What proportion of cells in a malignant neoplasm have the potential to proliferate extensively: all cells, most of them, or only a small minority? This fundamentally important question has direct implications for clinical practice. Which cancer cells need to be killed to cure patients? It is critical both for cancer biologists and for investigators who are seeking to develop new treatments for cancer to know exactly which cells drive cancer growth.
Traditionally, it has been thought that more or less all cells in a malignant neoplasm have a similar potential to proliferate, propagating the disease in a stochastic (random) manner (Figure, A). This theory led to the development of “hatchet” treatments, ie, surgery, radiation therapy, and cytotoxic agents, that sought to eliminate every cell in a malignant neoplasm. Such treatments are of course effective if they eliminate every cancer cell, albeit at the cost of collateral damage to normal tissues. However, when cancers evade early detection or spread early in their development, the hope of killing every cell with a hatchet approach diminishes. This problem is compounded in cancers such as melanoma that are notoriously resistant to conventional systemic therapies.
Models of cancer growth (adapted by permission from Macmillan Publishers Ltd1). A, The traditional (stochastic) model in which most cancer cells can proliferate despite being phenotypically heterogeneous (colored cells), driving tumor growth in a stochastic manner. B, The cancer stem cell (CSC) model in which only a fraction of cells—the CSCs—proliferate, producing more CSCs as well as cells that undergo further genetic and epigenetic changes and do not proliferate extensively (called nontumorigenic cells [cells without circular arrows]). Important to the CSC model is the idea that CSCs are phenotypically distinct from nontumorigenic cells (colored cells), enabling their identification and specific targeting.
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