Adam Piecuch

Biomolecular Mechanisms in Varicose Veins Development

Varicose veins (VVs) can be described as tortuous and dilated palpable veins, which are more than 3 mm in diameter. They are one of the clinical presentations of chronic venous disorders, which are a significant cause of morbidity. The prevalence of VVs has been estimated at 25-33% in women and 10-20% in men and is still increasing at an alarming rate. Family history, older age, female, pregnancy, obesity, standing occupations, and a history of deep venous thrombosis are the predominant risk factors. A great amount of factors are implicated in the pathogenesis of VVs, including changes in hydrostatic pressure, valvular incompetence, deep venous obstruction, ineffective function of calf muscle pump, biochemical and structural alterations of the vessel wall, extracellular matrix abnormalities, impaired balance between growth factors or cytokines, genetic alterations, and several other mechanisms. Nevertheless, the issue of pathogenesis in VVs is still not completely known, even if a great progress has been made in understanding their molecular basis. This kind of studies appears promising and should be encouraged, and perhaps the new insight in this matter may result in targeted therapy or possibly prevention.

The role of Snail1 transcription factor in colorectal cancer progression and metastasis

Snail1 is a zinc-finger transcription factor, which plays a role in colorectal cancer development by silencing E-cadherin expression and inducing epithelialmesenchymal transition (EMT). During EMT tumour cells acquire a mesenchymal phenotype that is responsible for their invasive activities. Consequently, Snail1 expression in colorectal cancer is usually associated with progression and metastasis. Some studies revealed that about 77% of colon cancer samples display Snail1 immunoreactivity both in activated fibroblasts and in carcinoma cells that have undergone EMT. Therefore, expression of this factor in the stroma may indicate how many cells possess the abilities to escape from the primary tumour mass, invade the basal lamina and colonise distant target organs. Blocking snail proteins activity has the potential to avert cancer cell metastasis by interfering with such cellular processes as remodelling of the actin cytoskeleton, migration and invasion, which are clearly associated with the aggressive phenotype of the disease. Moreover, the link between factors from the snail family and cancer stem cells suggests that inhibitory agents may also prove their potency as inhibitors of cancer recurrence.

Notch signalling pathway as an oncogenic factor involved in cancer development.

Notch signalling is an evolutionarily conserved signalling pathway, which plays a significant role in a wide array of cellular processes including proliferation, differentiation, and apoptosis. Nevertheless, it must be noted that Notch is a binary cell fate determinant, and its overexpression has been described as oncogenic in a broad range of human malignancies. This finding led to interest in therapeutically targeting this pathway especially by the use of GSIs, which block the cleavage of Notch at the cell membrane and inhibit release of the transcriptionally active NotchIC subunit. Preclinical cancer models have clearly demonstrated that GSIs suppress the growth of such malignancies as pancreatic, breast, and lung cancer; however, GSI treatment in vivo is associated with side effects, especially those within the gastrointestinal tract. Although intensive studies are associated with the role of γ-secretase in pathological states, it should be pointed out that this complex impacts on proteolytic cleavages of around 55 membrane proteins. Therefore, it is clear that GSIs are highly non-specific and additional drugs must be designed, which will more specifically target components of the Notch signalling.

Immunohistochemical assessment of mitochondrial superoxide dismutase (MnSOD) in colorectal premalignant and malignant lesions

Introduction It is generally accepted that mitochondria are a primary source of intracellular reactive oxygen species (ROS). Under physiological circumstances they are permanently formed as by-products of aerobic metabolism in the mitochondria. To counter the harmful effect of ROS, cells possess an antioxidant defence system to detoxify ROS and avert them from accumulation at high concentrations. Mitochondria-located manganese superoxide dismutase (MnSOD, SOD2) successfully converts superoxide to the less reactive hydrogen peroxide (H2O2). To the best of our knowledge, there are no available data regarding immunohistochemical expression of MnSOD in colorectal neoplastic tissues. Aim To investigate the immunohistochemical expression status of MnSOD in colorectal premalignant and malignant lesions. Material and methods This study was performed on resected specimens obtained from 126 patients who had undergone surgical resection for primary sporadic colorectal cancer, and from 114 patients who had undergone colonoscopy at the Municipal Hospital in Jaworzno (Poland). Paraffin-embedded, 4-µm-thick tissue sections were stained for rabbit polyclonal anti SOD2 antibody obtained from GeneTex (clone TF9-10-H10 from America Diagnostica). Results Results of our study demonstrated that the development of colorectal cancer is connected with increased expression of MnSOD both in adenoma and adenocarcinoma stages. Samples of adenocarcinoma with G2 and G3 grade showed significantly higher levels of immunohistochemical expression of this antioxidant enzyme. Moreover, patients with the presence of lymphovascular invasion and higher degree of regional lymph node status have been also characterised by higher levels of MnSOD expression. The samples of adenoma have been characterised by higher levels of MnSOD expression in comparison to normal mucosa as well. Interestingly, there was no significant correlation between expression and histological type of adenoma. Conclusions Development of colorectal cancer is connected with increased expression of MnSOD both in adenoma and adenocarcinoma stages.

