Marek Baltaziak

Leptin - From Regulation of Fat Metabolism to Stimulation of Breast Cancer Growth

Leptin restricts intake of calories as a satiety hormone. It probably stimulates neoplastic proliferation in breast cancer, too. Growth of malignant cells could be regulated by various leptininduced second messengers like STAT3 (signal transducers and activators of transcription 3), AP-1 (transcription activator protein 1), MAPK (mitogenactivated protein kinase) and ERKs (extracellular signalregulated kinases). They seem to be involved in aromatase expression, generation of estrogens and activation of estrogen receptor α (ERα) in malignant breast epithelium. Leptin may maintain resistance to antiestrogen therapy. Namely, it increased activation of estrogen receptors,therefore,it was suspected to reduce or even overcome the inhibitory effect of tamoxifen on breast cell proliferation. Although several valuable reviews have been focused on the role of leptin in breast cancer,the status of knowledge in this field changes quickly and our insight should be continuously revised. In this summary,we provide refreshed interpretation of intensively reported scientific queries of the topic.(Pathology Oncology Research Vol 12, No 2, 69–72)

E-cadherin and β-catenin adhesion proteins correlate positively with connexins in colorectal cancer.

The majority of solid cancers present with qualitative and quantitative aberrations of adhesion proteins, including E-cadherin and β-catenin, and connexin (Cx) gap junction proteins, which is consistent with alterations in the expression and location of such proteins in neoplastic cells. Since there are no data on the correlation between adhesion proteins and Cxs in human colorectal cancer (CRC), the aim of the present study was to evaluate the expression and correlation between these proteins. Tissue specimens were obtained from 151 cases of surgically removed colorectal adenocarcinomas. The samples were examined by immunohistochemistry with the use of antibodies against E-cadherin, β-catenin and the three Cxs: Cx26, Cx32 and Cx43. The aberrant expression of the studied adhesion proteins (primarily cytoplasmic for E-cadherin and cytoplasmic and/or nuclear for β-catenin) was observed, whereas only a minority of cases revealed normal membranous distribution of the labeling. The present study is the first in the literature to reveal a correlation between the expression of E-cadherin and β-catenin and the examined Cxs in CRC in humans. The positive correlation between the Cxs, particularly Cx26 and Cx32, and the adhesive proteins occurred in patients without lymph node metastases and in the moderately differentiated tumors (G2). Such a dependency was not observed in the analysis of the correlation between Cx43 and E-cadherin. However, a positive correlation between these proteins was observed in patients with lymph nodes metastases. Additionally, a link between the expression of these adhesion proteins was observed. The present study indicates, for the first time, that the expression of adhesion proteins, E-cadherin and β-catenin, is closely associated with the expression of three studied Cxs in CRC, and that this correlation may improve an understanding of the carcinogenic process in this cancer.

Aberrant Distributions and Relationships Among E-cadherin, β-catenin, and Connexin 26 and 43 in Endometrioid Adenocarcinomas

During carcinogenesis, loss of intracellular cohesion is observed among cancer cells with altered expression of such adhesion molecules as E-cadherin and β-catenin, and aberrant expression and cellular location of intercellular gap junction proteins-connexins. The aim of this study was to evaluate immunohistochemically the expression and relationship between E-cadherin and β-catenin, and the connexins Cx26 and Cx43 in 86 endometrioid adenocarcinomas. The aberrant cytoplasmic translocation of the studied proteins was a predominant finding, whereas only a minority of cases showed normal, nuclear β-catenin labeling or membranous distribution of the remaining molecules. E-cadherin was positively and significantly associated with β-catenin (P=0.001, r=0.366), as was Cx26 with Cx43 (P<0.001, r=0.719), E-cadherin with Cx26 (P<0.001, r=0.413), and E-cadherin and Cx43 (P<0.001, r=0.434) in all cancers. A subgroup of endometrioid adenocarcinomas (FIGO IB+II) exclusively showed a positive significant association between the expression of β-catenin and Cx26 (P=0.038, r=0.339). In addition, there were significantly more β-catenin-positive carcinomas among superficially spreading cancers (FIGO IA) than among deeper invading neoplasms (FIGO IB+II) (P=0.056). The altered location of the studied proteins indicates impairment of their physiological functions. In particular, normal membranous distribution of E-cadherin and connexins is lost and replaced by abnormal cytoplasmic accumulation in most cancers, and thus intercellular ties are expected to be weakened and loosened as a consequence. In contrast, the lack of relationship between β-catenin and connexins, E-cadherin seems to be closely associated with the expression of Cx26 and Cx43 in endometrioid adenocarcinomas.

