Riparian ecosystems in human cancers

Abstract

Intratumoral evolution produces extensive genetic heterogeneity in clinical cancers. This is generally attributed to an increased mutation rate that continually produces new genetically defined clonal lineages. Equally important are the interactions between the heritable traits of cancer cells and their microenvironment that produces natural selection favoring some clonal 'species' over others. That is, while mutations produce the heritable variation, environmental selection and cellular adaptation govern the strategies (and genotypes) that can proliferate within the tumor ecosystem. Here we ask: What are the dominant evolutionary forces in the cancer ecosystem? We propose that the tumor vascular network is a common and primary cause of intratumoral heterogeneity. Specifically, variations in blood flow result in variability in substrate, such as oxygen, and metabolites, such as acid, that serve as critical, but predictable, environmental selection forces. We examine the evolutionary and ecological consequences of variable blood flow by drawing an analogy to riparian habitats within desert landscapes. We propose that the phenotypic properties of cancer cells will exhibit predictable spatial variation within tumor phenotypes as a result of proximity to blood flow. Just as rivers in the desert create an abrupt shift from the lush, mesic riparian vegetation along the banks to sparser, xeric and dry-adapted plant species in the adjacent drylands, we expect blood vessels within tumors to promote similarly distinct communities of cancer cells that change abruptly with distance from the blood vessel. We propose vascular density and blood flow within a tumor as a primary evolutionary force governing variations in the phenotypic properties of cancer cells thus providing a unifying ecological framework for understanding intratumoral heterogeneity.

Keywords: riparian zone; terrestrial-aquatic interactions; tumor biodiversity; tumor cords; tumor ecosystems.

Figure 1

Micrograph of a invasive breast cancer following staining with hematoxylin and eosin and immunohistochemical stain for CD44 to identify endothelial cells forming blood vessel. In the two right panels, tumor cells are seen densely clustered around small blood vessels (stained brown). Distant to the blood vessels, there is an abrupt transition to regions of necrosis with sparse cellularity.

Figure 2

Riparian habitat in the Sonoran Desert of Arizona. The riparian zone is seen around the river beds and densely populated by mesquite and ironwood trees. There is an abrupt transition to the adjacent xeric zone, which is sparsely populated by creosote, bur-sage, and salt bushes (Satellite image from zoogle Maps).

Figure 3

Schematic of the abiotic gradients around intratumoral blood vessels that select for specific phenotypic adaptations.