The "game" of glial fibrillary acidic and S100 proteins in pituitary adenomas: two players or several?

INTRODUCTION: S100 protein and GFAP expression in pituitary adenomas tumour cells is not well known; few correlations with other prognostic or therapeutic factors have previously been reported in pituitary adenomas. We aim to elucidate their involvement in the pathogenesis of pituitary adenomas and to establish the correlation of their expression with different growth factors and growth factor receptors known to have a prognostic and/or therapeutic role. MATERIAL AND METHODS: Sixty-one cases of pituitary adenomas were immunohistochemically assessed for the expression of GFAP and S100 protein in both tumour cells and FS cells, in close relationship with hormone profile, and correlated with vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression, previously studied by our team. RESULTS: GFAP and S100 protein were expressed both in tumour cells and FS cells. Differences between morphology, distribution, and density of GFAP+ FS cells and S100+ FS cells were observed according to the hormone profile of pituitary adenomas. GFAP and S100 protein expression in tumour cells was significantly related to hormone profile of pituitary adenomas and also with VEGF and EGFR expression. CONCLUSIONS: GFAP and S100 protein expressions in tumour cells from pituitary adenomas are influenced by hormone profile. Our re-sults support the presence of two molecular subtypes of FS cells GFAP+/VEGF+/S100 respectively and another one that is GFAP-/S100+/EGFR+ simultaneously with the classical variant GFAP+/S100+. It is possible that S100+/EGFR+ pituitary adenomas represent a group of pituitary adenomas with an aggressive behaviour and a high ability of invasion and recurrence.

Adipose Tissue Graft Improves Early but not Late Stages of Nerve Regeneration.

AIM: The aim of the study was to assess the effect of autologous fat graft on nerve regeneration by means of immunohistochemistry. MATERIALS AND METHODS: The rat sciatic nerve was used; complete transection followed by primary neurorrhaphy was performed on both hind legs, on the left side a processed fat graft was applied, surrounding the nerve. Nerve biopsies were collected and immunohistochemical procedures were performed for glial fibrillary acidic protein (GFAP) and for neurofilament-associated protein(NFAP). RESULTS: At 4 weeks, GFAP-positive cells were observed in the connective tissue formed between the two nerve endings on the left side only. At 10 weeks, GFAP-positive structures were present and exhibited a tendency to become linear on both sides, with an increased density on the left. NFAP-positive expression was present in the left treated limb with a disorganized pattern. CONCLUSION: Adipose tissue led to the stimulation of GFAP-positive Schwann cells, which could have a positive impact on nerve regeneration in the clinical setting.

Molecular Portrait of the Normal Human Breast Tissue and Its Influence on Breast Carcinogenesis.

Normal human breast tissue consists of epithelial and nonepithelial cells with different molecular profiles and differentiation grades. This molecular heterogeneity is known to yield abnormal clones that may contribute to the development of breast carcinomas. Stem cells that are found in developing and mature breast tissue are either positive or negative for cytokeratin 19 depending on their subtype. These cells are able to generate carcinogenesis along with mature cells. However, scientific data remains controversial regarding the monoclonal or polyclonal origin of breast carcinomas. The majority of breast carcinomas originate from epithelial cells that normally express BRCA1. The consecutive loss of the BRCA1 gene leads to various abnormalities in epithelial cells. Normal breast epithelial cells also express hypoxia inducible factor (HIF) 1α and HIF-2α that are associated with a high metastatic rate and a poor prognosis for malignant lesions. The nuclear expression of estrogen receptor (ER) and progesterone receptor (PR) in normal human breast tissue is maintained in malignant tissue as well. Several controversies regarding the ability of ER and PR status to predict breast cancer outcome remain. Both ER and PR act as modulators of cell activity in normal human breast tissue. Ki-67 positivity is strongly correlated with tumor grade although its specific role in applied therapy requires further studies. Human epidermal growth factor receptor 2 (HER2) oncoprotein is less expressed in normal human breast specimens but is highly expressed in certain malignant lesions of the breast. Unlike HER2, epidermal growth factor receptor expression is similar in both normal and malignant tissues. Molecular heterogeneity is not only found in breast carcinomas but also in normal breast tissue. Therefore, the molecular mapping of normal human breast tissue might represent a key research area to fully elucidate the mechanisms of breast carcinogenesis.

VEGF/VEGFR2 Axis in Periodontal Disease Progression and Angiogenesis: Basic Approach for a New Therapeutic Strategy.

Periodontal lesions are associated with activation of pathological angiogenesis and a high number of newly-formed blood vessels. Most angiogenic growth factors have been studied in the crevicular fluid or serum, but tissue correlations with vascular density or endothelial proliferation, are very rare, even inexistent. We assessed the VEGF/VEGFR2 axis expression in a multimodal fashion, in both epithelial and stromal compartments, with emphasis to endothelial proliferation and severity of periodontal lesions. Compared to normal gingiva, negative for VEGF/VEGFR2, periodontal lesions had a progressive increase for these markers from low to severe periodontal lesions. The transition from low to moderate periodontal lesions represents the milestone in disease progression and implies an active angiogenesis based on the highest angiogenic parameter variability observed for these lesions. Epithelial vascularization was firstly observed in moderate periodontal lesions and persists during severe periodontal disease. All the parameters used to quantify angiogenesis in periodontal lesions, were significantly increased in severe periodontal lesions dependent on VEGF expression in both the epithelial and stromal compartment. Our results support the use of anti-VEGF/VEGFR2-targeted therapy as adjuvant treatment for severe periodontal lesions.

Platelet-derived growth factors induced lymphangiogenesis: evidence, unanswered questions and upcoming challenges.

Crosstalk between angiogenesis and lymphangiogenesis in embryonic development continues during postnatal life and has specific mechanisms involving factors that initiate activation of the intracellular cascade for their specific receptors. Platelet-derived growth factors (PDGFs) and their corresponding receptors (PDGFRs) are known as important regulators of blood vessel development in both normal and pathologic angiogenesis. Despite some recent papers which reported a potential role of the PDGF/PDGFR axis in lymphatic spread of tumor cells, a few papers have suggested the potential role of PDGFs in tumor lymphangiogenesis development. The present paper summarizes the potential lymphangiogenic role of the PDGF/PDGFR axis, underlying upcoming challenges in the field.

Tryptase-positive and CD117 Positive Mast Cells Correlate with Survival in Patients with Liver Metastasis.

The prognostic value of mast cells (MCs) in patients with liver metastases is a relatively new topic. The present study comparatively assessed tryptase-positive (MCT(+)) and CD117(+) MCs in liver metastases from various sites and correlated their expression with clinicopathological prognostic factors and survival. Our data pointed to differences in MCT and CD117 expression in liver metastases that seem to be related to the origin of the primary tumor. For colon cancer metastases, intra-tumor MCT(+) MCs were significantly correlated with tumor grade and nodal status, while peritumoral MCT(+) MCs and peritumoral CD117(+) MCs were significantly correlated with overall survival. No significant correlations between MCT(+) and CD117(+) MC number and clinicopathological parameters or survival were found for gastric cancer metastases. To the best of our knowledge, this is the first report regarding MC involvement in liver metastases from different malignant tumors correlated with clinicopathological parameters and overall survival. Different mast cell phenotype together with their specific correlation with tumor grade, nodal status and survival suggest their involvement in the metastatic process in a specific manner related to tumor origin. Mast cells from liver metastases remain a questionable issue regarding their origin, pathogenic role and their ability to be potential targets for adjuvant therapy.