Gerasimos Vandoros

Oestrogen receptor beta (ERβ) is abundantly expressed in normal colonic mucosa, but declines in colon adenocarcinoma paralleling the tumour's dedifferentiation

Oestrogen Receptor beta (ERbeta) may protect against prostate and mammary cell proliferation and malignant transformation. Epidemiological studies indicate that oestrogens may reduce colon cancer risk. Since ERalpha is minimally expressed in normal and malignant colon, the aim of this study was to investigate the expression of ERbeta in both normal colonic wall and colon cancer. ERbeta expression was evaluated by immunohistochemistry in 90 cases of colon adenocarcinoma and nearby (>30-cm away) normal colonic wall, using a monoclonal antibody. Moderate or strong nuclear immunostaining was detected in superficial and crypt epithelium, endothelial cells, vascular smooth muscle cells, lymphocytes, enteric neurons and smooth muscular cells of the normal colonic wall. Superficial epithelial cells in normal colon demonstrated a significantly higher ERbeta expression than colon adenocarcinoma cells in both genders. The decline in ERbeta expression paralleled the loss of differentiation of malignant colon cells, regardless of the tumours localisation. These findings suggest a protective role for ERbeta against colon carcinogenesis.

Expression of the 27-kDa heat shock protein (HSP27) in gastric carcinomas and adjacent normal, metaplastic, and dysplastic gastric mucosa, and its prognostic significance.

Abstract Purpose. The investigation of heat shock protein 27 (HSP27) expression in gastric cancer and adjacent normal, metaplastic, and dysplastic gastric mucosa and its correlation with clinicopathological parameters and survival of patients. Methods. Immunohistochemical methodology was performed on formalin-fixed paraffin-embedded sections by using a monoclonal anti-HSP27 antibody. HSP27 expression was screened and compared in 86 cases of gastric carcinoma and adjacent normal, metaplastic, and dysplastic gastric mucosa. Results. In the normal mucosa, HSP27 was detected in 68 out of 86 cases (79%) and was more intense in the surface and upper two-thirds of gastric foveolae. In dysplastic gastric mucosa, HSP27 immunoreactivity was usually higher than that of the adjacent normal epithelium and was parallel to the severity of dysplasia. HSP27 expression was found in 54 out of 86 (62.7%) gastric carcinomas and was significantly related to more than six metastatic lymph nodes (P =0.03). HSP27 expression was also higher in tumors of advanced stage and in those of female patients. HSP27 expression was associated with shorter overall survival in univariate analysis (P =0.04), but this relationship was not retained in multivariate analysis. Conclusions. Our findings indicate that: i) HSP27 is commonly expressed in normal gastric epithelium where it seems to exert a protective role; and ii) HSP27 is involved in gastric carcinogenesis and its expression appears to be associated with parameters of unfavorable prognosis and shorter overall survival.

PPAR-gamma is expressed and NF-kB pathway is activated and correlates positively with COX-2 expression in stromal myofibroblasts surrounding colon adenocarcinomas

Purpose: Accumulated evidence indicates that carcinogenesis is closely associated with the transformation of normal stroma into a ‘reactive’ stromal phenotype. The present study investigated the role of PPARγ, COX-2 and p-IkB-α—important molecular targets of colon cancer chemoprevention—in this stromal remodeling by evaluating and comparing the expression of these factors in stromal myofibroblasts, macrophages and endothelial cells that surround normal colonic mucosa and colon cancer. Methods: Immunohistochemical methodology was employed on archived paraffin-embedded sections prepared from tumors and adjacent normal colon from 45 patients with colon adenocarcinomas. Double immunostaining with the universal marker for myofibroblasts (alpha-smooth muscle actin/α-SMA) as second primary antibody was also performed. Results: Stromal macrophages and endothelial cells expressed these factors both in normal colonic mucosa and colon cancer. By contrast, stromal myofibroblasts expressed PPARγ, COX-2 and p-IkB-α only in colon adenocarcinomas (77.7%, 100% and 100% of cases, respectively) and not in normal colon. COX-2 and p-IkB-α expressions were strongly correlated in these cells (P<0.001). PPARγ, COX-2 and p-IkB-α expression did not correlate with the stage or differentiation of the adenocarcinomas. Conclusions: NF-kB pathway is activated and COX-2 expression is upregulated in stromal myofibroblasts surrounding colon adenocarcinomas compared to normal colon. Induction of COX-2 expression is primarily induced by NF-kB. NSAIDs, selective COX-2 inhibitors and PPARγ ligands may exert their chemoprophylactic properties through direct actions on these cells.

