Inhibition of cutaneous ultraviolet light B-mediated inflammation and tumor formation with topical celecoxib treatment

Inflammation, which includes the release of growth factors, proinflammatory cytokines and prostaglandins, the infiltration and activation of inflammatory cells, and the induction of oxidative DNA damage, is known to play a role in cancer development. The combination of damage to the skin resulting from chronic ultraviolet light B (UVB) exposure itself and the inflammatory response it induces is a major source of skin cancer development. Cyclooxygenase-2 (COX-2), an inflammatory enzyme responsible for the production of prostaglandins, is now implicated in the development of epithelial cancers, including squamous cell carcinoma in the skin. Previous work conducted in our laboratory has shown that topical treatment with celecoxib following UVB irradiation inhibits several parameters of acute inflammation, including vascular permeability, the infiltration and activation of neutrophils, and the production of prostaglandin E(2) (PGE(2)). The present studies expanded these observations, demonstrating the ability of topical celecoxib to inhibit acute oxidative damage. In addition, long-term studies illustrate the effectiveness of topical treatment with this drug in reducing chronic inflammation and UVB-induced papilloma/carcinoma formation. This data provides compelling evidence to explore the clinical efficacy of topically applied COX-2 inhibitors for the prevention of human skin cancers.     

The effect of nitric oxide on cyclooxygenase-2 (COX-2) overexpression in head and neck cancer cell lines

The overexpression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) has been previously reported in head and neck squamous cell carcinoma (HNSCC), as well as in many cancers. We hypothesized that endogenous nitric oxide (NO) might increase the expression of COX-2 in cancer cells. Therefore, we investigated the cross-talk between NO and the prostaglandin (PG) pathways in HNSCC cell lines. We found that COX-2 and iNOS expressions were elevated simultaneously. On adding the NO donor, SNAP, the PGE2 level was increased 2-20 times due to increased COX-2 expression. This increase of COX-2 expression by SNAP or PMA (potent inducer of both iNOS and COX-2) was blocked to various degrees by NO scavengers and NOS inhibitors (L-NAME and 1400W). Also, the expression of COX-2 in resting cells was inhibited by NOS inhibitors. Moreover, COX-2 expression, induced by SNAP, was inhibited by ODQ, a soluble guanylate cyclase (sGC) inhibitor. The effect of dibutyryl-cGMP on COX-2 expression was similar to that of SNAP. These results imply that endogenous or exogenous NO activates sGC and that the resulting increase of cGMP induces a signaling that upregulates the expression of COX-2 in HNSCC cell lines. We also observed that NO increased COX-2 expression in different cancer cell lines, including cervic and gastric cancer cell lines. These findings further support the notion that NO can be associated with carcinogenesis through the upregulation of COX-2, and that NOS inhibitor may be also useful for cancer prevention.     

Would you bet on PET? Evaluation of the significance of positive PET scan results post‐microwave ablation for non‐small cell lung cancer

Fluodeoxyglucose‐positron emission tomography (FDG‐PET) imaging is an acknowledged modality for the follow‐up of solid tumours treated with thermal ablation, with persistent or new FDG uptake at the ablation site considered to be a reliable indicator of local recurrence. Several cases of proven false‐positive FDG‐PET scans are illustrated in this pictorial essay with uptake at the site of the ablated tumour, remote from the ablated lesion and in mediastinal and hilar lymph nodes. Positive FDG‐PET scans post‐thermal ablation of lung tumours therefore cannot always reliably predict local tumour recurrence or nodal spread. It is important to be familiar with FDG uptake patterns post‐ablation and their significance. FDG‐PET avid lesions post‐ablation may require histological confirmation before further therapy is planned or management is changed.     

