Figure 1

Tumor composition. Generalized schematic representation of a tumor, showing both components that make up the malignancy: Mutated tumor cells, both putative tumor stem cells in their niche (11) and various differentiated subclonal populations (5), which can be in direct competition (8). The microenvironment, composed of newly formed (2) and forming (6) blood vessels, components of the extracellular matrix, such as fibronectin (9), normal surrounding tissue, and cells altered by their proximity to the mutated tumor cells, including fibroblasts (13). Of note, the highly motile TAMs (7), which do not penetrate the malignancy deeply, but at the tumor periphery can either facilitate tumor growth and invasion or enhance the chemotoxic effects of therapy. Several forms of interaction between mutated tumor cell and microenvironment are also shown, such as the destruction of the microenvironment during invasion (12), the co-opting of blood vessels to increase dissemination (10), and the creation of a novel microenvironment during invasion (1), establishing a premetastatic niche prior to its colonization by cancer cells (3) and the possible formation of distant metastasis by de-differentiation (4). This view of cancer leads to additional potential therapeutic avenues to pursue [5], such as the possibility of blocking the tethering points between cancer cell and matrix and the communication between mutated cancer cells and tumor-associated cells, which can lead to reversion of the tumor microenvironment to `normal' tissue that does not necessarily support tumor growth and either death of the tumor cell by a specialized form of cell death (anoikis) (14) or at least its sensitization towards conventional therapy, i.e., the inhibition of AMAR. Importantly, therapeutic targets must be carefully chosen, as not to enhance cell motility and thereby increase potential invasion/metastasis.