Researchers have been studying metastasis for more than 100 years, and only recently have we gained insight into the mechanisms by which metastatic cells arise from primary tumours and the reasons that certain tumour types tend to metastasize to specific organs. Stephen Paget's 1889 proposal that metastasis depends on cross-talk between selected cancer cells (the 'seeds') and specific organ microenvironments (the 'soil') still holds forth today. It is now known that the potential of a tumour cell to metastasize depends on its interactions with the homeostatic factors that promote tumour-cell growth, survival, angiogenesis, invasion and metastasis. How has this field developed over the past century, and what major breakthroughs are most likely to lead to effective therapeutic approaches?
Metastases resistant to therapy is the major cause of death from cancer. Despite almost 200 years of study, the process of tumor metastasis remains controversial. Stephen Paget initially identified the role of host-tumor interactions on the basis of a review of autopsy records. His “seed and soil” hypothesis was substantiated a century later with experimental studies and numerous reports have confirmed these seminal observations. Inarguably, an improved understanding of the metastatic process and the attributes of the cells selected by this process are critical to the treatment of patients with systemic disease. In many patients, metastasis has occurred by the time of diagnosis, such that metastasis prevention may not be relevant, and treatment of systemic disease, as well as the identity of patients with early disease, should be our goal. During the last three decades, revitalized research has focused on new discoveries in the biology of metastasis. While our understanding of the molecular events that regulate metastasis has improved; nonetheless, the relevant contributions and timing of molecular lesion(s) potentially involved in its pathogenesis remain unclear. The history of pioneering observations and discussion of current controversies should help investigators understand the complex and multifactorial interactions between the host and selected tumor cells that contribute to fatal metastasis and allow for the design of successful therapy.
Clones derived in vitro from a parent culture of murine malignant melanoma cells varied greatly in their ability to produce metastatic colonies in the lungs upon intravenous inoculation into syngeneic mice. This suggests that the parent tumor is heterogeneous and that highly metastatic tumor cell variants preexist in the parental population.
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