Upregulated interleukin‐6 expression contributes to erlotinib resistance in head and neck squamous cell carcinoma

Despite the role of epidermal growth factor receptor (EGFR) signaling in head and neck squamous cell carcinoma (HNSCC) development and progression, clinical trials involving EGFR tyrosine kinase inhibitors (TKIs) have yielded poor results in HNSCC patients. Mechanisms of acquired resistance to the EGFR TKI erlotinib was investigated by developing erlotinib‐resistant HNSCC cell lines and comparing their gene expression profiles with their parental erlotinib‐sensitive HNSCC cell lines using microarray analyses and subsequent pathway and network analyses. Erlotinib‐resistant HNSCC cells displayed a significant upregulation in immune response and inflammatory pathways compared to parental cells. Interleukin‐6 (IL‐6) was one of thirteen genes that was significantly differentially expressed in all erlotinib‐resistant HNSCC cell lines, which was validated using RT‐PCR and ELISA. Blockade of IL‐6 signaling using the IL‐6 receptor antagonist tocilizumab, was able to overcome erlotinib‐resistance in erlotinib‐resistant SQ20B tumors in vivo. Overall, erlotinib‐resistant HNSCC cells display elevated IL‐6 expression levels compared to erlotinib‐sensitive HNSCC cells and blockade of the IL‐6 signaling pathway may be an effective strategy to overcome resistance to erlotinib and possibly other EGFR TKIs for HNSCC therapy.     

Association of α1 acidic glycoprotein and squamous cell carcinoma of the head and neck

Serum from patients with different malignancies contain an abnormal concentration of a a1-acidic-glycoprotein (AAG) and also, increased levels of AAG are associated with the presence of tumor mass. In the present report, serum levels of AAG were measured by radial immunodiffusion in squamous cell carcinoma of the head and neck (SCCHN) patients taking into account disease status parameters such as tumor localization, stage and extension of disease. Immunohistochemical methods, SDS-PAGE and Western-blotting were employed to study the expression of AAG and a carbohydrate related antigen (sialyl Lewis x) in tumor tissues and derived fractions. AAG showed abnormal levels in 7/15 oral cavity tumor patients sera, 2/5 oropharynx and 5/10 larynx tumors; increased AAG serum levels belonged to patients with disseminated disease. On the other hand, the presence of AAG and sialyl Lewis x were demonstrated in carcinoma cells and in derived fractions from tumor tissues belonging to patients with elevated AAG serum levels. In the present study, we have found elevated levels of AAG in serum samples from SCCHN patients; these neoplastic cells are capable to express AAG.     

Integration of taxanes into primary chemotherapy for squamous cell carcinoma of the head and neck: promise fulfilled?

Chemotherapy has become integrated into the treatment of head and neck cancer in not only the palliative but now also the primary setting. Organ preservation is possible using induction chemotherapy, and improved survival results have been confirmed for concomitant chemoradiotherapy. The taxanes, paclitaxel and docetaxel, appear to be as active as any other drugs in head and neck cancer. When used in combination in the induction, recurrent, or metastatic settings, response rates rival those of the standard cisplatin/5-fluorouracil regimen. At least one ongoing study will help to establish superiority of cisplatin/paclitaxel versus cisplatin/5-fluorouracil in the recurrent or metastatic setting, and another between cisplatin/5-fluorouracil and doctaxel/cisplatin/5-fluorouracil in the induction setting. Both paclitaxel and docetaxel are being extensively studied as radiosensitizers. They are relatively well tolerated and have good efficacy but have not yet been adequately studied in comparison with other regimens. In conclusion, the taxanes have significantly expanded our effective treatment options in both the primary and recurrent or metastatic settings.     

Fludarabine: risk factor for aggressive behaviour of squamous cell carcinoma of the skin?

Fludarabine, a purine analogue, is effective in the therapyof low-grade non-Hodgkin's lymphomas. Side-effects include fever,peripheral neuropathy, pulmonary toxicity and significant depletionof T-lymphocyte populations. In addition, flare up and aggressivebehaviour of squamous cell carcinoma (SCC) during fludarabinetherapy has been observed [1]. We report on a     

ACR appropriateness criteria® adjuvant therapy for resected squamous cell carcinoma of the head and neck

