Tissue invasion and metastasis: Molecular, biological and clinical perspectives.

Cancer is a key health issue across the world, causing substantial patient morbidity and mortality. Patient prognosis is tightly linked with metastatic dissemination of the disease to distant sites, with metastatic diseases accounting for a vast percentage of cancer patient mortality. While advances in this area have been made, the process of cancer metastasis and the factors governing cancer spread and establishment at secondary locations is still poorly understood. The current article summarizes recent progress in this area of research, both in the understanding of the underlying biological processes and in the therapeutic strategies for the management of metastasis. This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), ß-catenin/zinc finger E-box binding homeobox 1 (ZEB-1) and transforming growth factor beta (TGF-ß), together with inactivation of activator protein-1 (AP-1) and suppression of matrix metalloproteinase-9 (MMP-9) activity as key targets and the use of phytochemicals, or natural products, such as those from Agaricus blazei, Albatrellus confluens, Cordyceps militaris, Ganoderma lucidum, Poria cocos and Silybum marianum, together with diet derived fatty acids gamma linolenic acid (GLA) and eicosapentanoic acid (EPA) and inhibitory compounds as useful approaches to target tissue invasion and metastasis as well as other hallmark areas of cancer. Together, these strategies could represent new, inexpensive, low toxicity strategies to aid in the management of cancer metastasis as well as having holistic effects against other cancer hallmarks.

Oxidative stress based-biomarkers in oral carcinogenesis: how far have we gone?

Oral cancer accounts for 2-3% of all malignancies and according to the World Health Organization (WHO) is the fifth most common cancer worldwide. On the other hand, "oxidative stress" implies a cellular state whereby reactive oxygen species (ROS) production exceeds its metabolism resulting in excessive ROS accumulation and overwhelmed cellular defenses. Such a state has been shown to be involved in the multistage process of human carcinogenesis (including oral cancer) via many different mechanisms. Amongst them are ROS-induced oxidative modifications on major cellular macromolecules like DNA, proteins and lipids with the resulting byproducts being involved in the pathophysiology of human oral malignant and pre-malignant lesions. Throughout this manuscript, we review the current state of knowledge on the role of these oxidative-modified cellular byproducts in serving as reliable biomarkers for oral cancer detection, prognosis and diagnosis.

Targeting DNA damage and repair: embracing the pharmacological era for successful cancer therapy.

DNA is under constant assault from genotoxic agents which creates different kinds of DNA damage. The precise replication of the genome and the continuous surveillance of its integrity are critical for survival and the avoidance of carcinogenesis. Cells have evolved an arsenal of repair pathways and cell cycle checkpoints to detect and repair DNA damage. When repair fails, typically cell cycle progression is halted and apoptosis is initiated. Here, we review the different sources and types of DNA damage including DNA replication stress and oxidative stress, the repair pathways that cells utilize to repair damaged DNA, and discuss their biological significance, especially with reference to cancer induction and cancer therapy. We also describe the main methodologies currently used for the detection of DNA damage with their strengths and limitations. We conclude with an outline as to how this information can be used to identify novel pharmacological targets for DNA repair pathways or enhancers of DNA damage to develop improved treatment strategies that will benefit cancer patients.

Nanotechnology in cancer therapy: targeting the inhibition of key DNA repair pathways.

Cancer therapy has been changing over the decades as we move away from the administration of broad spectrum cytotoxic drugs and towards the use of therapy targeted for each tumor type. After the induction of DNA damage through chemotherapeutic agents, tumor cells can survive due to their proficient DNA repair pathways, some of which are dysregulated in cancer. Latest improvements in nanotechnology and drug discovery has led to the discovery of some very unique, highly specific and innovative drugs as inhibitors of various DNA repair pathways like base excision repair and double strand break repair. In this review we look at the efficacy and potency of these small chemical molecules to target the processing of DNA damage induced by standard therapeutic agents. Emphasis is given to those drugs currently under clinical trials. We also discuss the future directions of using this nanotechnology to increase the therapeutic ratio in cancer treatment.

