The main steps in the progression of cancer (carcinogenesis and the three steps of dissemination) are shown in the center panels, along with the key tumor-cell-intrinsic factors (top; blue text) and tumor-cell-extrinsic factors (bottom; grey text) that influence progression. We will use step 2 of dissemination to explain the different types of causal relationships proposed in the figure. An example of an intrinsic factor acting at a given step (a type 'a' event) is the formation of clusters of tumor cells to enhance migration efficiency (2a, top), and an example of an extrinsic factor is the protection provided by vascular elements against immune attack and physical stress, during the same step (2a, bottom). Events during a given step can also exert an influence on a later step (type 'b' events): for instance, the initiation of the epithelial-to-mesenchymal transition (EMT) during step 1 of dissemination triggers the possibility of long-distance circulation in step 2 (2b, top). Events during a given step can also exert an influence on an earlier step (type 'c' events): for instance, the elements in the secondary tumor microenvironment (TME), which are part of step 3 of dissemination, also act as attractors for cancer cells during step 2 (2c, bottom). PMN: pre-metastatic niche.