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A devious cube of cancer

DOI: 10.1002/jcp.21425 Cancers progress through stages from bad to worse. What are these stages, and how are they connected? Normal cells are regulated by specialized mechanisms that act at many molecular levels to keep cells in metabolic balance. A critical idea is that regulatory molecules additional to the cell’s functional molecules are required. Mutations mis-regulate at least a half dozen molecular control systems of normal cells during progression to metastatic cancer, changing biochemistry and biology that alter cell structures and functions, and interactions between nearby cells become disorganized. Tumor suppressor and oncogene proteins are altered. Major advances being made in understanding these mechanisms are summarized (Weinberg, 2006). Increase in the number of cells (proliferation) and cell cycle control are the most investigated regulatory processes, of several that must be changed for a normal cell to develop into a lethal cancer (Stein and Pardee, 2004). These include controls of cell death (apoptosis), differentiation into specialized cells, activation of a blood supply (angiogenesis) required to provide nutrients and oxygen for growth, and metastatic movement of cells out of a tumor with the capacity to multiply when and where they should not. All are targets for therapy. The sequence of these changes can vary, and thereby produce different cancers. Six pathways of progression from normal cell to malignant cancer are assembled in Figure 1. The major pathway is shown with dark arrows. A single normal cell is mutated to produce defective cellular regulatory mechanisms. Step 1, proliferation, is probably the most frequently mis-regulated event, because it produces a million further mutable cells as a micro-tumor. Initiation from quiescence into the cell cycle can become less dependent on external factors. Many cancers proliferate from mutations that inactivate tumor suppressors such as retinoblastoma protein, which inhibits passage beyond the restriction point in late G1 phase. Net cell number can increase if replication exceeds cell death. Programmed cell death (apoptosis) is often decreased in cancer cells. Prostate cancers develop resistance to apoptosis when androgen is decreased, because their p53 protein is mutated. Also, other anti-proliferation process are changed. Normal cells can permanently stop growing but continue to function, an arrest named senescence. Cancer cells, in contrast, are immortalized and their growth are not arrested. Cell growth is arrested when multi-potential stem cells differentiate to function in specialized ways, and cancer cells lose the ability to differentiate, and they continue dividing. The left side of the cube (Fig. 1) indicates pathways that are less traveled, because few cells are initially involved relative to the above pathways. A mutation to angiogenesis could produce angiomas, small non-malignant red spots. Alternatively, an initial metastatic mutation could produce an isolated dormant cell that may never become lethal (Townson and Chambers, 2006). Angiosarcomas (Gupta et al., 2007) could be produced when these two steps are activated, in either order. And subsequently activated proliferation could produce rare cancers. Step 2 is necessary for further growth after proliferation is arrested and cells have formed a micro-tumor of about 1 mm in diameter. A micro-tumor may develop into a clinically apparent