Parallel pathways of tumorigenesis.

While we believe that virtually all cancers must acquire the same six hallmark capabilities, (a) their means of doing so will vary significantly, both mechanistically and chronologically (b). Thus, the order in which these capabilities are acquired seems likely be quite variable across the spectrum of cancer types and subtypes. Moreover, in some tumors, a particular genetic lesion may confer several capabilities simultaneously, decreasing the number of distinct mutational steps required to complete tumorigenesis. Thus, loss of function of the p53 tumor suppressor can facilitate both angiogenesis and resistance to apoptosis (e.g., in the five-step pathway shown), as well as enabling the characteristic of genomic instability. In other tumors, a capability may only be acquired through the collaboration of two or more distinct genetic changes, thereby increasing the total number necessary for completion of tumor progression. Thus, in the eight-step pathway shown, invasion/metastasis and resistance to apoptosis are each acquired in two steps.