Just as organisms evolve, tissue (somatic) cells can also evolve within an animal. Somatic cell evolution, which can lead to tissue-disrupting tumors and cancer, is clearly detrimental to the fitness of the organism (with the exception of cell evolution within the immune system). The reason that cancer is so rare during youth is that multi-cellular organisms, particularly long-lived and large ones, have evolved potent tumor-suppressive mechanisms (but see Box 2 for evolutionary explanations for childhood cancers). Indeed, the evolution of multi-cellularity required it. We can imagine that the first multi-cellular organisms, no matter how simple, would not have been able to evolve significant organization or complexity without mechanisms to avoid rogue cell growth. But how could a group of cells representing a recently evolved multi-cellular organism have prevented one of their own from acquiring a short-term advantage (i.e. rogue cells, out-proliferating their peers), even if it was to the eventual detriment of the organism? Successful multi-cellular organisms evolved mechanisms to limit these nonconformist outgrowths. We will refer to these tumor-suppressive mechanisms as either intrinsic (how cells avoid becoming tumor cells) or integral (cancer avoidance at the level of tissues and the whole organism).
Intrinsic Tumor Suppression
Cells of multi-cellular organisms have evolved mechanisms to maintain appropriate numbers of cells within tissues. Both cell division and cell survival are regulated by various “social” cues including circulating factors and contact with other cells (Hanahan and Weinberg 2011). Importantly, there are often mechanisms to penalize disobedient cells. For example, dividing outside of the appropriate structure, such as a well-ordered duct, can lead to cell suicide (a program that is activated within the cell that leads to cell death) (Hipfner and Cohen 2004). These mechanisms are essential for the proper development and function of complex tissues and organs. Animals have also evolved cell suicide and cell senescence responses to inappropriate signals, such as those engendered by cancer-causing (oncogenic) mutations (Lowe et al. 2004). Similar cell death and senescence responses are initiated following cellular damage, particularly damage to DNA. These intrinsic mechanisms contribute to tumor suppression (Lowe et al. 2004) by limiting the chances that damaged, and possibly oncogenic, cells are propagated. In addition, oncogenic mutations are avoided in cells by effective DNA repair (Hoeijmakers 2009), which even unicellular organisms use to maintain the integrity of their genetic material.
Another intrinsic tumor-suppressive mechanism is mediated by telomeres, which cap chromosome ends to help maintain the integrity of the DNA code (Sharpless and DePinho 2004; Chan and Blackburn 2004). Single-cell organisms as well as germ cells of animals maintain telomeres continuously as a means to ensure correct propagation of their genetic code. But somatic cells in adult tissues do not maintain telomeres continuously, and these structures are reduced in length with age, until a critically short length stimulates cell death or senescence (which may contribute to tissue decline with aging). Larger animals appear to particularly favor this mechanism to limit telomere maintenance during aging, which by restricting each somatic cell's lifespan is thought to limit cancer (which requires immortal cells; Gorbunova and Seluanov 2009). Together, all of these mechanisms function within cells to limit their ability to disobey tissue rules, thus reducing the risk of cancer.
Integral Tumor Suppression
Compared to other animals (and with notable exceptions), vertebrates have longer lives and bigger bodies, providing a bigger pool of cells over longer time periods in which an oncogenic mutation may arise. Consequently, vertebrates should have increased requirements for suppression of rogue cell growth. While enhancements in the intrinsic tumor-suppressive mechanisms discussed above may have contributed to improved tumor suppression in the large and long-lived, additional mechanisms operating at the tissue and animal levels clearly function in vertebrates (and to varying extent in other animals) to limit cancer development. These integral tumor-suppressive mechanisms include immunity, tissue organization, and the fitness of stem cell pools.
Vertebrates have evolved effective immune systems, and even invertebrates possess simple immune systems (Robert 2010). In particular, vertebrates have evolved antigen-specific immunity, with lymphocytes that are tailored to recognize and respond to specific foreign or abnormal proteins (“antigens,” whether these antigens are part of viruses, bacteria, or cancer cells). In addition to eliminating pathogens and limiting infections, these systems can target precancerous and cancerous cells for destruction, thus contributing to tumor suppression (Robert 2010). Indeed, patients with defective cellular immunity have increased cancer risk (Dunn et al. 2004).
