Gene alterations in head and neck carcinomas and their role in promoting malignant behavior (Review).

Head and neck squamous cell carcinoma (HNSCC) survival remains poor despite continuing efforts toward prevention, early detection, and improved treatment modalities. In part, this is thought to be due to a relative lack of molecular targeted therapeutic strategies beyond general mitosis inhibition, which sets a limit to what modern head and neck surgery can accomplish for advanced disease. The past 30 years have produced a large quantity of data, leading to a better understanding of HNSCC carcinogenesis and novel therapeutic agents, such as epidermal growth factor receptor blockers. This article reviews literature on the current understanding of molecular HNSCC carcinogenesis, and highlights the most promising therapeutic approaches.

Financial incentives to promote prolonged renal graft survival: potential for patients and public health.

Non-adherence to immune modulating agents is the single most common cause of renal graft rejection and failure with not only devastating consequences for patients, but also increased dialysis and transplant organ demands causing substantial medical expenses. Financial incentives used to reward and promote patient compliance with immune modulating therapy and post transplantation management could constitute a motivation that might increase renal graft survival, and thereby improve individual patient outcome as well as alleviate public health spending for renal replacement therapy.

Overexpression of Pim-1 in head and neck squamous cell carcinomas.

Despite ongoing developments of treatment protocols head and neck squamous cell carcinomas (HNSCC) show only marginal improvement in outcome, which has been attributed to a lack of therapy individualized to tumor biological properties. We compared mRNA expression profiles of HNSCC and normal epithelial cells using differential display to identify gene fragments showing differential expression in HNSCC cells. We identified a 127-bp long fragment to be overexpressed in HNSCC cells that revealed a 98.4% homology with the Pim-1 mRNA. The differential expression was confirmed by Northern hybridization. Immunohistochemistry showed overexpression of the Pim-1 protein in 98% (41/42) of invasive HNSCC. Analysis of Pim-1 protein expression in relation to TNM stage and histological grade of the tumors exhibited no significant correlation. However, when samples of primary tumor and metastasis retrieved from the same patients (n=26) were analyzed, nearly significant correlation of Pim-1 expression with histological grade was found (p=0.06). The high frequency of the Pim-1 expression of HNSCC of different grades and stages in conjunction with its absence in non-neoplastic head and neck squamous cell epithelium underlines the functional role of Pim-1 in molecular processes of HNSCC.

Fibronectin suppression in head and neck cancers, inflammatory tissues and the molecular mechanisms potentially involved.

Epithelial cellular fibronectin is frequently repressed after malignant transformation in a variety of cancers. This change has been associated with a loss of contact inhibition. To determine if these findings are unique to malignant processes and to identify mechanisms responsible for fibronectin suppression, we investigated fibronectin expression patterns in 46 head and neck carcinomas, 16 samples of adenoid tissue, and 10 benign mucosal biopsies. We report fibronectin suppression in 78% of the head and neck cancer samples, occurring most prominently within tumor cells, as opposed to the adjacent stroma which exhibited abundant fibronectin. Interestingly, fibronectin was also strongly repressed in chronically inflamed adenoid samples. We showed that fibronectin suppression is mediated by different mechanisms in both benign as well as malignant scenarios: In adenoids, macrophages and T-cells were visualized throughout epithelium that has lost its tight cellular array, allowing leukocyte passage. We have shown that tumor necrosis factor-alpha secreted by macrophages is capable of inducing epithelial derangement via activator protein-1 and nuclear factor-kappaB mediated fibronectin suppression. In head and neck carcinomas, we identified human papilloma virus early protein-2 as a fibronectin transcription inhibitor. We conclude that epithelial fibronectin suppression may not be a hallmark of malignancy, because it can concur with benign processes that involve leukocyte migration. Furthermore, our data suggest that the pattern of fibronectin suppression within the tumor structure largely depends on the cancer cell-stroma relation, which could explain previous conflicting reports on its repression or overexpression along with malignant transformation. In addition, our data support an involvement of human papilloma virus as a mechanism of carcinogenesis mediated via a loss of fibronectin gene expression.

Overexpression of p68 mRNA in head and neck squamous cell carcinoma cells.

BACKGROUND: Head and neck squamous cell carcinomas (HNSCC) are aggressively growing tumors with only marginal improvement in outcome despite ongoing developments in treatment protocols. This problem has been associated with a lack of therapy individualization on tumor biological properties. MATERIALS AND METHODS: mRNA expression profiles of HNSCC and normal epithelial cells were compared in order to identify genes associated with cancer formation. Differential display was used to trace gene fragments showing differential expression in HNSCC cells, which were than isolated, re-amplified, cloned and sequenced. RESULTS: A 131-bp-long fragment was identified to be overexpressed in HNSCC cells that revealed a 99.3% homology with p68 mRNA. The differential expression was confirmed by Northern hybridization. CONCLUSION: The data presented suggest an involvement of p68 in the process of malignant transformation or progression of HNSCC.

