Relationship between inflammation and cancer progression: Recent advances in interleukin-6 signaling and its blockage in cancer therapy

Interleukin-6 (IL-6) is a well-known pro-inflammatory cytokine with pleiotropic bioactivity and is mainly produced by inflammatory cells. Several diseases are influenced by IL-6; thus, the anti-IL-6 receptor antibody has been used clinically e.g., in the treatment of rheumatoid disease and Castleman disease. Signal transduction through gp130 occurs primarily via the JAK/STAT pathway and secondarily via the PI3K and MAPK pathways. Activation of STAT3 is an important step for the expression of various genes associated with carcinogenesis and cancer progression. Experiments using STAT3 inhibitor and IL-6 shRNA have shown that the activation of STAT3 is necessary for cancer cell proliferation and survival. Several studies have also demonstrated that IL-6 exhibits characteristics associated with both inflammatory cytokines and proangiogenic factors. These studies have demonstrated that IL-6 contributes to angiogenesis as a potent inducer of VEGF, which is one of the most important angiogenic factors. Recently, it has also been reported that cancer–stromal interactions are necessary steps during cancer progression, such as during angiogenesis. These mechanisms of IL-6, which affect cancer cells directly and through cancer–stromal interactions are essential for cancer progression and are of various types. Therefore, increasing attention is being paid to IL-6 signaling as a novel cancer therapeutic approach. This review summarizes the role of IL-6 signaling from the viewpoint of cancer progression and the potency of the anti-IL-6 signaling antibody during cancer therapy

Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth

Cancer tissues are composed of cancer cells and the surrounding stromal cells (e.g., fibroblasts, vascular endothelial cells, and immune cells), in addition to the extracellular matrix. Most studies investigating carcinogenesis and the progression, invasion, metastasis, and angiogenesis of cancer have focused on alterations in cancer cells, including genetic and epigenetic changes. Recently, interactions between cancer cells and the stroma have attracted considerable attention, and increasing evidence has accumulated on this. Several researchers have gradually clarified the origins, features, and roles of cancer-associated fibroblasts (CAFs), a major component of the cancer stroma. CAFs function in a similar manner to myofibroblasts during wound healing. We previously reported the relationship between CAFs and angiogenesis. Interleukin-6 (IL-6), a multifunctional cytokine, plays a central role in regulating inflammatory and immune responses, and important roles in the progression, including proliferation, migration, and angiogenesis, of several cancers. We showed that CAFs are an important IL-6 source and that anti-IL-6 receptor antibody suppressed angiogenesis and inhibited tumor-stroma interactions. Furthermore, CAFs contribute to drug-resistance acquisition in cancer cells. The interaction between cancer cells and the stroma could be a potential target for anti-cancer therapy

Preoperative Serum Interleukin-6 Is a Potential Prognostic Factor for Colorectal Cancer, including Stage II Patients

Aims. To evaluate the prognostic significance of serum interleukin-6 (IL-6) in colorectal cancer (CRC). Patients and Methods. Preoperative serum IL-6 was measured in 233 CRC patients and 13 healthy controls. Relationships between IL-6 and various clinicopathological factors were evaluated, and the overall survival (OS) and disease-free survival (DFS) rates according to IL-6 status were calculated for all patients and according to disease stage. Results. The mean IL-6 level was 6.6 pg/mL in CRC patients and 2.6 pg/mL in healthy controls. Using a cutoff of 6.3 pg/mL, obtained using receiver operating characteristic curve analysis, 57 patients had a high IL-6 level. The mean value was higher for stage II disease than for stage III disease. IL-6 status correlated with C-reactive protein (CRP) and carcinoembryonic antigen levels, obstruction, and pT4 disease. The OS differed according to the IL-6 status for all patients, whereas the DFS differed for all patients and for those with stage II disease. The Cox proportional hazards model showed that pT4 disease was an independent risk factor for recurrence in all CRC patients; IL-6, CRP, and pT4 were significant risk factors in stage II patients. Conclusions. The preoperative IL-6 level influences the risk of CRC recurrence

The role of initial neck dissection for patients with node-positive oropharyngeal squamous cell carcinomas

Background: The current study sought to assess the role of initial neck dissection (ND) for patients with node-positive oropharyngeal squamous cell carcinomas (OPSCC). Methods: The data for 202 patients with previously untreated node-positive OPSCC were gathered from 12 institutions belonging to the Head and Neck Cancer Study Group in the Japan Clinical Oncology Group. These patients were categorized into two groups, consisting of the initial ND group and the wait-and-see group, according to treatment policy. Results: Regional recurrence was observed in 17 of 93 patients undergoing initial ND, whereas, recurrent or persistent diseases were observed in 40 of 109 patients who did not undergo initial ND. The 4-year overall survival rates (OS) for the wait-and-see group and initial ND groups were 74.0% and 78.7%, respectively, and the 4-year regional control rates (RC) for each group were 77.6% and 84.9%. There were no significant differences in either OS or RC (p = 0.3440 and p = 0.2382, respectively). However, for patients with N3 disease, the 4-year OS of the initial ND group (100%) was favorable. For patients with N2a disease, the 4-year RC of the initial ND group was higher than that of the wait-and-see group statistically (100% vs 62.5%, p = 0.0156). Conclusions: The role of initial ND was limited in patients with node-positive OPSCC. The treatment strategy not involving initial ND is considered feasible and acceptable when nodal evaluation after definitive radiotherapy or chemoradiotherapy is applied adequately. However, it is possible that initial ND improves outcomes in patients with resectable large-volume nodal disease. (C) 2014 Elsevier Ltd. All rights reserved

A case of condyloma acuminatum of the bladder concurrently diagnosed with urothelial carcinoma

Introduction Condyloma acuminatum usually occurs in the external genitalia and rarely in the bladder mucosa. Here, we report a case of condyloma acuminatum of the bladder that was detected concurrently with urothelial carcinoma. Case presentation A 42‐year‐old man was referred to our urology department with positive urine cytology for urothelial carcinoma. Cystoscopy revealed a broad‐base nonpapillary bladder tumor. The patient underwent a transurethral resection of the bladder tumor. Pathological examination revealed urothelial carcinoma, high‐grade pT1, and concurrent resection of condyloma acuminatum. DNA was extracted from the paraffin‐embedded transurethral resection of the bladder tumor tissue specimens. HPV11 was detected in condylomas by PCR and in situ hybridization, whereas HPV was not detected in urothelial carcinomas. Conclusion We report a rare case of condyloma acuminatum of the bladder that was concurrently diagnosed with urothelial carcinoma from the same site

Renal function and oropharyngeal cancer

BACKGROUND: Renal function influences decisions regarding treatment for patients with squamous cell carcinoma of the oropharynx (SCC-OP). However, the importance of renal function in SCC-OP has not yet been reported. METHODS: Four hundred and sixty patients with SCC-OP treated with curative intent between April 2005 and March 2007 in 12 institutions in Japan were analyzed retrospectively. RESULTS: Four hundred and three patients (87.6%) showed a Ccr ≥50 mL/min and 57 (12.4%) a Ccr <50 mL/min. Age was associated with worse overall survival (OS), while stage IVB, radiotherapy, and Ccr<50 were associated with worse OS on univariate analyses. Surgery and hypertension were associated with better OS on univariate analyses. On multivariate analysis, age, stage, hypertension, and Ccr were also found to be significantly associated with OS. CONCLUSIONS: Based on this retrospective study, impaired renal function is an independent predictor of increased risk of death in patients with SCC-OP