Cellular hyperproliferation and cancer as evolutionary variables

Abstract

Technological advances in biology have begun to dramatically change the way we think about evolution, development, health and disease. The ability to sequence the genomes of many individuals within a population, and across multiple species, has opened the door to the possibility of answering some long-standing and perplexing questions about our own genetic heritage. One such question revolves around the nature of cellular hyperproliferation. This cellular behavior is used to effect wound healing in most animals, as well as, in some animals, the regeneration of lost body parts. Yet at the same time, cellular hyperproliferation is the fundamental pathological condition responsible for cancers in humans. Here, I will discuss why microevolution, macroevolution and developmental biology all have to be taken into consideration when interpreting studies of both normal and malignant hyperproliferation. I will also illustrate how a synthesis of evolutionary sciences and developmental biology through the study of diverse model organisms can inform our understanding of both health and disease.

Figure 1. Microevolutionary variation in human tumors and butterflies

(A) A representative pattern for common, solid cancers. Selective pressures allow some mutant subclones to expand while others become extinct or remain dormant. Vertical lines represent restraints or selective pressures. Adapted from [7]. (B) Morphological diversity of wing patterns in Heliconius butterflies [64]. Recent molecular evidence shows that the many adaptive multi-locus polymorphisms seen in this butterfly arise from chromosomal reorganization of a co-adaptive gene set found in a chromosomal interval of about 400 kb [19].

Figure 2. Phylostratigraphic map of cancer genes

The log-odds statistics of documented human cancer genes in four different databases are illustrated on the y-axis. Positive values denote over-representation, while negative values indicate under-representation. The x-axis values indicate phylogenetic transitions, with ‘1’ representing the origin of the first cells and ‘5’ representing the transition from single-celled to multicellular organisms. (Adapted and reproduced with permission from Domazet-Lozo and Tautz [27].) The colored arrows indicate significant over-representation of cancer genes at these specific phylogenetic positions (for a complete list of the phylostrata positions please consult [27]).

Figure 3. Developmental biology and the study of variation

(A) Diversity of embryonic developmental strategies displayed (clockwise) by: polar lobe extrusion (p³) in a vegetative view of the marine scaphopod mollusk Dentalium embryo (adapted from [65]); invariant lineages of the cephalopod endosymbiont dycemid mesozoan embryo (adapted from [66]); rear view of a 6 hour 15 min Nereis embryo (a marine, polychaete worm) depicting cell lineages of the various blastomeres [67]); chromosome diminution in Ascaris embryos (small fragments in division plane, large blastomere, middle) as described by Theodor Boveri in 1910 [68] (images kindly supplied by Dr J.G. Gall). (B) Cyril Darlington’s schema integrating fertilization, recombination and genetics to explain the connection between genetics and the physical entity of chromosomes (adapted from [69]). (C) The most recent gene regulatory network of sea urchin primary mesenchyme cells (PMCs) at 6–30 hours of development [70].

Figure 4. P53 and tumor suppression in planarians

(A) Phylogenetic tree of the Metazoa, highlighting the number, family members and functions of P53 and PTEN (adapted from [5]). TSG: tumor suppressor gene. (B) The planarian Schmidtea mediterranea. Scale bar: 200 μm. (C) Smed-p53(RNAi) causes hyperproliferation (blue line) and reveals the tumor suppression function of this molecule in planarians. Mitotic figures are visualized using the marker H3ser10p, which marks cells during the G2/M transition of the cell cycle. Normal and hyperproliferatrion shown in representative animals on the left. Loss of cell division at the latest time point shown by representative animals at right. Statistical differences: Student’s t-test. Error bars are SEM. Scale bars: 100 μm. (D) Cross-sections of control and RNAi-treated animals. Dorsal on top. Smed-p53(RNAi) causes an increase in numbers in stem cells (Smedwi-1, arrowhead) and cell proliferation (PCNA, arrowhead), and a concomitant decrease in the number of progenitor cells (NB21.11e, arrow-head). (C) and (D) modified from [4].