Association between human beta defensin expression and cholesteatoma formation.

OBJECTIVE: To investigate an association between human beta defensin (hBD) expression and cholesteatoma formation. METHODS: hBD-2 mRNA expressions were assessed in healthy external acoustic meatus skin organ cultures before and after stimulation with Pseudomonas aeruginosa. In addition, hBD-1 and hBD-2 protein production of stimulated and non-stimulated external acoustic meatus skin was visualized by immunohistochemistry. Furthermore, hBD-1 and hBD-2 mRNA expression was analyzed in 25 external acoustic meatus skin, 29 cholesteatoma, and 18 non-cholesteatoma control samples. Non-stimulated meatal tissue preparation did not express hBD-2, whereas incubation with P. aeruginosa demonstrated hBD-2 induction. RESULTS: The hBD-1 mRNA expression was detected in cholesteatoma (14/17), meatal skin, and middle ear mucosa (11/18). hBD-2 mRNA expression was shown in eight cholesteatoma (28.5%) and in three middle ear mucosa tissue samples (37.5%). CONCLUSION: Our data suggest constitutional hBD-1 and inducible hBD-2 expression in chronic middle ear infection and cholesteatoma. Failure of hBD-1 and hBD-2 expression might dispose to exacerbation of cholesteatoma disease. The organ culture model of the external acoustic meatus skin is effective in order to evaluate germ stimulation experiments.

Defensin and chemokine expression patterns in the palatine tonsil: a model of their local interaction.

Defensins and chemokines are an essential part of the immune response mechanisms in the head and neck mucosa. This work investigates their correlation and their expression pattern in tonsillar disease. Forty-four tonsil tissue samples were obtained from patients who underwent tonsillectomy between 1998 and 1999 for chronic tonsillitis with (n =9) and without (n =25) inflammatory infiltrates and hyperplasia of the tonsil (n =10). Defensin (hBD-1, hBD-2, HNP-1 and HNP-4) and chemokine (RANTES, eotaxin, eotaxin-2, MCP-3, MCP-4 and IL-8) mRNA expressions were analyzed by SQRT-PCR. HNP-4 and eotaxin-2 expressions were positively correlated (P <0.05) in the acute tonsillitis group. HBD-2 and MCP-3 expressions were positively correlated in the hyperplastic tonsils group. Within all groups together, HNP-4 and RANTES expressions were highly positively correlated (P <0.01), and HNP-1 and hBD-2 were positively correlated with IL-8 expressions. Immunohistochemistry demonstrated eotaxin-1 as well as IL-8 production to be predominantly located within the lymphoid follicles and submucosa. RANTES production was shown in the epithelial lining and perivascular tissue. The expression of hBD-1 and hBD-2 was limited to the epithelial lining. Our data support an association between the innate and acquired immune systems on the defensin-chemokine level. The finding of positively correlated hBD-2 and IL-8 expression is biologically relevant because of the proximity of hBD-2 (epithelium) and IL-8 (submucosa) release, as well as the synergistic support of the Th1 system. In addition, our data suggest RANTES as a first-line mediator of perivascular leukocyte recruitment.

Implications of galactocerebrosidase and galactosylcerebroside metabolism in cancer cells.

Galactosylcerebroside is known to be overexpressed upon the cellular surface of a variety of cancers. In squamous cell carcinomas of the head and neck, one explanation for galactosylcerebroside accumulation has been identified as a transcriptional repression of the galactocerebrosidase gene. Galactocerebrosidase is the enzyme responsible for degrading galactosylcerebroside to ceramide. Ceramide is an important apoptosis activator, whereas galactosylcerebroside functions as an inhibitor. A shift of the ceramide metabolism balance in favor of glycosylated forms has been identified as a mechanism of drug resistance for several antineoplastic agents. Our review elaborates on possible explanations for galactocerebrosidase suppression and on other explanations for increased glycosphingolipid concentration within cancer cell membranes. Furthermore, conjecturable influences of a repressed galactocerebrosidase expression on tumor biology are to be explained. The inhibiting transcription factors YY1 and AP2 have been identified as potential galactocerebrosidase gene suppressors. The resulting accumulation of galactosylcerebroside promotes a reduction of cellular adhesion and inhibits apoptosis, leading to increased cellular growth, migration and prolonged cell survival contributing to carcinogenesis.