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PubMed2005

Dendritic cells and HNSCC: a potential treatment option? (Review).

Patient survival in head and neck squamous cell cancer (HNSCC) has not changed significantly in many years, despite progress in surgical, radiotherapy and chemotherapy techniques. Immunotherapy, a rapidly progressing alternative cancer treatment, aims to prompt or assist the body's immune system to combat the disease itself. A number of strategies exist including the use of dendritic cells, natural antigen presenting cells capable of stimulating an anti-tumor immune response. Encouraging work has been performed using these cells as vaccines against a number of tumors especially melanoma. Work with head and neck cancer is also encouraging, but less advanced. Dendritic cell presence in head and neck squamous cell cancers is associated with an improved prognosis, however due to immunosuppression, the exact mechanism of which remains poorly understood, these cells do not function efficiently. This prevents the stimulation of an effective anti-tumor immune response by the patient and allows tumor growth to continue. This review summarises the current level of understanding of dendritic cells and their relationship with HNSCC. It briefly summarises work with dendritic cells and other cancers where relevant to HNSCC; dendritic cells and head and neck cancer; the possible causes of dendritic cell impairment; the techniques used to restore their function and the methods used to prime the dendritic cells prior to their use as vaccines for the stimulation of an anti-tumor response.

Antigen Presentation↗
PubMedDate not supplied

Carcinogen metabolism, DNA damage repair and oral head and neck squamocellular carcinoma (HNSCC). A review.

Head and neck squamocellular carcinoma (HNSCC) has now become the 6th most common cancer among men in the developed world and affects the oral cavity, salivary glands, larynx and pharynx. Tobacco chewing, alcohol consumption and last but not least, smoking seem to be the most important risk factors. In particular in non-drinkers, smoke increases the relative risk (RR) of developing HNSCC of the oral cavity and pharynx from 2 to 20 fold; especially in the oral cavity, the association between alcohol and smoke could have a multiplier effect. Cancer arises from damage to DNA of genes located at various points of the short (p) and long (q) arms of a number of chromosomes, caused by exposure to various carcinogens. Thus, the carcinogenic process requires continuous exposure to environmental carcinogens (i.e., longstanding history of smoking and drinking), an increased susceptibility to carcinogens (induced by xenobiotic metabolizing enzyme polymorphism) and an impaired DNA repair capacity (both inherited and acquired). Our purpose in this paper is to review advances in the understanding of the role of the European or Caucasian genetic aberrations that affect carcinogen metabolism and DNA repair genes in oral HNSCC development: we consider that those abnormalities will be useful in assessing individuals at risk.

Carcinogens↗
PubMed2005

[Antiangiogenic and anti-immunosuppressive therapeutic strategies in human head and neck squamous cell carcinoma (HNSCC)].

BACKGROUND: Angiogenesis and tumor-associated immunosuppression are two of the hallmarks of carcinogenesis. In previous studies we demonstrated in vitro that HNSCC tumor cells attract monocytes via monocyte chemotactic protein-1 (MCP-1) and activate them via transforming growth factor-beta 1(TGF-beta1) to secrete interleukin (IL)-1alpha, which in turn stimulates tumor cells to secrete increased levels of the angiogenic and immunosuppressive vascular endothelial growth factor (VEGF). These findings suggest that interaction between the immune system and VEGF-mediated angiogenesis is important for progression of HNSCC. Recent studies in vitro show that retinoic acid (RA) downregulates the release of MCP-1 and TGF-beta1 by tumor cells. Therefore, we investigated the ability of RA to modulate the ability of tumor cells to recruit and activate monocytes for participation in VEGF-mediated angiogenesis and immunosuppression in vivo. MATERIAL AND METHODS: Mice (ten/group) were injected daily with RA (160 microg/kg) for 3 weeks. After that time mice were sacrificed, and paraffin sections of tumors were obtained and stained for VEGF-A, CD68, and PECAM (CD31) by immunohistochemistry. The lungs, liver, and myocardium were analyzed for macro- and micrometastases. The plasma protein levels of VEGF-A and MCP-1 were determined by ELISA. RESULTS: In RA-treated mice tumors regressed completely and RA prevented metastases (p=0.00) and macrophage infiltration (p=0.007). Treated mice downregulated VEGF-A (0 pg/ml) and MCP-1 (12 pg/ml) in peripheral blood (p=0.001). CONCLUSION: Our findings suggest a new therapeutic possibility: the development of treatment protocols that can block each of the ways in which tumors induce new blood vessel growth and immunosuppression of the host.

