Citation: (2004) Deterministic Tumor Evolution. PLoS Biol 2(8): e284. https://doi.org/10.1371/journal.pbio.0020284
Published: August 17, 2004
Copyright: © 2004 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The essential difference between cancer cells and normal cells is that cancer cells evolve. Most cancers arise from a single cell through a sequential evolutionary process of mutation and selection. Cancer cells harbor mutations in a number of critical genes that, at various stages during the evolution of the tumor, provide those cells with a selective advantage. Many of the phenotypes, or physical outcomes, conferred by these mutant genes are subverted from a normal cell's repertoire, including proliferation, invasion, migration, loss of differentiation, and loss of apoptosis (programmed cell death); other phenotypes, such as immortalization, are novel. Tumor evolution is thought to adhere to Darwinian principles, with mutations arising randomly within an individual cell, followed by selection for mutant clones with favorable traits.
Support for this idea stems from the observation that end-stage tumors have mutations in a number of genes. But linking mutations in particular genes with defined stages is difficult for most human cancers and especially so for the last and deadliest stage: when cancer disseminates throughout the body during metastasis. It's unclear, for example, whether there are mutations in particular genes or sets of genes that enhance metastasis. That is, do metastatic lesions develop through a continuation of Darwinian evolution, or is metastasis an intrinsic property of the primary tumor, meaning that further genetic evolution is not required? It is also unclear whether there is a “preferred” sequence of mutations, such that selective pressure for particular mutations depends on preexisting mutations.
Since the earliest days of research on oncogenes—genes that can cause a cell to become cancerous—it has been known that certain oncogenic mutations cooperate to transform normal cells into cancer cells. For example, an “activating” mutation in the oncogene Ras and the loss of the tumor suppressor p53 cooperate to transform cells.
The paper by Christopher Kemp and his colleagues at the Fred Hutchinson Cancer Research Center sheds light on some of these questions, and many of the issues center around the most notorious oncogene: Ras. Using a well characterized mouse model of squamous cell carcinogenesis, which generates a form of skin cancer, the authors examine both the functional and evolutionary relationships between three cancer genes that play major roles in most human cancers: Ras and the tumor suppressors Arf and p53.
Two seminal early observations set the stage: mutational activation of Ras is the initiating genetic event in this cancer model, while mutation of p53 occurs later, during the benign to malignant transition; and expression of mutant Ras in cells activates p53 via signaling through the protein encoded by Arf.
Kemp et al. confirm that this pathway is active in “autochthonous” tumors—which grow and develop where they are initiated—by showing that p53 expression in tumors with Ras mutations is dependent on the presence of Arf. Thus, during the early benign stages of tumor growth, Ras activates Arf, which in turn activates p53, thereby inhibiting tumor progression. This provides strong selective pressure in favor of cells with mutations in either Arf or p53, and these mutations are indeed observed as the tumors progress to malignancy. That Arf and p53 function as tumor suppressors was confirmed by demonstrated accelerated tumor progression in mice lacking either Arf or p53. This answers a longstanding question concerning the nature of the signal that activates p53 during autochthonous tumor development: Mutation of Ras not only initiates tumor development but, through its intracellular signaling through Arf and p53, directly influences the subsequent evolutionary trajectory of the tumors. In this view, secondary evolutionary events are determined by the preexisting genetic lesion, as a result of direct signaling interactions.
The authors go on to show that tumors lacking Arf or p53 show accelerated metastatic dissemination, a phenomenon rarely seen in mouse squamous cell cancer models. Thus both benign and malignant tumors lacking these tumor suppressors are at high risk for metastasis. As Ras is well known to confer many phenotypes required for the metastatic process, it appears that Ras, together with loss of its inhibitors, Arf and p53, may be sufficient to drive this process. More direct evidence that metastasis does or does not require further genetic evolution awaits.