Cellular Mechanisms Underlying Intertumoral Heterogeneity

Intertumoral heterogeneity is driven by a combination of intrinsic and extrinsic mechanisms. Intrinsic mechanisms include the genetic/epigenetic mutational profile of cells and the nature of the 'cell of origin'. There is accumulating evidence that distinct 'cells of origin' within an organ can give rise to different subtypes of cancer. Tissue-specific stem and progenitor cells are the predominant targets exploited for tumor initiation. Extrinsic factors imposed by the microenvironment may also directly influence the cell of origin by eliciting dedifferentiation. Identification of these target cell populations is important for earlier diagnosis, the detection of premalignant clones during relapse, and the design of prevention therapies for high-risk cancer families. Here we review recent developments in deciphering the cellular origins of solid cancers.