Angiogenesis Inhibitors↗
PubMed2006

Meta-analysis of the prognostic significance of perinodal spread in head and neck squamous cell carcinomas (HNSCC) patients.

To assess the risk factor of capsular rupture for individual prognosis and potential therapeutic decision making, the present meta-analysis elaborated the prognostic significance of perinodal spread in a large group of patients suffering from head and neck squamous cell carcinomas (HNSCC). A review of the published literature was conducted, and fixed and random effects models were applied for estimation of the summarised odds ratio and 95% confidence intervals, including a test for homogeneity of the odds ratios. Study methodology allowed the enrollment of only nine studies of 115 published papers. Excluded studies lacked regarding primary tumour location, number and location of lymph node metastases, values on five-year survival, or adequate follow-up data. A summarised odds ratio of 2.7 leads to the conclusion that perinodal spread negatively impacts the five-year survival. The lower confidence limit of more than 2 also supports the concept that perinodal spread significantly reduces (doubled risk) the five-year-survival. These results support the conclusion that perinodal spread is a significant adverse risk factor for survival in patients with HNSCC.

Carcinoma, Squamous Cell↗
PubMed2006

Treatment of HNSCC cell lines with the EGFR-specific inhibitor cetuximab (Erbitux) results in paradox phosphorylation of tyrosine 1173 in the receptor.

Overexpression of the epidermal growth factor receptor (EGFR, ErbB1, HER1) is frequent in head and neck squamous cell carcinomas (HNSCCs) and correlates with disease progression. Inhibition of EGFR with the kinase inhibitor AG1478 abolished receptor phosphorylation and reduced cell proliferation. However, treatment of HNSCC cells with cetuximab (Erbitux), a monoclonal antibody designed to block the EGFR ligand binding site, led to paradox EGFR activation due to hyperphosphorylation of tyrosine 1173, however, with a concomitant reduction in Erk1/2 phosphorylation levels. No pronounced influence on cell proliferation levels could be observed after treatment with this antibody. Since cetuximab appears able to activate EGFR in HNSCC cell lines, it is necessary to rethink the exact mechanisms by which cetuximab that recently was approved for the treatment of advanced head and neck cancer, inhibits tumor growth.

Antibodies, Monoclonal↗
PubMed2005

Prognostic relevance of CD105+ microvessel density in HNSCC patient outcome.

Angiogenesis is essential for the development and progression of malignant tumours, and there is increasing evidence that microvessel density (MVD) can be considered an indirect marker of neo-angiogenesis. However, there is still disagreement concerning the clinical relevance and prognostic significance of MVD in head and neck squamous cell carcinomas (HNSCCs). MVD was evaluated in 127 HNSCC patients by means of immunohistochemistry using monoclonal antibodies (mAbs) against CD34 and CD105 (endoglin), which has recently been described as a potent marker of neo-vascularisation in various malignancies. MVD was expressed as the mean number of vessels/mm2. The mean CD34+ and CD105+ MVD values were significantly higher in T3-T4 tumours and those in an advanced clinical stage; furthermore, CD105+ MVD was significantly higher in N+ tumours. The patients with a high CD105+ MVD had a significantly shorter disease-free and overall survival; CD34+ MVD was not associated with survival. Similarly, in the subset of lymph-node negative patients, higher CD105+ MVD values were significantly associated with either OS and DFS. Multivariate analysis showed that a high CD105+ MVD was the only independent marker of tumour recurrence or death. Our data suggest that CD105+ MVD may represent an additional prognostic factor in HNSCC patients providing more accurate data for the determination of prognosis and management in the subset of lymph node negative patients.

Adult↗
PubMed2005

Amplification of Cyclin L1 is associated with lymph node metastases in head and neck squamous cell carcinoma (HNSCC).

