Increased expression of interleukin-6 predicts poor response to chemoradiotherapy and unfavorable prognosis in oral squamous cell carcinoma

Abstract

Recent studies have revealed that cancer cells are exacerbated by chronic inflammation. The present study examined the immunohistochemical expression for interleukin-6 (IL-6), a pleiotropic inflammatory cytokine, in oral squamous cell carcinoma (OSCC) to elucidate the association of IL-6 expression with tumor progression, chemoresistance and prognosis. Seventy-eight patients with primary OSCC were analyzed by immunohistochemical staining for IL-6. These labeling indexes (LIs) were calculated and evaluated in association with the clinicopathologic characteristics and prognosis in the OSCC patients. The patients were divided into three groups as follows: negative group = LI <5%; low IL-6 group = 5% ≤ LI <30%; high IL-6 group = LI ≥30%. The patient numbers of the negative, low and high expression groups were 24, 22 and 32, respectively. In the high IL-6 expression group, IL-6 receptor (IL-6R), phospho-signal tranducer and activator of transcription 3 (p-STAT3) were also detected in almost all the cancer cells. The prevalence of the cervical lymph node or the distant metastasis in the high expression group was significantly higher than those in the negative and low expression groups. Furthermore, the high expression group had a significantly poorer tumor response to the preoperative chemoradiotherapy and a more unfavourable prognosis than the negative and the low expression groups. Interestingly, IL-6, IL-6R and p-STAT3 were expressed in the residual cancer cells of all the patients in the high expression group with poor response to chemoradiotherapy. These results suggested that IL-6 signaling possibly is involved in the progression and treatment-resistance of OSCC and IL-6 expression in cancer cells could be a useful predictive factor of poor response to chemoradiotherapy and unfavorable prognosis.

Benefits of Multifaceted Chemopreventives in the Suppression of the Oral Squamous Cell Carcinoma (OSCC) Tumorigenic Phenotype

“…STAT3 in conjunction with IL-6 participates in an intracrine “feed forward” loop made possible by IL-6's reciprocal activation of STAT3 [13]. High OSCC tumor levels of IL-6 positively correlate with elevated intratumor pSTAT3 levels and a worse prognosis including higher rates of regional and distant metastases [15]. Furthermore, OSCC recurrences are accompanied by elevated serologic levels of IL-6, along with C-reactive protein and serum amyloid [16].…”

“…the vitamin A derivative fenretinide (4-HPR), the estrogen metabolite 2-methoxyestradiol (2-ME) and the humanized monoclonal antibody to the IL-6R receptor tocilizumab (TOC) to modulate OSCC cell gratuitous signaling and tumorigenesis. These agents possess complementary mechanisms of action that include induction of apoptosis (4-HPR, 2-ME) and differentiation (4-HPR), capacity to inhibit intracellular signaling proteins and invasion (4-HPR) and reduce IL-6-mediated signaling (TOC) [15, 21-25]. Corresponding studies on OSCC tumors (from which cell lines were isolated) provided corresponding in situ data while molecular modeling studies depicted 4-HPR-cell target interactions.…”

TG2 and NF-κB Signaling Coordinates the Survival of Mantle Cell Lymphoma Cells via IL6-Mediated Autophagy

“…Studies have reported the association of IL-6 expression with tumor progression, poor prognosis and chemotherapeutic resistance (34–36). Targeting IL-6 has been regarded as an adjuvant therapy for human cancers (37,38).…”

Matrix metalloproteinase (MMP) and immunosuppressive biomarker profiles of seven head and neck squamous cell carcinoma (HNSCC) cell lines

“…IL-6 is involved in inflammatory processes indicative of tumor proliferation, but it also has immunosuppressive effects on dendritic cells by preventing dendritic cell maturation (29,30). High expression of IL-6 in OSCC cells has been suggested as a predictive factor of poor response to chemoradiotherapy (31). The anti-inflammatory cytokine IL-1RA, which competes with IL-1β by binding to the IL-1 receptor, is also found in elevated levels in the saliva of patients with OSCC (32).…”