Ecology of the Metastatic Process

Metastasis is the dispersal and colonization of cancer cells from a primary tumor to a distant organ in the body. Metastases are associated with more than 90% of all cancer deaths. Yet our ability to decrease the rate of metastasis or improve patient survival has not changed in decades. We see cancer cells as experiencing ecological and evolutionary dynamics within their tumor ecosystem. Metastasis occurs when one or several cancer cells enter the blood stream or lymphatic system, survive in circulatory system, emerge in a distant organ, survive, and proliferate. Similar concepts have been studied in ecology for centuries. The metastasizing cancer cells are like exotic species found in nature which traverse long distances and successfully invade distant location. Metastatic progression can and should be viewed through the lens of invasion ecology. As such, metastases become a matter of weighted probabilities. First, no cancer cell is actually under selection to metastasize. Natural selection cannot adapt a cancer cell clade to something it has yet to experience. Second, metastases are not propagule limited. The sheer number of circulating tumor cells means that most organs likely experience a steady inoculum of cancer cells. Third, the successful cancer cell that metastasizes is unlikely to be a random draw from the primary tumor. Important preadaptations include motility, the ability to move in and out of the blood system, self-sufficiency, and ability to evade the immune system. New organs likely provide ample nutrients but lack safety or structure for the inoculum of one or more cancer cells. Fourth, the pairing of donor organs and recipient organs is highly nonrandom. Organs seem to be nested in their propensity to send and receive metastases. Organs with very high ratios of blood supply to normal cell density seem prime recipients of metastases. Food, safety, and the preadaptations of the cancer cells may best explain metastatic progression. Ultimately the goal of this understanding is to provide therapies that reduce the likelihood of metastases, and the control of disseminated cancers once they have occurred. An understanding of the Darwinian dynamics underlying metastasis invites new therapeutic perspective, such as adaptive therapy.