NK4 (HGF‐antagonist/angiogenesis inhibitor) in cancer biology and therapeutics

Abstract

hough knowledge of the molecular mechanisms of tumorigenesis has greatly advanced in recent years, the cure rate of cancer has not been substantially improved. Cancers are still the first or second most common cause of death in developed countries. Tumor metastasis is the most important factor affecting the survival of cancer patients. Many cancer patients die as a consequence of a metastatic, not a primary tumor. If metastasis could be controlled, the rate of cancer cures should show a marked improvement.The dissociation and migration of tumor cells, adhesive interaction of cancer cells towards the extracellular matrix (ECM), and extracellular proteolysis of ECM proteins all play key roles in tumor invasion and metastasis. Although mutational alterations that occur in oncogenes and tumor suppressor genes are responsible for tumorigenic transformation of cells, the metastatic behavior of tumor cells is largely regulated by extracellularly acting growth factors. Among these factors, hepatocyte growth factor (HGF), a ligand for the c-met protooncogene product, affects metastatic behavior in a wide variety of cells.

Accumulative copy number increase of MET drives tumor development and histological progression in a subset of ovarian clear-cell adenocarcinomas

“…12,[34][35][36][37] Taken together with our present data, MET appears to be an important therapeutic target in the treatment of ovarian clear-cell adenocarcinomas with MET alterations, justifying the exploration of anti-MET treatment strategies. Moreover, as HGF is the only known ligand for the MET receptor, neutralization of HGF using ribozymes 38 or antagonistic fragments such as NK4, 39 and neutralizing antibodies 40 may also be the potentially attractive compounds for inhibiting HGF/MET signaling.…”

Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells

“…Especially, tumor cells have been shown to secrete various humoral factors (for example, VEGF, platelet-derived growth factor, endo thelial growth factor, transforming growth factor-a and interleukin-8) into the tumor microenvironment, [29][30][31][32] and tumor growth requires the formation of mesenchymal stroma to promote angiogenesis and metastasis to specific distant organs. 33 Although angiogenesis has been the focus of tumor progression, lymphangiogenesis also plays an important role in tumor progression and metastasis. Nicole et al 34 reported that inhibition of VEGFR3 signaling was effective in suppressing regional and distant tumor metastases.…”

Bi-directional Regulation of Ser-985 Phosphorylation of c-Met via Protein Kinase C and Protein Phosphatase 2A Involves c-Met Activation and Cellular Responsiveness to Hepatocyte Growth Factor

“…These biological activities of HGF are triggered by tyrosine phosphorylation of c-Met, a specific receptor tyrosine kinase for HGF (7). Biological activities of HGF support tissue organization during development and regeneration of organs, including the liver, kidney, placenta, and skeletal muscle (4 -6), but unregulated and/or constitutive activation of the c-Met receptor endows tumor cells with invasive and metastatic characteristics (8,9).…”