Modeling Steps from Benign Tumor to Invasive Cancer: Examples of Intrinsically Multiscale Problems
Cancer arises from a series of mutations manifested in phenotypic changes of both the cells and the local tissue structure. At the stage of an in situ tumor or neoplasia, a pre-state on the path to invasive cancer, cells divide out of control but still form a compact colony well separated from its environment. The transition from an in situ tumor to invasive cancer is marked by a number of steps. This includes angiogenesis, the formation of new blood vessels to supply the growing tumor with oxygen and nutrients, and detachment of cells from the tumor that subsequently invade the tissue and the blood vessels to be transported into distant organs where they can lead to the formation of secondary tumors called metastases. Angiogenesis is the process during which endothelial cells divide and generate new vessels sprouting toward the tumor as a response to angiogenesis factors secreted directly and indirectly by the tumor cells. Many angiogenesis factors have been identiﬁed . The most prominent one is probably VEGF, which is related to platelet-derived growth factors (PDGF). A shortage of oxygen triggers an increase in the intracellular concentration of an active form of the protein hypoxia-inducible factor 1 (HIF1), which then stimulates transcription of the VEGF gene. The protein VEGF is secreted into the extracellular space acting on the nearby endothelial cells as described above. A lack of oxygen favors cells that can survive at a lower oxygen concentration, which explains why in hypoxic regions cells with a small oxygen demand can be found.