Overrepresentation of chromosomal bands 3q25-q29 has been associated with shortened disease-specific survival in head and neck squamous cell carcinoma (HNSCC). To assess the prevalence of copy number gains (>4 signals per cell) and high-level amplifications (>8 signals per cell) from putative oncogenes in this chromosomal region (CCNL1, SNO, PIK3CA, TP73L), tissue microarray analysis was applied on 280 HNSCCs by fluorescence in situ hybridization. Overall frequency of additional copy numbers was 34.3% for CCNL1, 31.8% for SNO, 39.0% for PIK3CA and 38.3% for TP73L, respectively. In general, gains were more frequently detected in stage IV compared to stage I-III tumours. Performing multivariate logistic regression analysis, a significant association of CCNL1 gains and the presence of lymph node metastases was found, which was independent of anatomical site and T-stage of the primary tumour (P=0.049). Site-specific subgroup analysis further showed that copy number gains of CCNL1 and SNO occurred more frequently in oral carcinomas in advanced clinical stages as compared to N0 oral lesions (CCNL1: P=0.03; SNO: P=0.03). Finally, Kaplan-Meier analysis revealed that high-level amplifications of CCNL1 correlated with shorter overall survival of the patients. Our results indicate that CCNL1 plays a critical role in the loco-regional progression of HNSCC and may serve as an indicator for occult advanced tumour stages.

Biomarkers, Tumor↗
PubMedDate not supplied

Integrins in head and neck squamous cell carcinoma (HNSCC): a review of the current literature.

Integrins are a family of adhesion molecules performing a major role in multiple cellular functions. Their contribution in carcinogenesis and metastatic process are the object of intense research activity worldwide during the last decades. This review focuses on the existing knowledge about integrin expression in head and neck squamous cell carcinoma (HNSCC) as it has been acquired mainly by immunohistochemical methods and by in vitro assays. The elucidation of the exact role of integrins and the study of expressive alterations of these molecules in cancer cells, may result in novel therapeutical approaches for useful applications in the clinical routine of HNSCC in the future.

Carcinoma, Squamous Cell↗
PubMed2001

Molecular biomarkers in HNSCC: prognostic and therapeutic implications.

The prognosis of squamous cell carcinoma of head and neck (HNSCC) is influenced by many factors, such as performance status, TNM staging and pathological grading of differentiation. However, these factors are not sufficient for predicting outcome. Therefore, recent research has focused on the identification of molecular biomarkers. These markers help to stage patients in more meaningful prognostic groups and identify high-risk patients who may benefit from a more aggressive treatment approach. They also identify patients who are resistant to radiotherapy or chemotherapy, potentially avoiding the morbidity and cost of ineffective therapies. They can also identify patients with a high risk of recurrence who may benefit from chemoprevention. Finally, these markers may serve as targets for novel therapies, which would eventually change the outcome of HNSCC.

Biomarkers, Tumor↗
PubMed2005

Dual role of VEGF family members in the pathogenesis of head and neck cancer (HNSCC): possible link between angiogenesis and immune tolerance.

BACKGROUND: Antigen presenting cells, in particular dendritic cells (DCs), are critical elements in antitumor immunity induction. Some of the angiogenic factors released by tumor and stroma cells, including vascular endothelial growth factor (VEGF), are thought to affect DC function. MATERIAL/METHODS: The expression of Vascular Endothelial Growth Factor (VEGF) isoforms VEGF-A (121, 145,165, 189, 206), VEGF-C and VEGF-D were determined by immunohistochemistry, Western blotting and ELISA in 46 patients with Head and Neck Squamous Cell Carcinoma (HNSCC), 30 healthy donors, and two HNSCC tumor cell lines (PCI-1 and PCI-13). RESULTS: Increased expression of VEGF-A and VEGF-C was found in tumor tissues compared to normal epithelium (P=0.001). However, VEGF-D levels were decreased in patients with cervical nodal metastasis as compared to patients with negative lymph node status. VEGF-A plasma levels were increased in patients with lymph node metastasis (266 pg/ml) compared to patients with negative lymph node status (19.8 pg/ml). Multivariate analysis demonstrated that VEGF-A correlated with microvessel density (P=0.01), disease progression (P=0.038), a reduced number of local and peripheral mature dendritic cells (DC) (P=0.015) and an increased number of peripheral immature DCs (P=0.05). DCs incubated with tumor supernatant or VEGF-A differentiated into immature DCs and did not develop full allostimulatory activity. Allogenic T cells, when co-cultured with these immature DCs, expressed the T regulatory cell marker CD25, CTLA-4, and CD45Ro, and secreted TGF-beta, VEGF-A and IL-10. CONCLUSIONS: Taken together, our results identify VEGF-A as a multifunctional factor involved in angiogenesis, tumor progression, immunosuppression and immune tolerance.

