Drug development against metastasis-related genes and their pathways: A rationale for cancer therapy

Abstract

It is well recognized that the majority of cancer related deaths is caused by metastatic disease. Therefore, there is an urgent need for the development of therapeutic intervention specifically targeted to the metastatic process. In the last decade, significant progress has been made in this research field, and many new concepts have emerged that shed light on the molecular mechanism of metastasis cascade which is often portrayed as a succession of six distinct steps; localized invasion, intravasation, translocation, extravasation, micrometastasis and colonization. Successful metastasis is dependent on the balance and complex interplay of both the metastasis promoters and suppressors in each step. Therefore, the basic strategy of our interventions is aimed at either blocking the promoters or potentiating the suppressors in this disease process. Toward this goal, various kinds of antibodies and small molecules have been designed. These include agents that block the ligandrecepter interaction of metastasis promoters (HGF/c-Met), antagonize the metastasis promoting enzymes (AMF,uPA and MMP) and inhibit the transcriptional activity of metastasis promoter (β-Catenin). On the other hand, the intriguing roles of metastasis suppressors and their signal 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, 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.

KAI1 Gene Is Engaged in NDRG1 Gene-mediated Metastasis Suppression through the ATF3-NFκB Complex in Human Prostate Cancer

“…Recent studies demonstrated that the NDRG1 gene is controlled by a variety of factors and stimuli related to cancer progression, including oncogenes, tumor suppressors, hypoxic microenvironment, and hormone dysregulation (30,31). Clinical studies also provided compelling evidence that reduced expression of the NDRG1 gene was significantly associated with poor overall survival rate in pancreatic ductal adenocarcinoma, glioma, prostate, breast, and colorectal cancers (32). The significant inverse correlation of NDRG1 expression with the extent of metastasis in a clinical setting raised an important question as to whether the down-regulation of NDRG1 is cause or result of metastases.…”

Kisspeptins (KiSS-1): Essential Players in Suppressing Tumor Metastasis

“…KiSS-1 (formerly known as metastin) occur naturally in human placenta which was named for its role as a suppressor sequence (SS); the letters "Ki" were appended to the prefix "SS" to form "KiSS" in homage to the location of its discovery, Hershey, Pennsylvania, home of the famous "Hershey Chocolate KiSSes" (Kotani et al, 2001;Shevde et al, 2003;Iiizumi et al, 2008;Smith and Theodorescu, 2009). It is well known that KiSS-1 gene involve in tumor biology and metastatic process, therefore, in this review we discuss the potential roles of the KiSS-1 gene during tumor progression and how it could be used as a potential molecular target for cancer therapy.…”

Breast Cancer and Current Therapeutic Approaches: From Radiation to Photodynamic Therapy

“…Some genes hold great promise as potential drug targets. Reactivation of metastasis-suppressor genes and their signal pathways such as MKK/JNK, PTEN/Akt and NDRG/ATF is also a rational strategy (Iiizumi et al, 2008). In accord with the PTEN studies undertaken in the last decade, we would like to point out the very important role of lipid phosphatase in suppression of tumour growth.…”