Abstract C42: Suppression of tumor invasion by inorganic nanoparticles
Authors: Alili Lirija , Karakoti Ajay S. , Seal Sudipta , Brenneisen Peter 
Published: May 2012

Tumor progression is characterized by local accumulation of extracellular matrix components and connective tissue cells surrounding the tumor cluster, a phenomenon called tumor-stroma interaction. Disturbance in the stroma, composed of endothelial, fibroblastic and myofibroblastic cells as well as inflammatory cells, is suggested to be essential during the invasion process. A range of cytokines and growth factors are expressed by tumor and stromal cells in melanoma and carcinoma that enhance the invasive and metastatic capacity of tumor cells. It was shown previously that the reactive oxygen species (ROS) dependent transdifferentiation of fibroblasts to α-smooth muscle actin expressing myofibroblasts (mesenchymal-mesenchymal transition, MMT) by tumor cell-derived transforming growth factor β-1 (TGFβ1) is a prerequisite for an increase in the aggressive behavior of the tumor cells. In the following work the question was addressed of whether typical antioxidants or inorganic nanoparticles attenuate or completely abrogate tumor-stroma interaction. Cell biological, biochemical, and molecular biological approaches showed that antioxidants such as the thiol N-acetyl L-cysteine and the micronutrient selenite significantly lowered the generation of myofibroblasts and the secretion of proinvasive soluble factors resulting in thinning the capacity of tumor invasion. However, the exclusive treatment of the tumor cells resulted in an opposite effect, namely enhanced tumor cell migration. Therefore, the ability of cerium oxide nanoparticles (CNPs) to control the invasion of tumor cells and specifically the expression of α-smooth muscle actin in stromal cells was evaluated. CNPs can scavenge ROS analogous to naturally occurring enzymes. However, CNPs have an added advantage of being regenerative through changes occurring at molecular level and surrounding electrochemical media, and, therefore, under certain intracellular or extracellular conditions function as pro-oxidant. It is hypothesized that structural oxygen vacancies in nanoceria can act as trapping sites for ROS thereby regulating their over expression in one single dose. As the mode of action of CNPs depends on different physical qualities, it is very important to engineer CNPs carefully thereby providing them with medium dependent properties. Different types of nanoceria were studied for their antioxidant and proxoxidant properties. It was found that the nanoceria treatment showed decreased cell viability of squamous carcinoma cell line (SCL-1) by more than 60% while protecting the human dermal fibroblasts viability at 100%. Such an acute effect of ROS scavenging nanoparticles on lowering the number of myofibroblasts can reaffirm the stromal therapy by protecting the stromal cells against dominating influence of the tumor cells in tumor-stroma interaction. Thus treatment with inorganic nanoceria as antioxidant may form the basis for the prevention of MMT as benign strategy for chemoprevention of tumor invasion.

Citation Information: Cancer Res 2009;69(23 Suppl):C42.