Tumor Evolution


 

General Principles

To quote Merlo et al 2006:

"Neoplasms are microcosms of evolution.  Within a neoplasm, a mosaic of mutant cells compete for space and resources, evade predation by the immune system and can even cooperate to disperse and colonize new organs.  The evolution of neoplastic cells explains both why we get cancer and why it has been so difficult to cure.  The tools of evolutionary biology and ecology are providing new insights into neoplastic progression and the clinical control of cancer."

and

"A neoplasm can be viewed from an evolutionary perspective as a large, genetically and epigenetically heterogeneous population of individual cells.  Genetic and epigenetic alterations that are beneficial to a neoplastic clone, enabling it to expand, are generally deleterious to the host ...  Because these somatic abnormalities have differing, heritable effects on the fitness of neoplastic cells, mutant clones might expand or contract in the neoplasm by natural selection and genetic drift, regardless of any negative effects on the organism.  The fitness of a neoplastic cell is shaped by its interactions with cells and other factors in its microenvironment (its ecology), including interventions to prevent or cure cancer.  Clonal evolution generally selects for increased proliferation and survival, and might lead to invasion, metastasis and therapeutic resistance."

Key points summarized in their paper are as follows (quoting directly):

"Neoplasms are composed of an ecosystem of evolving clones, competing and cooperating with each other and other cells in their microenvironment, and this has important implications for both neoplastic progression and therapy.
  • Selection at the different levels of genes, cells and organisms might conflict, and have resulted in a legacy of tumour-suppression mechanisms and vulnerability to oncogenesis in our genomes.
  • Most of the dynamics of evolution have not been measured in neoplasms, including mutation rates, fitness effects of mutations, generation times, population structure, the frequency of selective sweeps and the selective effects of our therapies.
  • Many of the genetic and epigenetic alterations observed in neoplasms are evolutionarily neutral.
  • Cancer therapies select for cancer stem cells with resistance mutations, although various evolutionary approaches have been suggested to overcome this problem, including selecting for benign or chemosensitive cells, altering the carrying capacity of the neoplasm and the competitive effects of neoplastic and normal cells on each other.
  • Dispersal theory suggests that high cell mortality and variation of resources and population densities across space might select for metastasis.
  • There is evidence of competition, predation, parasitism and mutualism between co-evolving clones in and around a neoplasm.
  • We will need to interfere with clonal evolution and alter the fitness landscapes of neoplastic cells to prevent or cure cancer.  Evolutionary biology should be central to this endeavor."
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    Also see Wikipedia's somatic evolution in cancer and Pepper et al 2009 for reviews of principles of tumor evolution.

    For a large collection of papers, many of which are related to tumor evolution, see NCI PS2 Readings.

    Practical Implications for Brain Tumor Treatment

    While tumor evolution can be expected to usually result in increasing aggressiveness and treatment resistance of tumors over time, this will (fortunately) not necessarily always be the case for each patient (see Spiegl-Kreinecker et al 2007).

    For a general discussion of potential treatment strategies based on an understanding of tumor evolution, see Sadee 2003.  Also see Maley et al 2004, who discuss two related treatment strategies: (a) "boosting" growth of less malignant (or benign) cells in and around a tumor, so that they can outcompete and thereby repress malignant cells and (b) boosting growth of more chemosensitive tumor cells (again so that they outcomptete less chemosensitive tumor cells), and then applying cytotoxic chemotherapy.

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