Locoregional recurrence following surgical resection alone for stage III/IV head and neck cancer is common. Adjuvant radiotherapy has been shown to improve post-operative locoregional control when compared to pre-operative radiotherapy for head and neck cancers. Following surgical resection, adverse pathological features determine the need for adjuvant therapy. High-risk pathologic features include extranodal tumor spread and involved surgical margins. Other adverse pathologic features include T 3-4 tumors, perineural invasion, lymphovascular space invasion, low neck adenopathy, and multiple tumor involved cervical lymph nodes. The standard adjuvant therapies are post-operative radiation therapy or post-operative chemoradiotherapy. Post-operative chemoradiotherapy yields superior locoregional control, progression-free survival, and in some studies, overall survival compared to post-operative radiotherapy for high-risk patients in multiple randomized studies. Pooled analyses of randomized data demonstrate that post-operative concurrent chemoradiotherapy is associated with overall survival benefits for patients with involved surgical margins as well as those with extranodal tumor spread. Post-operative radiotherapy concurrent with cisplatin at 100 mg/m(2) every 21 days is the current standard chemoradiotherapy platform adjuvant head and neck cancer treatment. Post-operative radiotherapy and post-operative chemoradiotherapy radiation treatment volumes are not standardized and should be designed based on the risk of recurrence and clinically occult involvement of head and neck subsites and nodal regions. Evidence supports a post-operative radiotherapy and chemoradiotherapy radiation dose of at least 63 Gy for high-risk patients and at least 57 Gy for low risk patients.     

Loss of TGF-β signaling and PTEN promotes head and neck squamous cell carcinoma through cellular senescence evasion and cancer-related inflammation

The molecular mechanisms that contribute to the initiation and progression of head and neck squamous cell carcinoma (HNSCC) have not been completely delineated. Our observations indicate that defects in the transforming growth factor-β and PI3K/Akt signaling pathways are common in human HNSCCs. Conditional activation of the PI3K/Akt pathway due to Pten deletion in the mouse head and neck epithelia gives rise to hyperproliferation, but only a few lesions progress to HNSCC. However, Pten-deficient mice developed full-penetrance HNSCC in combination with type I TGF-β receptor (Tgfbr1) deletion. Molecular analysis revealed enhanced cell proliferation, decreased apoptosis, and increased expression of CCND1 in the basal layer of the head and neck epithelia, as well as in the tumors of Tgfbr1/Pten double conditional knockout (2cKO) mice. Furthermore, neoplastic transformation involves senescence evasion, and is associated with an increased number of putative cancer stem cells. In addition, the nuclear factor-κB pathway activation, myeloid-derived suppressor cell infiltration, angiogenesis and immune suppression in the tumor microenvironment, all of which are characteristics of human HNSCCs, contribute significantly to head and neck carcinogenesis in 2cKO mice. These tumors display pathology and multiple molecular alterations resembling human HNSCCs. This suggests that the Tgfbr1/Pten 2cKO mouse model is suitable for preclinical intervention, and that it has significant implications in the development of diagnostic cancer biomarkers and effective strategies for prevention and treatment of HNSCCs.     

Efficacy and safety of apatinib treatment for advanced progressive head and neck squamous cell carcinoma北大核心CSCD

Objective: To evaluate the efficacy and safety of apatinib combined with individualized chemoradiotherapy for advanced progressive head and neck squamous cell carcinoma (HNSCC). Methods: A retrospectively analysis was performed by using the clinical data of 44 patients with advanced progressive HNSCC who were admitted in the First Affiliated Hospital of Zhengzhou University from 2017 to 2018. All patients were treated with apatinib 500 mg once a day until the disease progressed. During the treatment period, if the patient was intolerant to the toxicity of the drug, the dose of apatinib was reduced to 250 mg once a day. At the same time, all patients were treated with individualized radiotherapy or chemotherapy. Intensity modulated radiation therapy (IMRT) was used for the recurrent or metastatic lesions. The chemotherapy regimen was synchronous platinum + fluorouracil or paclitaxel + platinum or paclitaxel + fluorouracil + platinum. The clinical efficacy and adverse reactions were observed. Results: Among 44 patients with advanced progressive HNSCC, there was no complete remission, 9 (20.45%) patients with partial remission, 22 (50.00%) patients with stable disease, and 13 (29.55%) patients with disease progression. The objective response rate was 20.45%, the disease control rate was 70.45%, and the median progression-free time was 5 months (95% confidence interval: 3.26-6.74). All patients were well tolerated to apatinib without any grade 3 or 4 adverse events. The most common adverse reactions were oral ulcers in 29 (65.91%) cases, liver function abnormalities in 16 (36.36%) cases, and headache in 13 (29.55%) cases. Conclusion: The application of apatinib combind with individualized radiotherapy or chemotherapy for the patients with advanced progressive HNSCC is feasible, and its safety is controllable. © 2019 by TUMOR All rights reserved.     

