Originally titled “Clonal selection in cancer progression… a.k.a. the stem cell theory of neoplasms versus the evolution of tumors.”
Cancer biology is an amazingly complex field, with science and medicine only beginning to gain a grasp at the molecular mechanisms behind this disease and how to develop effective therapies. Nevertheless, cancer deaths are decreasing, and this disease is becoming increasingly understandable in terms of a small number of underlying principles, as observed both in the laboratory and in the clinic.
Here I present the state of scientific knowledge on how cancer develops and progresses.
As described by Hanahan & Weinberg1: several lines of evidence indicate that tumorigenesis is a multistep process and that these steps reflect genetic alterations that drive the progressive transformation of normal human cells into highly malignant derivatives. Many types of cancers are diagnosed in the human population with an age-dependent incidence implicating four to seven rate-limiting, stochastic events. Pathological analyses of a number of organ sites reveal lesions that appear to represent the intermediate steps in a process through which cells evolve progressively from normalcy via a series of premalignant states into invasive cancers.
These four to seven rate-limiting, stochastic events can be enumerated as six acquired traits in an abberant lineage of cells (see figure), including self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of programmed cell death (apoptosis), limitless replicative potential, sustained angiogenesis, and tissue invasion (metastasis).
How, then, do these acquired capabilities occur phenotypically in cancer? A traditional view has been the somatic mutation theory of carcinogenesis, which proposes that successive DNA mutations in a single cell cause cancer (monoclonality). This view has largely been superceded by observations that the default state of cells is not quiescence but regulated proliferation, and that the remaining acquired capabilities (as described by Hanahan & Weinberg) of cancer confer greater fitness to a cell lineage2. In this newer view, each successive trait acquired by a developing cancer confers an advantage over surrounding cells, that is selected for to the point where the new phenotype takes over the developing tumor.
The stem cell theory of tumorigenesis is a similar view, which recognizes the existense of tumor heterogeneity and survival of only a subset of cancer cells capable of clonal expansion. Reya et al. note3:
…some of the cancer cell heterogeneity would arise as a result of environmental differences within the tumour and continuing mutagenesis… [but] whatever the environment or mutational status of the cells, only a small, phenotypically distinct subset of cancer cells has the ability to proliferate extensively or form a new tumour.
However, despite the similarity of tumorigenesis to clonal expansion as in the stem cell origin of tissues and cell types, and the identication of supposed tumorigenic stem cells in several cancer types, I find the label “stem cell” theory to be a misnomer. While both stem cells and tumorigenic cancer cells share the capacity to renew themselves and undergo clonal expansion, cancer cells are not regulated physiologically, nor do they differentiate into different cell types. As such, tumorigenic cancer cells (the subset of cancer cells capable of advancing tumor development) can only be described as stem-like cells.
Recently, Maley et al.4 have contributed to further replacing the somatic mutation and stem cell theories of cancer by identifying that Genetic clonal diversity predicts progression to esophageal adenocarcinoma:
The generation of cellular genetic variants and clonal diversity on which natural selection acts may be a fundamental evolutionary mechanism of neoplastic progression with profound clinical implications… If confirmed in other neoplasms, then neoplasms may be considered as evolving ecosystems in which evolutionary and ecological measures of diversity are widely applicable for assessment of risk of progression to cancer because they quantify genetic heterogeneity within viable, evolving clones and integrate all mechanisms geneting genomic instability…
It’s that second part that is of the greater importance, I would claim, because the description of neoplasms as evolving ecosystems has the potential to unify our understanding of cancer overall. The fact that (as remarked by the renowned geneticist Dobzhansky several decades ago) nothing in biology makes sense except in the light of evolution, including cancer, is an interesting side note as well.
Thus, I give you the Evolving Ecosystem Model of Neoplasms.
- The hallmarks of cancer. Hanahan D, Weinberg RA. Cell. 2000 Jan 7; 100(1):57-70. Pubmed
- Somatic mutation theory of carcinogenesis: why it should be dropped and replaced. Sonnenschein C, Soto AM. Mol Carcinog. 2000 Dec; 29(4):205-11. Pubmed
- Stem cells, cancer, and cancer stem cells. Reya T, Morrison SJ, Clarke MF, Weissman IL. Nature. 2001 Nov 1; 414(6859):105-11. Pubmed
- Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Maley CC, Galipeau PC, Finley JC, Wongsurawat VJ, Li X, Sanchez CA, Paulson TG, Blount PL, Risques RA, Rabinovitch PS, Reid BJ. Nat Genet. 2006 Apr; 38(4):468-73. Pubmed
- For further blog reading on Maley et al. and its medical/scientific implications, check out:
Respectful Insolence: Medicine and Evolution (Part 2).