Notch and its oncogenic activity in human malignancies.

BACKGROUND: Increasing evidence has demonstrated that Notch signaling is deregulated in human hematological malignancies and solid tumors. This signaling has a protumorigenic effect but may also act as a tumor suppressor. How induction of a single pathway gives rise to the opposite effects in different cell types is still unknown. METHODS: This review article includes available data from peer-reviewed publications associated with the role of Notch signaling during cancer pathogenesis. RESULTS: Numerous reports have indicated that alterations in Notch signaling and its oncogenic activity were originally associated with the pathogenesis of T­cell acute lymphoblastic leukemia/lymphoma (T-ALL), an aggressive hematologic tumor affecting children and adolescents. The possibility that Notch could play a significant role in human breast cancer development comes from studies on mouse mammary tumor virus-induced cancer. Numerous findings over the past several years have indicated that alterations in Notch signaling are also responsible for ovarian cancer development. Mention should also be made of the connection between expression of Notch 3 and increased resistance to chemotherapy, which remains a major obstacle to successful treatment. Notch as an oncogenic factor is also involved in the development of colon cancer, lung carcinoma and Kaposi's sarcoma. CONCLUSION: Notch is a binary cell fate determinant and its overexpression has been described as oncogenic in a wide array of human malignancies. This finding led to interest in therapeutically targeting this pathway, especially by the use of gamma-secretase inhibitors (GSIs) blocking the cleavage of Notch receptors at the cell membrane by the inhibition of Notch intracellular domain (NICD) releasing. Preclinical cancer models have revealed that GSIs suppress the growth of cancers such as pancreatic, breast and lung cancer.

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.

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.

The role of tumour microenvironment in gastric cancer angiogenesis.

Gastric cancer is one of the most common cancers in the world. More than 95% of gastric cancers are adenocarcinomas originating from the glandular epithelium of the stomach lining. Unfortunately, a large number of patients are diagnosed when the tumour is at unresectable stage. Therefore, it is very important to understand the mechanisms involved in gastric cancer pathogenesis. One of them is angiogenesis, which means the formation of new blood vessels from pre-existing vasculature. This process is dependent on interactions between the tumour and surrounding stromal cells which create the tumour microenvironment. Moreover, both tumour and stromal cells release a wide array of angiogenic factors that have an influence on endothelial cell recruitment and thus affect the process of angiogenesis. In this paper we discuss the role of tumour microenvironment in gastric cancer angiogenesis.

Role of Notch signaling pathway in gastric cancer pathogenesis.

Notch signaling pathway is activated dynamically during evolution playing significant role in cell fate determination and differentiation. It has been known that alterations of this pathway may lead to human malignancies, including gastric cancer. Despite a decline in the overall incidence, this disease still remains an important global health problem. Therefore, a better understanding of the molecular alterations underlying gastric cancer may contribute to the development of rationally designed molecular targeted therapies. It has been reported that Notch1 receptor could become a prognostic marker of gastric cancer and novel target for gastric cancer therapy. Among the novel and targeted approaches for the treatment of gastric cancer is also the process of Notch receptors regulation by specific microRNA. γ-secretase inhibitors are also taken into consideration.

Protective effect of intermittent clamping of the portal triad in the rat liver on liver ischemia-reperfusion injury.

BACKGROUND: Intermittent clamping (IC) of the portal triad is an effective method of protecting the liver from ischemia-reperfusion injury (IR). In clinical practice, this method is employed during a resection, but its mechanism is still not clear. OBJECTIVES: To evaluate the effect of IC on rat liver and determine its mechanisms. MATERIALS AND METHODS: Wistar rats were submitted to 60-min IC (cycles of 12-min clamping followed by 4-min reperfusion), and the samples were collected after 1, 6, and 72 hrs of reperfusion. We determined the serum activity of alanine aminotransferase (ALT), and measured the concentration of TNF-α, malondialdehyde (MDA) and myeloperoxidase (MPO) in liver homogenates. The apoptosis of hepatocytes was evaluated immunohistochemically. RESULTS: When compared to the IR rats, the activity of ALT decreased in the IC group in all periods of observation (the highest decrease of ~48% after 1 hr of reperfusion). When compared to the IR group, a statistically significant decrease (p < 0.05) in the TNF-α concentration (~33%) in the IC rats occurred only after 1 hr of reperfusion, and it was accompanied by a decrease in the MPO concentration after 1 and 6 hrs of reperfusion. IC reduces the effects of reactive oxygen species (ROS) activity, which has been confirmed by a statistically significant decrease in MDA concentration by 25%-35% in all studied periods. The limitation of hepatocytes apoptosis due to IC occurs in the early (~26%; p < 0.05) and late (~45%; p < 0.01) phases of reperfusion. CONCLUSIONS: The use of IC in early phase of reperfusion brings about a decrease in TNF-α release, which can be related to liver injury due to neutrophil infiltration and apoptotic cell reduction. It seems that the reduction of lipid peroxidation may also limit the liver injury.

RNA and protein synthesis in different organs of rat offspring after chronic cadmium exposure during pregnancy.

Despite binding by placental metallothionein, cadmium (Cd) relatively easily enters fetal circulation and may be harmful to tissues and organs of offspring. Although Cd toxicology is relatively well described in the literature there are only few studies on Cd toxicity exerted during fetal life. We examined the influence of cadmium exposure during pregnancy on RNA and protein synthesis in different organs of the rat offspring. Their dams were fed diet containing cadmium chloride-treated drinking water during the whole pregnancy period at 50 ppm dose level. The offspring, 6-weeks-old male Wistars rats, weighing 105 + 10 g were subjected to examination. Synthesis of RNA and proteins was quantitated by scintillation technique, which measured incorporation of tritiated uridine and alanine, respectively. A set of 17 organs and tissues was examined. RNA synthesis increased significantly in buccal mucosa, tongue, parotid gland, cardiac muscle, brain and bone marrow. A strong induction of RNA synthesis in all four studied brain regions attracts special attention. The activation of RNA metabolism may be partly explained by the increased expression of genes involved in detoxication and adaptation (e.g., metallothionein, stress response proteins, etc.). A profile of protein synthesis was much more heterogenous with elevated H3-alanine uptake in 12 organs of experimental animals, however without any statistical significance. Since the study of protein synthesis did not demonstrate any significant changes in Cd-treated animals, the profile of RNA synthesis cannot be simply extrapolated on protein synthesis, probably because of complex post-transcriptional and post-translational genetic modifications.