NF-κB participates in chemokine receptor 7-mediated cell survival in metastatic squamous cell carcinoma of the head and neck

Metastatic squamous cell carcinoma of the head and neck (SCCHN) has been shown to express chemokine receptor 7 (CCR7), which activates phosphoinositide-3 kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signal pathway to promote the invasion and survival of SCCHN cells. Since nuclear factor-kappa B (NF-κB) is shown to be the downstream signal molecule of PI3K/Akt in many tumors, we investigated whether it also exists in the CCR7 pathway in SCCHN, and the relationship between NF-κB and PI3K/Akt/mTOR, and the role it plays in SCCHN. We assayed the phosphorylation of the inhibitor of NF-κB (IκBα), the NF-κB DNA-binding capacity and location. The results showed that the interaction between CCR7 and the ligand for CCR7, CCL19, induces phosphorylation of IκBα, causes NF-κB to translocate to the nucleus and raises the DNA-binding capacity of NF-κB. The phosphorylation and DNA-binding capacity were abolished by the inhibition of CCR7, PI3K, Akt and mTOR. Further research demonstrated that inhibitors of NF-κB and CCR7-PI3K attenuate the survival of CCR7-mediated cells, causing decreased viability, increased apoptosis and increased cell cycle arrest in SCCHN cells. In clinical samples from 78 patients, immunohistochemical assay also showed that CCR7 and NF-κB are not only highly expressed in SCCHN, but also correlated with each other, and related to lymph node metastasis and clinical stage. Together, our data indicate that NF-κB is activated by CCR7 via PI3K/Akt/mTOR, and this signal pathway plays an important role in regulating the cell survival and prognosis of SCCHN.     

Can gene expression profiling predict survival for patients with squamous cell carcinoma of the lung?

Background  

Lung cancer remains to be the leading cause of cancer death worldwide. Patients with similar lung cancer may experience quite different clinical outcomes. Reliable molecular prognostic markers are needed to characterize the disparity. In order to identify the genes responsible for the aggressiveness of squamous cell carcinoma of the lung, we applied DNA microarray technology to a case control study. Fifteen patients with surgically treated stage I squamous cell lung cancer were selected. Ten were one-to-one matched on tumour size and grade, age, gender, and smoking status; five died of lung cancer recurrence within 24 months (high-aggressive group), and five survived more than 54 months after surgery (low-aggressive group). Five additional tissues were included as test samples. Unsupervised and supervised approaches were used to explore the relationship among samples and identify differentially expressed genes. We also evaluated the gene markers' accuracy in segregating samples to their respective group. Functional gene networks for the significant genes were retrieved, and their association with survival was tested.     

Is E-cadherin immunoexpression a prognostic factor for head and neck squamous cell carcinoma (HNSCC)? A systematic review and meta-analysis

We summarized existing evidence about whether the aberrant E-cadherin expression is a prognostic factor for patients with HNSCC. Identifying relevant articles, filtrating studies and extracting data were independently conducted by two reviewers. The quality of eligible studies was assessed according to systematic score criteria. Associations between aberrant E-cadherin expression and overall survival (OS) or disease-free survival (DFS) were summarized by hazard ratio (HR) estimates. Random or fixed effects models were used to investigate the effect of E-cadherin across the studies. According to the multivariate and univariate analyses, the meta-analysis of the included studies gave a statistically significant pooled HR for OS in HNSCC [the pooled HR=2.533; 95% confidence interval (CI)=1.971-3.254]. In addition, the subgroup analyses showed that the pooled HR of each subgroup also exhibited statistical significance according to the subpopulations (Asian and other subpopulations), treatments (surgery and other treatments), locations of primary tumors (oral cavity and other subsites), and data sources of HR (reported and estimated HR). Similar to the results of OS, the analysis of four included trials showed that the aberrant E-cadherin expression could predict low DFS. Meanwhile, a cumulative meta-analysis showed that the pooled HR became statistically significant. However, a meta-regression analysis showed that the OS was not statistically significant with the cutoff values of the included studies. Our study gives an important piece of evidence that aberrant E-cadherin expression was associated with a poor prognosis in patients with HNSCC.     

Role of β-catenin in cisplatin resistance,relapse and prognosis of head and neck squamous cell carcinoma

Background

Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of cancer in India with high incidence and rapid recurrence rates. Here, we aimed to investigate the role of β-catenin, a developmental pathway gene, in HNSCC therapy resistance, DNA damage response, recurrence and prognosis.

Methods

In total 80 HNSCC samples were included. Western blot, immunohistochemistry and qRT-PCR analyses were performed to assess β-catenin expression in the cut margin and tumor areas of each sample. Kaplan-Meier analyses were performed to correlate β-catenin expression with the survival and prognosis of HNSCC patients. In addition, chemo-resistance, DNA damage response and DNA repair capacities were evaluated in HNSCC-derived cell lines through LiCl-mediated up-regulation and siRNA-mediated silencing of β-catenin expression.

Results

We observed β-catenin up-regulation in cut margin areas of recurrent patients compared to their corresponding tumor regions, which subsequently could be associated with poor prognosis. In addition, we found that LiCl-mediated up-regulation of β-catenin in HNSCC-derived cells led to cisplatin resistance, evasion of apoptosis, enhanced DNA repair and enhanced migration. The effects of β-catenin silencing correlated with its putative role in chemo-resistance and DNA damage response.

Conclusion

From our results we conclude that β-catenin may contribute to HNSCC therapy resistance and disease relapse. As such, β-catenin may be explored as a therapeutic target along with conventional therapeutics.