Expression of Bcl-xL, Bax, and p53 in Primary Tumors and Lymph Node Metastases in Oral Squamous Cell Carcinoma

Abstract:  Disturbances in expression of apoptosis‐associated proteins take part in the development and progression of many human malignancies. The aim of this study was the assessment of correlations among proteins involved in apoptosis—Bcl‐xL, Bax, and p53—as well as relationships of these proteins with selected clinicopathological features in oral squamous cell carcinoma. Consequently, we examined by immunohistochemistry, using the avidin–biotin–peroxidase method, Bcl‐xL, Bax, and p53 expression in 56 samples of primary oral squamous cell carcinoma and in 22 matched pairs of primary and metastatic tumors. The evaluation of immunostaining of Bcl‐xL, Bax, and p53 was analyzed in 10 different tumor fields, and the mean percentage of tumor cells with positive staining was evaluated. The significance of the associations was determined using Spearman correlation analysis and the chi‐square test. We found positive Bcl‐xL, Bax, and p53 immunostaining in 44.6%, 28.6%, and 58.9% of the studied primary tumors and in 63.6%, 45.5%, and 72.7% of lymph node metastases, respectively. Analysis of associations among studied proteins revealed positive correlation between Bcl‐xL and Bax in primary tumors (P < 0.03, r= 0.307). Statistically significant relationship between p53 expression in primary oral cancers and its expression in lymph node metastases (P < 0.02) as well as increased expression of Bcl‐xL, Bax, and p53 in metastatic sites compared with primary tumors could indicate an association of these proteins with oral cancer progression and development of metastases. Moreover, we suppose that knowledge about heterogeneity between primary and metastatic tumor might help to understand mechanisms of oral cancer progression.

Widespread myocardial and pulmonary bone marrow embolism following cardiac massage

Widespread fatal massive bone marrow embolism of the coronary and the pulmonary arteries are described in a 71-year-old man with a respiratory disease. Cardiac massage was carried out during the cardiac arrest. In autopsy findings there were no fractures of the ribs or the sternum. The authors suggested that the cardiac massage was the most important predisposing factor for the bone marrow embolism.

The relationships between hypoxia-dependent markers: HIF-1alpha, EPO and EPOR in colorectal cancer

Hypoxia triggers production of several cytoprotective proteins. Hypoxia-inducible factor 1alpha (HIF-1α) is a powerful stimulator of transcription of many genes, including erythropoietin (EPO) in hypoxia-affected cells. Recent data have also implicated signaling by EPO receptor (EPOR) as a new factor influencing tumor progression. The aim of the study was to detect by immunohistochemistry the presence of HIF-1α, EPO and EPOR in colorectal cancer (CRC) in reference to clinicopathological variables. We found the presence of the studied proteins in specimens of all 125 CRC patients which is suggestive of the occurrence of hypoxia in colorectal cancer tissues. The expression of HIF-1α correlated significantly with the presence of EPO and EPOR in all samples (P < 0.001, r = 0.549 and P < 0.001, r = 0.536, respectively). Significant correlations (from P < 0.024 to P < 0.001) were found in the analyses of CRC subgroups such as histopathological type tumor, tumor grade, tumor stage and patients with lymph nodes metastases. The same high significant correlations (P < 0.001) were observed in group of sex, age and tumor location. However, the values of the correlation coefficients (r) which usually ranged from 0.5 to 0.6 suggest the existence of independent or concurrent mechanism stimulating generation of these proteins in colorectal cancer.

Hypoxia related growth factors and p53 in preoperative sera from patients with colorectal cancer - evaluation of the prognostic significance of these agents

Abstract Background: Insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) belong to a group of hypoxia related proteins. IGF-I induces expression of VEGF and decomposes wild type p53 in cancer cell lines. The goal of our study was to evaluate serum IGF-I, VEGF and p53 with respect to overall and disease free survival of patients with colorectal cancer (CRC) patients compared with healthy volunteers. Methods: Preoperative blood samples from 125 patients with CRC and 16 healthy volunteers were examined using ELISA for serum IGF-I, p53 and VEGF concentrations. Results: Concentrations of p53 and VEGF were significantly higher in CRC patients than in controls (p<0.0006 and p<0.0001, respectively). IGF-I was not statistically different between both groups. Serum IGF-I showed negative correlation with p53 in CRC patients (p<0.04, r=−0.193). IGF-I and VEGF showed negative correlation in poorly differentiated cancers (G3) (p<0.03, r=−0.339). Patients with VEGF concentrations that were above average for the cancer population survived for a shorter period of time (p=0.065 in evaluation of overall survival and 0.071 in estimation of disease-free survival during a 3-year follow-up) compared with patients with serum VEGF lower than the highest values seen in controls. Conclusions: Comparisons between serum IGF-I and p53 appear to confirm the metabolism of p53 by IGF-I. Serum VEGF showed prognostic significance in our study. Serum concentrations of IGF-I and VEGF did not show positive correlation, as expected due to IGF-I induction of VEGF in malignant colon cell lines. Clin Chem Lab Med 2009;47:1439–45.