In addition to the phenotypic heterogeneity associated with the presence of stem cells, cancers show considerable genetic and morphologic heterogeneity both within and between patients. The genetic instability associated with cancer development, together with the stochastic nature of oncogenic mutations, supports genetic drift and the coevolution of cancer cells with different genetic lesions within a tumour. Morphologic heterogeneity within tumours is particularly noticeable in the stroma, which is affected not only by the ability of cancers to recruit different cell types but also by random factors such as tumour depth, variations in vascularization, and differences in the surrounding tissue. The resultant variation in microenvironment produces different evolutionary pressures that select for regional heterogeneity within the cancer cells of a tumour. Even in apparently homogeneous cancers that arise from clonal expansion of genetically identical cells, small variations in the microenvironment may allow for the survival of subpopulations of genetically distinct cells.
Heterogeneity across tumours has implications for therapy that are analogous to those seen with stem cells. Genetically distinct populations in different microenvironments would be expected to differ in their susceptibility to treatment. Thus, heterogeneous cancers are likely to have subpopulations of resistant cells that may evade therapy and lead to relapse. This is a particular concern for metastases, which are exposed to environmental pressures that are distinct from those of the original tumour.