Proinflammatory cytokines as serum biomarker in oral carcinoma—A prospective multi‐biomarker approach

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Oral squamous cell carcinoma (OSCC) is described as an aggressive epithelial neoplasm. Despite early detection and various treatments available, the overall survival rate of OSCC patients remains to be obviously low since the last decades.1 One of the reasons for these dissatisfying long‐term results may be that currently treatment decisions in these patients are guided by clinicopathological characteristics only. Although very important, these characteristics may not provide conclusive data considering the overall aggressiveness and recurrence potential of the tumor and the prognosis of the patient. Like most malign tumors, OSCC development is dependent on countless intracellular and intercellular transduction signals occurring in the tumor microenvironment between the heterogeneous tumor mass and the surrounding extracellular matrix.3 So far, diagnosis and clinical follow‐up of OSCC patients depends on physical examination and different imaging modalities. Specific or sensitive biomarkers are missing so far. Therefore, many patients are diagnosed late in the progression of the disease only. Obviously, clinically useful biomarkers are needed for early diagnosis and individual and specific treatment of this complex disease.
There is clear evidence that inflammation and cell‐mediated immunity have a key role in different stages of OSCC carcinogenesis. Proinflammatory cytokines such as interleukin‐6 (IL‐6), interleukin‐8 (IL‐8), soluble interleukin‐2 receptor (sIL‐2R), tumor necrosis factor alpha (TNF‐α), and MHC class I polypeptide‐related sequence B (MICB) feature the initiation and maintenance of inflammatory and immune responses as well as intercellular cross‐talking.4 IL‐6 is a multi‐functional cytokine that regulates differentiation and growth factor release of numerous cells like B and T lymphocytes and endothelial cells.7 IL‐8 is described as the prototype of the chemokine family and is released by neutrophils and macrophages in response to different stimuli.8 Serum levels of IL‐6 and IL‐8 have been studied in different types of head and neck cancer with contradictory results.9 sIL‐2R is the soluble form of the Interleukin‐2 receptor (IL‐2R) and is expressed by activated lymphocytes.11 High levels of sIL‐2R are a sign of general immune activation. As sIL‐2R can be measured quite easily in serum, sIL‐2R is an important monitoring index which can describe the cellular immunity function.12 Clinical studies showed a correlation between sIL‐2R levels and clinical parameters of different cancers.13 TNF‐α was described as an endogenous promotor of cancer via activation of NF‐kB transcriptional factor and is expressed by different tumor cells.14 Clinical studies showed that high levels of plasma TNF‐α influence survival in patients with head and neck cancer.15 A vital genetic component of the humane cellular immune response is the human leukocyte antigen (HLA) system.16 Within the HLA region, which is located on chromosome 6p21.3 lies the major histocompatibility complex (MHC) class I chain‐related (MIC) gene family.16 One of the 5 family members is MHC class I polypeptide‐related sequence B (MICB), which is a stress‐inducible, highly polymorphic natural killer group 2D (NKG2D) ligand.18 Its concentration is raised in virally infected and neoplastically transformed cells.18 Soluble MICB expressed by cancer cells down‐regulates NKG2D surface expression and conducts to a functional impairment of tumor antigen‐specific cytotoxic lymphocytes.17 Preliminary studies suggest that soluble MICB may play a critical role in tumor immune evasion.17 Recently, clinical studies indicated that MICB might decline cancer immunogenicity by reducing NKG2D ligand densities on malignant cells.17
As the evasion by tumor cells of immune surveillance is described as a major step in oncogenesis, tumor immunity is increasingly a target of research.20 Studies assessing serum levels of proinflammatory growth factors and cytokines are limited, especially in patients with premalignant lesions where early diagnosis would be precious.
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