| |
The subjects in this study included 175 patients who have been diagnosed with lung, oral, esophageal, and gall bladder cancer [Table 1]. The patients included 68 females and 107 males with an average age of 52 years. Patient details have been documented in a detailed pro forma.
Fifty healthy individuals served as controls.
The study was approved by the Ethics Committee of the institution.
IL-6 detection was carried out by the electrochemiluminescent immunoassay principle. IL-6 detection kits were kindly provided by Roche Diagnostics. IL-6 detection was carried out on the ELECSYS 2010, Roche.
| > Results|| |
IL-6 values have been determined in 175 patients; of which, 84% patients showed significantly elevated IL-6 levels as compared to the control group (normal range: <7 pg/ml) [Table 1].
The mean serum IL-6 level in all the patients with oral, lung, gall bladder, and esophageal cancer were observed to be 993 pg/ml, 813 pg/ml, 960 pg/ml, and 381 pg/ml, respectively. Whereas the mean serum level in the control group was observed to be 3 pg/ml.
The average serum IL-6 level of the cancer patients was observed to be higher than that of the control group. This clearly indicates a significant positive correlation between IL-6 overexpression and cancer development.
| > Discussion|| |
IL-6 levels in cancer patients have been reported to be 2-fold to 10-fold higher as compared to the noncancer patients. In this study, IL-6 levels in lung, oral, esophageal, and gall bladder cancer patients were observed to be significantly higher than the control group.
This study helps us to move a step further in determining the clinical significance of IL-6 level as a tumor marker for the diagnosis of cancer patients in India. However, to definitely conclude this, further extensive studies would be required. Furthermore, the clinical significance of IL-6 needs to be compared with the utility of the existing tumor markers - carcinoembryonic antigen, carbohydrate antigen (CA) 19-9, and CA 72-4.
This paper is an attempt to contribute to the still inadequate investigation of the effects of IL-6 on cancer in Indian patients. Our data supports the emerging notion that IL-6 may be a clinically significant predictor and suggests that IL-6 may represent a suitable target for cancer treatment. We recommend further extensive investigations on the effects of IL-6 on follow-up, prognosis, and tumor growth to contribute to the understanding of its pathogenesis.
The authors are thankful to the technical staff, Mr. Pramod, Mr. Sonu, and Ms. Chanchal for their technical assistance in laboratory testing.
Financial support and sponsorship
The kits used in the study were provided by Roche Diagnostics.
Conflicts of interest
There are no conflicts of interest.
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