Human Urine Extract (CDA-2) Eliminates Cancer Stem-Like Cells and Inhibits Metastasis: Its Potential Role on the Microenvironment of Primo Vascular System

Abstract

The concept of “cancer stem cell” may renew the notion of designing cancer therapy. The progression and relapse of tumor may be initiated by the remaining cancer stem cell that escapes from conventional cancer treatments such as chemotherapy and radiation. The research on therapeutics targeting this small population of cancer stem cells is badly needed. By UV laser-equipped flow cytometer and cell-permeable DNA binding dye Hoechst 33342, a distinct side population (SP) cells expressing high-level of ATP-binding cassette transporter protein ABCG2/Bcrp1, could be identified and sorted. These SP cells possess characteristics of stem cells such as self-renewal and expression of stemness genes. Using this stem-like SP cells as a model, we had found that a human urine extract CDA-2 could eliminate SP cells in Huh7 hepatoma cells and downregulate the expression of stemness genes such as ABCG2, Gli, and β-catenin. The mRNA levels of DNA methyltransferase 1, 3A, and 3B were obviously higher in SP cells and could be markedly downregulated by CDA-2 in a dose-dependent manner, suggesting the effects of CDA-2 on epigenetic modification. In addition, CDA-2 and its active component (P23.2) were also found to inhibit the EGF-induced epithelial–mesenchymal transition (EMT) in A549 lung cancer cells. It is proposed that the microenvironment may drive the cancer stem cell to undergo EMT and then migrate into blood stream as circulating tumor cells. Recently, a striking finding described that the Bonghan system (primo-vascular system) is a possible stem cell niche and pathway for cancer metastasis. Based on our results, it is interesting to study the potential role of CDA-2 on the inhibitory regulation of microenvironment existed in the Bonghan system. Further investigation on the manipulation of the Bonghan system by CDA-2 for developing a novel therapeutics is warranted.