FK228 (depsipeptide): a HDAC inhibitor with pleiotropic antitumor activities

Purpose: The fundamental role of epigenetic events in carcinogenesis has resulted in the evolution of epigenetic targeting as a new paradigm in anticancer therapeutics. Aberrant histone deacetylase (HDAC) activity has been documented in many human malignancies resulting in the repression of tumor suppressor genes and promotion of tumorigenesis. FK228, also known as depsipeptide, is a novel, natural, bicyclic tetrapeptide with significant antitumor properties which are mostly mediated by inhibition of HDACs. Results: FK228 induces the expression of genes linked to the inhibition of cell growth, induction of cell differentiation, promotion of apoptotic cell death and inhibition of angiogenesis. Conclusion: Its multitargeting properties, its ability to act on non-histone targets, its clinical activity and its acceptable side-effect profile render FK228 a very promising novel anticancer agent.

NF-κB/PPARγ and/or AP-1/PPARγ 'on/off' switches and induction of CBP in colon adenocarcinomas: correlation with COX-2 expression

Background and aimsSeveral studies indicate that peroxisome proliferator-activated receptor gamma (PPARγ) represses activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB) transcriptional activity and this negative cross-talk occupies an important role in carcinogenesis. The present study evaluated the differential expression profile of AP-1 constituents (c-FOS and phosphorylated-active pc-JUN), p-IκB-α (phosphorylated IκB-α, a signaling intermediate of NF-κB pathway), PPARγ, cyclic AMP-response element binding-binding protein (CBP, a known AP-1, NF-κB, and PPARγ transcriptional coactivator), epidermal growth factor receptor (EGF-R), p53, and COX-2 in normal colonic epithelial cells and colon adenocarcinoma cells.Materials and methodsImmunohistochemical methodology was performed on formalin-fixed, paraffin-embedded sections from 60 patients with colon adenocarcinomas. A molecular profile was created for each patient and the induction or down-regulation of each pathway from normal to cancer cells was documented. Relationships between transcription factors and downstream molecular targets were evaluated by Spearman’s rho correlation coefficient and validated by nonparametric Kruskal–Wallis test.Results/findingsP-IκB-α (P<0.001), CBP (P<0.001), c-FOS (P=0.047), pc-JUN (P=0.047), and EGF-R (P<0.001) were up-regulated in colon adenocarcinomas while PPARγ (P<0.001) was concomitantly down-regulated. p-IκB-α, CBP, pc-JUN, EGF-R, and p53 expression all correlated positively with COX-2 while PPARγ expression correlated inversely with COX-2.Interpretation/conclusionNF-κB/PPARγ and/or AP-1/PPARγ expressional ‘on/off’ switches are common molecular events during colorectal carcinogenesis. Down-regulation of PPARγ and induction of the CBP transcriptional coactivator can augment NF-κB and AP-1 transcriptional activities leading to up-regulation of COX-2 expression in colon adenocarcinoma cells. p-IκB-α, pc-JUN, and CBP could potentially provide the basis for future molecular-targeted anticancer therapies.

EGF-R is Expressed and AP-1 and NF-κ:B Are Activated in Stromal Myofibroblasts Surrounding Colon Adenocarcinomas Paralleling Expression of COX-2 and VEGF

Background: COX-2 and VEGF are important triggers of colon cancer growth, metastasis and angiogenesis. Cox-2 promoter contains transcriptional regulatory elements for AP-1 and NF-κ:B transcription factors whilst vegf is a known AP-1 downstream target gene. We investigated whether stromal myofibroblasts surrounding colon adenocarcinomas express COX-2 and VEGF and whether activation of AP-1 and NF-κ:B, as well as expression of EGF-R parallel expression of COX-2 and VEGF in these cells. Methods: Immunohistochemical methodology was performed on archival sections from 40 patients with colon adenocarcinomas. We evaluated c-FOS, p-c-JUN (phosphorylated c-JUN), p-Iκ:B-α (phosphorylated Iκ:B-α), EGF-R, COX-2, NF-κ:B and VEGF expression in stromal myofibroblasts surrounding colon adenocarcinomas. Double immunostaining with a-smooth muscle actin and each antibody was done to verify the expression of these molecules in stromal myofibroblasts. Results: VEGF, p-Iκ:B-α, NF-κ:B, c-FOS, p-c-JUN, EGF-R and COX-2 were expressed in stromal myofibroblasts surrounding colon adenocarcinomas in the majority of cases. EGF-R, p-Iκ:B-α, NF-κ:B, c-FOS and p-c-JUN correlated positively with COX-2 and VEGF expression. Conclusion: Stromal myofibroblasts surrounding colon adenocarcinomas are an important source of VEGF and COX-2 production, while AP-1 and NF-κ:B transcription factors are activated and EGF-R is expressed in these cells and associated with COX-2 and VEGF production.