Effects of radical scavengers on radiation-induced DNA double strand breaks.

PURPOSE: To investigate possible effects of Tris and phenol on the dynamic properties of gamma-irradiated DNA molecules in addition to their well known scavenging capacity. MATERIALS AND METHODS: Native and fragmented calf thymus DNA molecules were exposed to various doses of 60Co gamma-rays at approximately 4.5Gy/min. Using thermal transition spectrophotometry, pulsed field gel electrophoresis and standard agarose gel electrophoresis, the effects of Tris, phenol and NaCl on the double helix to single coil thermal transition temperature, Tm, and the yield of the double-strand breaks (Gdsb) of the irradiated DNA molecules have been studied. RESULTS: DNA molecules exposed to gamma-rays showed a decreased Tm and a corresponding increase of the Gdsb yield. Tris, as well as phenol, exhibited a strong protection against preventing these radiation-induced alterations. In addition, both substances strongly affected the thermal stability of the non-irradiated DNA samples. These results, compared with data obtained by NaCl and its effects on DNA thermostability and Gdsb, revealed that in the presence of both scavengers the observed dsb decrease was correlated to an increased molecular stability of DNA. CONCLUSIONS: This work suggests that the total protective effect of Tris and phenol against radiation-induced dsb is mainly attributed to their well-known radical scavenging properties, while relatively minor protective effects arise from their contribution to an increased molecular stability of DNA.

Alpha-particle-induced changes in the stability and size of DNA.

The effect of alpha-particle radiation on the thermal stability and size of calf thymus DNA molecules in deoxygenated aqueous solutions was investigated by thermal transition spectrophotometry, pulsed-field gel electrophoresis, and standard agarose gel electrophoresis. The thermal transition of DNA from helix to coil was studied through analysis of the UV A(260) absorbance. The results obtained for alpha particles of mean LET of 128 keV microm(-1) reveal a dual dose response: a tendency for thermal stability of the DNA helix at "low" doses, followed by an increasing instability at higher doses. The same phenomenon was observed for the mean molecular weight of DNA molecules exposed to alpha particles. The results reported here for alpha particles in the low-dose region of 0-16 Gy are consistent with our previous hypothesis of inter- and intramolecular interactions of a covalent character in gamma-irradiated DNA molecules in the dose region of 0-4 Gy.

Low doses of alpha- and gamma-radiation enhance DNA thermal stability.

Isolated calf thymus DNA in buffered solutions has been exposed to 0-150 Gy of alpha- and gamma-radiation. The effects of alpha- and gamma-radiation on the thermal stability and electrophoretic mobility of the DNA molecules have been studied by UV spectroscopic 'melting' and Pulsed Field Gel Electrophoresis (PFGE), respectively. The observed thermal denaturation parameters were fitted to the energy propagation descriptive model. The experimental results for the samples exposed to relatively low (low) doses indicate an increased thermal stability and a reduced mobility over that of the controls. The expected overall degradation of the DNA molecules was confirmed for the samples exposed to high doses. Our results are in good agreement with the predictions of the energy propagation model, which now is also tested in the low dose region and for an additional type of ionising radiation (alpha-particles). Our findings are consistent with conformational changes at low doses resulting in a DNA form characterised by localised alterations, which affect the energy flow along the DNA molecule.

Effects of gamma rays on the stability and size of DNA.

The effects of gamma radiation on the stability and size of mammalian DNA were studied by using thermal transition spectrophotometry and pulsed-field and standard agarose gel electrophoresis. The experiments were performed using deproteinized calf thymus DNA in buffered deaerated aqueous solutions. A dual dose response was observed: a tendency for increased helix stability at "low" doses (0-4 Gy) accompanied by a high tendency of the DNA molecules to interact, forming larger molecules, followed by a gradual increase of degradation and helix instability at higher doses. The results reported here for the low-dose region are consistent with the hypothesis of inter- and intramolecular interactions of covalent character (crosslinking) in irradiated DNA molecules.