Neoangiogenesis has been documented in small cell lung carcinoma (SCLC). In addition, antiangiogenic therapies are being tested in clinical trials that involve SCLC. However, study of the underlying mechanisms has been performed almost exclusively in cell lines. In the current study, we immunostained 30 biopsy samples of SCLC with antibodies to hypoxia inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor (VEGF), vascular endothelial growth factor-receptor 1 (VEGF-R1/flt-1) and vascular endothelial growth factor-receptor 2 (VEGF-R1/flk-1). The immunoreactivity was analyzed using a bivariate Spearman correlation test and linear regression analysis. We found significant correlation between HIF-1 alpha nuclear staining and VEGF staining. Moreover HIF-1 alpha+/VEGF+ cases were associated with poor survival. We also found a positive correlation between VEGF and VEGF-R2 expression. We suggest that a HIF-1 alpha/VEGF angiogenic pathway may exist in vivo in SCLC, similar to that in non-SCLC. Our data also suggest a potential VEGF/VEGFR-2 autocrine pathway in SCLC. The inclusion of novel inhibitors to HIF-1 alpha and other factors may optimize antiangiogenic interventions in SCLC.

Epithelial-mesenchymal transition (EMT) plays an important role in cancer metastasis. During EMT, tumor cells acquire the capacity to migrate and invade the stroma. Activation of the transforming growth factor-b (TGF-b) signaling pathway is of major importance for the initiation of EMT. Smad4, an essential protein of this pathway, is known to complex with multiple transcription factors (e.g. Snail-1, Slug, Twist-1), in various types of cancer, promoting the repression or activation of target genes. The role of Smad4 in colorectal cancer (CRC) is not straightforward so far. In the present study forty eight resected CRC tumor specimens were immunohistochemically examined in order to assess the expression of Smad4 and its association with E-cadherin, Snail-1, Slug, Twist-1 protein expression and with various pathological parameters. Smad4 was found to be positively correlated with Snail-1, Slug and Twist-1 expression (p < 0.001). On the other hand it was negatively correlated with the expression of E-cadherin (p < 0.001). Furthermore, lymphatic invasion could be clearly associated with Smad4 expression, a finding complying with the metastatic ability of EMT cells. In conclusion, Smad4 could be considered as a central component of EMT transition in human colorectal cancer that combines with transcriptional factors to reduce E-cadherin and alter the expression of the epithelial phenotype.

Overall, our findings imply that possible novel therapeutic intervention(s) on the HIF-1 alpha pathway may offer another approach in controlling the inflammatory activity of psoriatic lesions.

Inner centromere protein (INCENP) is a member of the Chromosomal Passenger Complex (CPC), which is a four member protein complex essential for proper completion of mitosis and cell division (cytokinesis). Inappropriate chromosomal segregation and cytokinesis due to deregulated expression of chromosome passenger proteins may lead to aneuploidy and cancer including lymphomas. According to our knowledge this is the first study investigating immunohistochemical expression of INCENP in lymphoma cases and cancer tissues in general. Our purpose was to characterize the expression of INCENP in cases of non-Hodgkin B-cell lymphomas, to compare the immunoreactivity between low and high grades and to evaluate the correlation between INCENP and MIB-1 labeling indices. We examined INCENP and MIB-1 immunoreactivity in paraffin sections of 55 samples of non-Hodgkin B-cell lymphomas, obtained from 55 patients, 31 men and 24 women. Thirty were of high grade and 25 were of low grade. Our results showed significantly higher nuclear immunohistochemical expression of INCENP in high grade B-cell lymphomas versus low grade ones. Also INCENP expression was significantly correlated with MIB-1 labeling index. Taken together our results point to a possible association between increased INCENP immunostaining and B-cell lymphoma aggressiveness and also stress the need for further investigating the expression of INCENP and other mitotic regulatory proteins in lymphomas and other malignant neoplasms.

Abstract. The immunoreactivity of hypoxia inducible factor 1 · (HIF-1·) has been considered a reliable indicator of the HIF-1 pathway activation in tissue hypoxia. However, HIF-1· immunoreactivity has been evaluated with different antibodies and heterogeneous protocols. The need to interpret contradictory findings requires, among other things, a comparison of the antibodies. This could be accomplished by using identical, well characterized antigenic targets and by decreasing the influence of other variables. We applied most of the commercially available antibodies, and an antibody developed in our laboratories, to the human cervical cancer HeLa cell line and tissue sections from a renal cell carcinoma systematically, and to other tumors selectively. The expression of HIF-1· in HeLa cells was induced by the hypoxia-mimetic DFO. Non-induced HeLa cells were used as 'genuine' negative controls in addition to routine ones. HeLa cells (both induced and not induced) were also examined by immunofluorescence and Western blotting. We found that the antibodies showed immunostaining patterns with remarkable qualitative and quantitative differences, an observation not emphasized in previous literature. Certain antibodies require careful application to avoid specificity issues, and others to avoid low sensitivity problems. Pairing certain antibodies can optimize evaluation of HIF-1· expression. Most previous immunohistochemical studies of HIF-1· have attempted to map hypoxic neoplastic tissues or to demonstrate hypoxia in studies of neoangiogenesis, rather than 'measuring' HIF-1· expression or activation, because this requires a validated immunoassay. Our study thus allows for the development of a controlled and comparative HIF-1· immunoassay, which could be valuable if HIF-1· becomes a therapeutic target.