Adult↗
PubMed2026

Regulation of the lncRNA NEAT1 by p53-ΔNp63 crosstalk modulates the DNA damage response and therapeutic efficacy in HNSCC.

Head and neck squamous cell carcinomas (HNSCCs) are characterized by recurrent genetic alterations, including the inactivation of the tumor suppressor TP53 gene and dysregulation of the TP63 gene. The TP63 gene encodes multiple isoforms, among which the N-terminal truncated isoform ΔNp63 is fundamental for the integrity of stratified epithelial tissues. We previously demonstrated that ΔNp63 represses the expression of the lncRNA NEAT1. Here, we investigated the functional crosstalk between p53 and ΔNp63 in modulating NEAT1 expression following genotoxic stress. We found that upon genotoxic insults, p53 activation and the concomitant downregulation of ΔNp63 promote NEAT1 transcription. In p53-proficient HNSCC cells, NEAT1 targeting leads to increased DNA damage, highlighting its potential role in maintaining genomic stability and facilitating efficient DNA repair. Importantly, we showed that histone deacetylase inhibitors (HDACis) upregulate NEAT1 expression independently of p53, and NEAT1 silencing enhances HDACis-induced DNA damage. Overall, our findings establish NEAT1 as an early regulator of the DNA damage response in HNSCCs and suggest that combining NEAT1 targeting with HDAC inhibition may potentiate therapeutic efficacy, particularly in TP53-mutant HNSCCs.

DNA damage↗
PubMed2004

A dendritic cell based hybrid cell vaccine generated by electrofusion for immunotherapy strategies in HNSCC.

OBJECTIVE: Hybrid cells generated from dendritic cells (DC) and tumor cells provide tumor-associated antigens (TAA) in a polyvalent mode and therefore they have aroused interest in cancer immunotherapy. The present study was designed to investigate the hybrid cell generation and optimize its implementation for a TAA-target treatment of head and neck squamous cell carcinoma (HNSCC). METHODS: Hybrid cells from mature DC and laryngeal carcinoma cell line UTSCC-19A were generated by electrofusion. Fusion efficiency and viability were determined by flow cytometry, light and fluorescence microscopy analyses. RESULTS: The gradual electrofusion process constituted real human tumor and dendritic cell hybrids characterized by polynuclear cells and double staining as a result of overlay of red (HLA-DR:R-PE) and green (HEA:FITC) fluorescence. Furthermore, analyses have proven viability of fusion results, and factors influencing fusion yield were determined. CONCLUSION: Physical fusion of mature dendritic cells with laryngeal carcinoma cells provides a dendritic cell based hybrid cell vaccine as a quantitative prerequisite for anti-cancer vaccination. Specific cytotoxic T-lymphocytes need to be induced before hybrid cell application in clinical studies.

Antigens, Neoplasm↗
PubMed1999

Mutation analysis of hBUB1 in aneuploid HNSCC and lung cancer cell lines.

Aneuploidy is frequently observed in many types of human cancer cells, suggesting that mutations of genes required for chromosomal stability may occur in human tumors. The BUB gene is a component of the mitotic checkpoint in budding yeast that delays anaphase in the presence of spindle damage thus increasing the probability of successful delivery of a euploid genome to each daughter cell. Recently, human homologues of the BUB gene were identified and mutant alleles of hBUB1 were detected in two colorectal tumor cell lines. Transfection of one mutant allele led to dominant disruption of the mitotic checkpoint control in a euploid cell, suggesting that aneuploidy in some tumors could be due to defects in the mitotic checkpoint. We analyzed the entire coding sequence of hBUB1 for mutation in 31 head and neck squamous cell carcinoma (HNSCC) and lung cancer cell lines, most with severe aneuploidy. We found expression of the hBUB1 gene in all cell lines and only a single nucleotide substitution in one cell line without a resultant change in amino acid sequence. Our study demonstrates that hBUB1 is rarely a target for genetic alterations in tumors of the respiratory tract.