Down-regulation of insulin-like growth factor binding protein-5 (IGFBP-5): novel marker for cervical carcinogenesis

To better understand the underlying pathways of cervical carcinogenesis, cDNA microarray analysis was performed on 2 sets of squamous cell carcinomas (SCCs) and their adjacent normal squamous epithelia. Consistently altered expression was detected for 32 genes. Real-time RT-PCR analysis was conducted on a selected subset of these genes (S100A2, GPC4, p72, IGFBP-5, TRIM2 and NAB2) for 14 additional SCCs and 10 normal epithelia. This found that, of the 6 candidate genes, only the insulin-like growth factor binding protein-5 (IGFBP-5) mRNA was generally and significantly under-expressed in SCCs (p < 0.001). All normal cervical epithelia (30 of 30) stained positively for IGFBP-5 protein, with 70% showing strong staining, whereas 65% (17/26) of SCC had complete loss of IGFBP-5, and only 8% (2/26) SCC retained strong expression (p < 0.001). Immunohistochemistry of premalignant cervical intraepithelial neoplasia (CIN) lesions shows a significantly weaker or negative staining in advanced CIN3 lesions compared with normal squamous epithelia (p = 0.001). This is the first study to show that down-regulation of IGFBP-5 protein correlates with cervical carcinogenesis and does so at a preneoplastic stage.     

Serum insulin-like growth factor I/free prostate specific antigen (IGF-I/fPSA) ratio enhances prostate cancer detection in men with total PSA 4.0-10.0 ng/ml

BACKGROUND: Recent studies have suggested that IGF-I and IGFBP-3, in combination with PSA, may enhance PCa detection. This study was to investigate the use of serum IGF-I and IGFBP-3, and their combinations with prostate volume and fPSA in enhancing the discriminatory diagnosis of PCa in men with tPSA of 4.0-10.0 ng/ml. METHODS: Serum IGF-I and IGFBP-3 were determined by ELISA from 586 men with tPSA between 4.0 and 10.0 ng/ml. Of them, 281 were diagnosed with PCa and 305 without. ROC, univariate and multivariate logistic regression analyses were performed to evaluate the predictive performance of those parameters. RESULTS: IGF-I, IGFD, IGF-I/fPSA, and IGFBP-3/fPSA were significantly higher in PCa cases than benign controls, whereas the differences of IGFBP-3 and IGFBPD were statistically insignificant between the two groups, respectively. The AUC values indicated enhanced performance of IGF-I/fPSA ratio (AUC = 0.753) in PCa detection compared with the currently used f/tPSA (AUC = 0.689). Multivariate logistic regression confirmed the observed relationships and identified IGF-I/fPSA as independent factor in PCa presence. CONCLUSION: Our data show that IGF-I/fPSA as a promising marker can enhance PCa detection in ambiguous cases often found in the tPSA between 4.0 and 10.0 ng/ml.     

Simultaneous cytoplasmic and nuclear protein expression of melanoma antigen‐A family and NY‐ESO‐1 cancer‐testis antigens represents an independent marker for poor survival in head and neck cancer

The prognosis of head and neck squamous cell carcinoma (HNSCC) patients remains poor. The identification of high‐risk subgroups is needed for the development of custom‐tailored therapies. The expression of cancer‐testis antigens (CTAs) has been linked to a worse prognosis in other cancer types; however, their prognostic value in HNSCC is unclear because only few patients have been examined and data on CTA protein expression are sparse. A tissue microarray consisting of tumor samples from 453 HNSCC patients was evaluated for the expression of CTA proteins using immunohistochemistry. Frequency of expression and the subcellular expression pattern (nuclear, cytoplasmic, or both) was recorded. Protein expression of melanoma antigen (MAGE)‐A family CTA, MAGE‐C family CTA and NY‐ESO‐1 was found in approximately 30, 7 and 4% of tumors, respectively. The subcellular expression pattern in particular had a marked impact on the patients' prognosis. Median overall survival (OS) of patients with (i) simultaneous cytoplasmic and nuclear expression compared to (ii) either cytoplasmic or nuclear expression and (iii) negative patients was 23.0 versus 109.0 versus 102.5 months, for pan‐MAGE (p < 0.0001), 46.6 versus 50.0 versus 109.0 for MAGE‐A3/A4 (p = 0.0074) and 13.3 versus 50.0 versus 100.2 months for NY‐ESO‐1 (p = 0.0019). By multivariate analysis, these factors were confirmed as independent markers for poor survival. HNSCC patients showing protein expression of MAGE‐A family members or NY‐ESO‐1 represent a subgroup with an extraordinarily poor survival. The development of immunotherapeutic strategies targeting these CTA may, therefore, be a promising approach to improve the outcome of HNSCC patients.     