Leiomyosarcoma of the Prostate: Case Report and Review of 54 Previously Published Cases

Prostate leiomyosarcoma is an extremely rare and highly aggressive neoplasm that accounts for less than 0.1% of primary prostate malignancies. We present a patient with primary leiomyosarcoma of the prostate and review 54 cases reported in the literature to discuss the clinical, diagnostic and therapeutic aspects of this uncommon tumor. Median survival was estimated at 17 months (95% C.I. 20.7–43.7 months) and the 1-, 3-, and 5-year actuarial survival rates were 68%, 34%, and 26%, respectively. The only factors predictive of long-term survival were negative surgical margins and absence of metastatic disease at presentation. A multidisciplinary approach is necessary for appropriate management of this dire entity.

Coordinated Upregulation of COX-2 and NF-κB Is a Steady Feature of Laryngeal Carcinogenesis

Background/Aims: Laryngeal cancer is the endpoint of a multistage process involving hyperplastic and dysplastic lesions, not adequately defined in their molecular aspect. Our objective was to evaluate the expression of the prostaglandin-synthesizing enzyme cyclooxygenase-2 (COX-2) and the chief transcription factor nuclear factor-ĸB (NF-ĸB) in laryngeal carcinomas and their precursors, as well as to explore any association between the two molecules. Methods: We performed paraffin section immunohistochemistry for COX-2 and the p65 subunit of NF-ĸB, in tissues from 129 patients with tumors or premalignancies. p65 cytoplasmic and nuclear immunostaining were listed individually. Results: COX-2 was positively correlated with histopathological grading from normal mucosa to carcinomas (Spearman’s coefficient rs = 0.286, p < 0.001). No association was revealed between COX-2 expression and tumor grade. p65 immunoreactivity, both of cytoplasmic and nuclear origin, increased along the carcinogenesis course, manifesting highest expression in invasive cancer (rs = 0.419, p < 0.001 and rs = 0.241, p < 0.001, respectively). Again, tumor grade had no influence on expression. COX-2 and p65 cytoplasmic, but no nuclear, expression showed a positive correlation (rs = 0.352, p < 0.001). Conclusions: This study demonstrates that lesional advance in the larynx towards cancer is marked by ongoing upregulation of COX-2 and NF-ĸB. Synchronism between individual expressions may denote a regulatory role of the latter in COX-2 transactivation.

Low COX2 in tumor and upregulation in stroma mark laryngeal squamous cell carcinoma progression

Invasive squamous cell carcinomas (SCC) of the larynx, like most solid tumors, are surrounded by a reactive stroma, in which cancer associated fibroblasts (CAFs) are the predominant cell type. This mesenchymal reaction may affect cancer progression multiply. The proinflammatory enzyme cyclooxygenase‐2 (COX‐2) has been correlated with head and neck cancer. This study aims to explore the impact of epithelial and stromal COX‐2 expression on SCC behavior.

Retinoid-X-receptor alpha (RXRα) expression during laryngeal carcinogenesis: Detrimental or beneficial event?

RXRalpha is an obligatory heterodimerization partner in many signal transducing pathways. To evaluate RXRalpha expression during laryngeal carcinogenesis, immunohistochemistry was performed on laryngeal epithelial specimens of 154 patients with normal-appearing, hyperplastic, dysplastic laryngeal epithelium and squamous cell carcinoma. RXRalpha up-regulation was detected from the early stages of laryngeal carcinogenesis compared with normal epithelium. Statistical analysis and correlation of the intensity of nuclear immunostaining among the various histologic entities revealed statistically significant results. We pose that RXRalpha overexpression might represent an early protective effect in the process of laryngeal carcinogenesis that might be overwhelmed by an epigenetic disability in forming heterodimers with PPARgamma.