Aneuploidy↗
PubMed2004

[Locoregional recurrences of HNSCC: place of re-irradiations].

Unresectable forms of HNSCC relapses occurring in a previously irradiated area are relatively common and may be difficult to manage from a therapeutic point of view. Full dose re-irradiation with concomitant chemotherapy constitutes an alternative to palliative chemotherapy. Indeed, the feasibility of this approach has been shown, and may be associated with a curative potential in a relatively low proportion of these relapses.

Clinical Trials, Phase II as Topic↗
PubMed2006

Role and expression patterns of E-cadherin in head and neck squamous cell carcinoma (HNSCC).

E- cadherin is a member of the cadherin superfamily known as the main mediator of the cell- cell calcium dependent adhesion interactions. Research evidence also yields to this adhesion molecule an important role in carcinogenesis and tumor progression. This review focuses on the differential expression of E- cadherin in the various anatomic sites of the human body where HNSCC arises. Controversies in the results of various studies are discussed and possible prospects for application of all this developing knowledge to prognosis and therapy of the disease are briefly mentioned.

Animals↗
PubMed1997

All-trans, 13-cis and 9-cis retinoic acids induce a fully reversible growth inhibition in HNSCC cell lines: implications for in vivo retinoic acid use.

Retinoids are a group of vitamin A analogues that have shown promise as chemopreventive and therapeutic agents in many types of malignancy and have been entered in clinical trials with some successful results. To better understand the mechanism that mediates retinoid action and the anti-proliferative effects, we treated 7 human oral squamous-cell carcinoma (SCC) cell lines (FADU, HEp-2, CCL-17, SCC-9, SCC-15, SCC-25 and HN-212) with 10(-6) M of all-trans retinoic acid (ATRA), 9-cis and 13-cis retinoic acid (RA) in continuous for different periods of time. We assessed the extent of growth inhibition, the stability of the anti-proliferative effect and the mRNA expression levels (by RT-PCR) of RA receptors (RARs), retinoid X receptors alpha (RXR alpha) and cytosolic RA-binding proteins (CRBP I and CRABP II) in treated cells compared with controls. The data obtained showed that all 3 RAs were able to inhibit the cellular growth of the tested cell lines, although to a different extent. The cis compounds were able to inhibit the proliferation of all cell lines, whereas ATRA was ineffective in inhibiting the proliferation of the CCL-17 cell line, which was naturally resistant to ATRA concentrations in the range between 10(-5) and 10(-6) M. All inhibitory effects were completely reversible since all cell lines restored their normal growth proliferation within few days after drug removal. RT-PCR analysis of the receptor and cell binding protein status of control and treated cells showed a good correlation between growth inhibition and induction of, or increase in, the expression levels of RAR beta in RA-treated cells. No differences were observed in RAR alpha and RXR alpha mRNA expression levels between control and treated cells. CRBP I, CRABP II and RAR gamma mRNA levels increased in some treated cell lines but not in all.

Alitretinoin↗
PubMed2006

Modified radical neck dissection and minimal invasive tumor surgery in the middle of split course of concomitant chemoradiotherapy of advanced HNSCC.

OBJECTIVE: The effectiveness of modified radical neck dissection with concomitant chemoradiotherapy in patients with N2/3 advanced head and neck cancer was evaluated. STUDY DESIGN AND SETTING: Retrospective study of 35 patients treated at the University Hospital, Medical University, Innsbruck. The treatment consisted of a split course radiation up to 70 Gy with concomitant chemotherapy with Mytomicin C and 5-fluorouracil. Neck dissection and/or tumor resection was performed between the two cycles of radiation and chemotherapy. RESULTS: The 2-year progression-free survival was 64%, locoregional control 92% and overall survival 55. Observed toxicities included mucositis (grade 3, 35%; grade 4, 16%), neutropenia (grade 4, 28%), and thrombocytopenia (grade 4, 26%). No complications related to modified radical neck dissection were observed. CONCLUSION: Intermittent neck dissection was highly effective in controlling the neck disease. Mitomycin C-based chemoradiotherapy for treatment of locally advanced cancer seems to be an option to cisplatin-based regimens.

Aged↗