Genetic variants in RORA and DNMT1 associated with cutaneous melanoma survival

Cutaneous melanoma (CM) is considered as a steroid hormone‐related malignancy. However, few studies have evaluated the roles of genetic variants encoding steroid hormone receptor genes and their related regulators (SHR‐related genes) in CM‐specific survival (CMSS). Here, we performed a pathway‐based analysis to evaluate genetic variants of 191 SHR‐related genes in 858 CMSS patients using a dataset from a genome‐wide association study (GWAS) from The University of Texas MD Anderson Cancer Center (MDACC), and then validated the results in an additional dataset of 409 patients from the Harvard GWAS. Using multivariate Cox proportional hazards regression analysis, we identified three‐independent SNPs (RORA rs782917 G > A, RORA rs17204952 C > T and DNMT1 rs7253062 G > A) as predictors of CMSS, with a variant‐allele attributed hazards ratio (HR) and 95% confidence interval of 1.62 (1.25–2.09), 1.60 (1.20–2.13) and 1.52 (1.20–1.94), respectively. Combined analysis of risk genotypes of these three SNPs revealed a decreased CMSS in a dose–response manner as the number of risk genotypes increased (p_trend < 0.001); however, no improvement in the prediction model was observed (area under the curve [AUC] = 79.6–80.8%, p = 0.656), when these risk genotypes were added to the model containing clinical variables. Our findings suggest that genetic variants of RORA and DNMT1 may be promising biomarkers for CMSS, but these results needed to be validated in future larger studies.     

Expression of granulocyte-colony-stimulating factor and its receptor in human Ewing sarcoma cells and patient tumor specimens: potential consequences of granulocyte-colony-stimulating factor administration

BACKGROUND: Ewing sarcoma (ES) is a highly vascular malignancy. It has been demonstrated that both angiogenesis and vasculogenesis contribute to the growth of ES tumors. Granulocyte-colony-stimulating factor (G-CSF), a cytokine known to stimulate bone marrow (BM) stem cell production and angiogenesis, is routinely administered to ES patients after chemotherapy. Whether ES cells and patient tumor samples express G-CSF and its receptor (G-CSFR) and whether treatment with this factor enhances tumor growth was examined. METHODS: Human ES cell lines were analyzed for expression of G-CSF and G-CSFR in vitro and in vivo. Sixty-eight paraffin-embedded and 15 frozen tumor specimens from patients with ES were also evaluated for the presence of G-CSF and G-CSFR. The in vivo effect of G-CSF on angiogenesis and BM cell migration was determined. Using a TC/7-1 human ES mouse model, the effect of G-CSF administration on ES tumors was investigated. RESULTS: G-CSF and G-CSFR protein and RNA expression was identified in all ES cell lines and patient samples analyzed. In addition, G-CSF was found to stimulate angiogenesis and BM cell migration in vivo. Tumor growth was found to be significantly increased in mice treated with G-CSF. The average tumor volume for the group treated with G-CSF was 1218 mm(3) compared with 577 mm(3) for the control group (P = .006). CONCLUSIONS: The findings that ES cells and patient tumors expressed both G-CSF and its receptor in vitro and in vivo and that the administration of G-CSF promoted tumor growth in vivo suggest that the potential consequences of G-CSF administration should be investigated further.