The complex interplay between Notch signaling and Snail1 transcription factor in the regulation of epithelial–mesenchymal transition (EMT)

SummaryBackgroundThe epithelial–mesenchymal transition (EMT) is a highly coordinated process observed during embryonic development and adult tissue repair. It is characterized by the loss of cell–cell adhesion and apicobasal polarity, and the transition to a cell type with a spindle-like phenotype able to migrate through the basal membranes.MethodsThis review article includes available date from peer-reviewed publications associated with the role of Notch signaling and Snail1 transcription factor in activation and regulation of EMT.ResultsGrowing evidences in the past few years demonstrated a significant role of Notch in EMT activation. It is not surprising because this pathway is the nexus of a unique and versatile signaling network, that regulates and is regulated by a variety of cellular mechanisms highly dependent on the biological context—especially tissue microenvironment. This compartment sends signals promoting and regulating EMT, which usually acts as a transcriptional repressors. Among them, Snail1 has been shown to be crucial for cellular movement during cancer progression and metastasis. In cancer patients, increased level of Snail1 is usually connected with poor clinical outcome, probably due to downregulation of E-cadherin expression. Moreover, the continuous expression of E-cadherin during developmental EMT in Snail1-deficient mouse embryos clearly supports the idea that its transcriptional repression is mostly related to Snail1 activity.ConclusionCooperation of Notch signaling and Snail1 plays very significant role in such pathologies as wound healing and cancer development. Nevertheless, they are also involved in tissue embryonic development.

Apoptosis in Primary Hyperparathyroidism

ABSTRACT Primary hyperparathyroidism (PHPT) is defined by inappropriate elevation of parathormone, caused by parathyroid hyperplasia, also known as multi-gland disease (MGD), parathyroid adenoma (PA), or parathyroid carcinoma (PC). Although several studies have already been conducted, there is a lack of a definite diagnostic marker, which could unambiguously distinguish MGD from PA or PC. The accurate and prompt diagnosis has the key meaning for effective treatment and follow-up. This review paper presents the role of apoptosis in PHPT. The comparison of the expression of Fas, TRAIL, BCL-2 family members, p53 in MGD, PA, and PC, among others, was described. The expression of described factors varies among proliferative lesions of parathyroid gland; therefore, these could serve as additional markers to assist in the diagnosis.

Angiogenesis in primary hyperparathyroidism

Angiogenesis can be described as a formation of new vessels from the existing microvasculature and is a process of great importance to the tumor development. Parathyroid tissue can trigger spontaneous induction of angiogenesis in vitro and in vivo models in a vascular endothelial growth factor (VEGF)-dependent manner. Autotransplantated parathyroid tissue after thyroidectomy is able to form new vasculature and produce parathormone, maintaining calcium homeostasis. A great amount of factors contributes to the process of new vessel formation in primary hyperparathyroidism, such as VEGF, transforming growth factor β, and angiopoietins. Studies demonstrated that markers for angiogenesis can be useful in distinguishing between parathyroid hyperplasia and neoplasia, due to the increased angiogenesis in parathyroid proliferative lesions compared with parathyroid adenomas. These factors include, inter alia, VEGF, VEGFR2, CD105, and fibroblast growth factor-2. Although these differences appear promising in the differential diagnosis, there is an overlap between benign and malignant parathyroid lesions and there is no definite cutoff value. Loss of heterozygosity and comparative genomic hybridization studies revealed chromosomal regions frequently altered in parathyroid tumorigenesis at 9p21, 1p21-22, 1p35-36, and 11q13. Therefore, immunohistochemistry and genetic testing should be an additional diagnostic marker in combination with the traditional criteria. A better understanding of angiogenesis in primary hyperparathyroidism could result in more precise assessment of diagnosis and more effective treatment, especially in those cases, in which the commonly used parameters are insufficient.