Therefore, HGF/SF is known as to be widely involved in the tumor metastatic process

Therefore, HGF/SF is known as to be widely involved in the tumor metastatic process. of metastasis promoter (-Catenin). On the other hand, the intriguing functions of metastasis suppressors and their transmission pathways have been extensively studied and various attempts have been made to potentiate these factors. Small molecules have been developed to restore the expression or mimic the function of metastasis suppressor genes such as NM23, E-cadherin, Kiss-1, Pipendoxifene hydrochloride MKK4 and NDRG1, and some of them are under clinical trials. This review summarizes our current understanding of the molecular pathway of tumor metastasis and discusses strategies and recent development of anti-metastatic drugs. 1. Introduction Malignancy is the second leading cause of death in the USA, and more than half a million people succumb to the disease every year [1]. Despite significant improvements in screening methods and treatment options, the majority of malignancy patients are still diagnosed at an advanced stage, and more than 90% of patients ultimately pass away from sequel of metastatic disease. Therefore, metastasis is usually a hallmark of malignancy, and no effective therapeutic option is currently available for those patients. Although the clinical importance of tumor metastasis is usually well recognized, improvements Pipendoxifene hydrochloride in understanding the molecular mechanism involved in metastasis formation have lagged behind other developments in the field of cancer research. This is attributed to the fact that malignancy cells are extremely heterologous in nature and that metastasis entails multiple actions with a high degree of complexity, and each step requires coordinated action of many promoters and suppressors. However, extensive efforts in the past decade have led to the discoveries of many previously unknown factors involved in metastasis and also unveiled several novel concepts in this research field [2,3]. These findings have shed new light on molecular pathways of metastasis, which also provided valuable information about potential targets for the treatment of metastatic disease. This review discusses our current understanding of molecular mechanism of metastatic process and summarizes recent information of drug development specifically targeted to the metastatic pathways. 2. Tumor metastasis entails multi-step process with high complexity A primary tumor generally consists of heterogeneous cell types including a small number of malignancy stem cells that are able to perpetually proliferate without responding to tumor suppressor function. The current theory predicts that these malignancy stem cells originate from a normal stem cell or a malignancy cell, which acquired a stem cell-like ability [4]. When a tumor develops more than 1mm3 in size at the primary site, it acquires active supply of oxygen and nutrients by promoting angiogenesis. Tumor cells accomplish this task by generating hypoxic environment followed by secretion of angiogenic growth factors (Fig 1). Tumor cells that gain growth advantage further proliferate and acquire metastatic phenotypes due to additional mutations. The first step in metastasis is the detachment of these tumor cells from the primary tumor mass by acquiring an invasive phenotype that results in the loss of cell-cell adhesion and cell-extracellular matrix adhesion followed by proteolytic degradation of the matrix (Fig 1) [5]. It is believed that autocrine motility factor(AMF) and hepatocyte growth factor (HGF) are crucial components of motility and that degradative enzymes including serine-, thiol-proteinases, heparanases and metalloproteinases such as MMP2 and 9 play crucial functions in the invasion [6C8]. When tumor cells intravasate surrounding tumor vasculature and neighboring Pipendoxifene hydrochloride lymphatic vessels, they must survive in this hostile environment that includes mechanical damage, lack of growth factor from the original environment and the host immune system (Fig 1) [9]. Tumor cells in the blood circulation often aggregate with platelets and fibrin, and Pipendoxifene hydrochloride they embolize in the capillaries or directly adhere to the endothelial cells by a mechanism much like leukocyte adhesion at the inflammatory site [10C12]. In some cases, arrested tumor cells extravasate before proliferating themselves using the same hydrolytic enzymes that are STAT2 used in the initial step of invasion (Fig 1) [13]. However, in many cases, cancer cells actually proliferate within the lumen of vessels to create a considerable tumor mass that can eventually obliterate the adjacent vessel wall by pushing aside the barrier composed of endothelial cells, pericytes and easy muscle mass cells that.