## 4 Role of Triterpenoids in Cancer Prevention
### Role of Triterpenoids in Invasion, Metastasis, and Angiogenesis  
Besides uncontrolled proliferation, the other major characteristics of cancer cells are invasion and metastasis. In metastasis the cancer cells migrate from their original site of origin to other parts of the body, either via the bloodstream or lymphatic system. Among the factors influencing invasion, which affects whether or not a tumor will metastasize, are MMPs and ICAM-1. MMPs (specifically MMP2 and MMP9) are endopeptidases that degrade the basement membrane components, separating the cells from their surrounding tissue and enabling them to move freely and spread to other tissues [214]. Chemokine receptor CCR7 is important for lymphatic invasion of cancer cells and is overexpressed in metastatic breast cancer cells; withanolide inhibits TAK1 to repress NF-kB-induced CCR7 expression in breast cancer cells and is useful for the prevention of lymphatic involvement by breast cancer cells [215]. Erythrodiol-3-acetate, a triterpenoid, reduced the level of MMP1 and induced type 1 procollagen in a dose dependent manner [216]. _Ganoderma lucidum_, a well known mushroom containing platycodon, showed a significant inhibitory effect on PMA-induced MMP9 and MMP2 activation in a dose dependent manner and further inhibited HT-1080 and HepG2 cell invasion and migration [217]. Another study found that boswellic acids potentiated the apoptosis induced by TNF and chemotherapeutic agents, suppressed TNF-induced invasion, and inhibited NF-kB-induced osteoclastogenesis [46]. Angiogenesis is the basis for solid tumor development and distribution, and antiangiogenic drugs have been demonstrated to be active at the site of cancer. The growth of human tumors and development of metastases depends on the _de novo_ formation of blood vessels [218]. Angiogenesis, the physiological process in which new blood vessels develop from pre-existing ones, normally occurs during growth, reproduction, and wound healing; however, this process is also a marker indicating that a tumor has progressed from a dormant to malignant state. Angiogenesis favors tumor growth by providing oxygen and nutrients to multiplying cells via the newly formed blood vessels. Some proangiogenic factors that favor development of new blood vessels include IL-8, TNF, fibroblast growth factor-2 (FGF-2), and PDGF. However, the most important factor in the whole process of angiogenesis is VEGF. Various studies have shown it to be a potent stimulator of angiogenesis _in vitro_[218]. Because of its critical role in angiogenesis, it has been targeted for controlling tumor progression. Limiting VEGF in tumors has been shown to lead to blood vessel destruction and to prevent the growth of new ones, thus reducing the blood supply to the tumor. Inhibition of the VEGF tyrosine kinase signaling pathway blocked angiogenesis in growing tumors, leading to stasis and regression of the tumors. Thus, agents that can downregulate or inhibit the expression of VEGF or its signaling pathway in tumor cells could prove to be very promising in preventing tumor growth and metastasis. Saikosaponin C, one of the saikosaponins present in a Chinese herb, _Radix bupleuri_, has been found to have a potent inducing effect on human umbilical vein endothelial cells' viability and growth. Saikosaponin C also induced endothelial cell migration and capillary tube formation. Saikosaponin C induced the gene expression or activation of MMP2, VEGF, and the p42/p44 MAPK that correlates with endothelial cell growth, migration, and angiogenesis, respectively [219]. Another study found that saikosaponins can inhibit the physiological angiogenesis of chicken embryos, especially for the medium and small vessels [220]. CDDO-Me and CDDO-Im were shown to inhibit the activation of the ERK1/2 pathway after stimulation with VEGF in human umbilical vein endothelial cells [221]. CDDO-Me also potentiated the cytotoxic effects of TNF and chemotherapeutic agents.