The evolution of animals and their tissues, organs, and systems has been constrained by the requirement to avoid tumors (Cairns 1975; reviewed in DeGregori 2011). These constraints on how tissues develop and are organized should be particularly severe for animals with larger bodies and longer lives, which require tissue maintenance and renewal throughout life. Tissue organization contributes to the “peer pressure” exerted on malignant cells, whereby normal tissue structure can suppress rogue cell expansion (Bissell and Hines 2011). Also contributing to tumor suppression, tissues in vertebrates are often maintained by a hierarchy of cells, with a small number of stem cells serving as the source of the much more numerous specialized cells that actually carry out the functions of the tissue (Weissman 2000). Stem cells are thought to often represent the targets for cancer initiation (Reya et al. 2001). These cells are maintained throughout life, increasing the opportunities for mutation accumulation. Importantly, hierarchical tissue organization, with a few stem cells at the top of the hierarchy, would reduce the pool of cells most susceptible to oncogenic mutations. Stem cells in tissues also appear to be positioned in protective locations (their niche). For example, blood stem cells are localized in the bone marrow, and gut stem cells are positioned distant from the nasty contents of the large intestine (Cairns 1975; Reya et al. 2001; Gatenby et al. 2010), which should reduce exposure to carcinogens. Most cell proliferation is delegated to non-stem cells (which are derived from stem cells) in the hierarchy, and these cells are generally short-lived. Indeed, for the intestines, these non-stem cells (even if they acquire an oncogenic mutation) are destined for a one-way trip out the anus (hence mutations get “flushed”) (Frank and Nowak 2004; Pepper et al. 2007). Thus, vertebrates have evolved effective strategies to minimize cancer rates, despite a dizzying number of cell divisions required daily to maintain some organs like the blood, skin, and intestines throughout life. For example, each human produces around 1011 (one trillion) blood cells each day (Gordon et al. 2002). There were probably other possible approaches to the development and maintenance of vertebrate organs, but each successful solution needed to be compatible with sufficiently low rates of cancer.
The fact that cancer has exerted developmental constraints during evolution provides another reason that cancer biologists need to understand evolutionary biology, and all biologists need to learn about cancer: Just as one cannot really understand cancer without understanding how evolution has limited it, one cannot fully understand the evolution of form and function in multi-cellular organisms without considering how the requirement for tumor suppression has constrained it. So cancer biology courses should not just be for medical students, and evolutionary biology should be required for all life science disciplines, including medicine. Teaching students about cancer from an evolutionary perspective would not only enhance the students' understanding of cancer, but would provide highly relevant examples for why evolutionary biology is so important. Students should learn that fighting cancer requires an understanding of its evolutionary origins and how it adapts to current therapies to the detriment of cancer patients.
Integral Tumor Suppression by Maintaining Tissue Fitness
Cancer progression occurs by a process of somatic cell evolution whereby a cell clone acquires a number of genetic changes over time and proliferates to generate a highly complex cancer (DeGregori 2011; Merlo et al. 2006; Bagby and Fleischman 2011). This evolutionary process is driven by two major forces:
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1)
genetic variation in somatic cell populations, which facilitates the acquisition of mutations in oncogenes and tumor suppressor genes;
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2)
selection for cells that harbor mutations increasing their cellular fitness relative to competing cells.
Certain cells in a tissue with potential to proliferate, like stem cells, are in competition with each other for nutrients, growth factors, survival factors, and spatial locations (Baker 2011; Fleenor et al. 2010), which together constitute their niche. How fit the competing cells are, as well as the state of the niche, can in a large part determine whether an acquired oncogenic mutation leads to expansion of the cell clone. Thus, consideration of cancer development as an evolutionary process within an individual provides a different perspective relative to the more widely accepted focus on oncogenic mutations as the primary drivers of cancer.
We have proposed that long-lived multi-cellular organisms have evolved highly fit stem cell populations, not only as a means of efficiently maintaining tissues but also because a highly fit cell population should oppose somatic cell evolution (DeGregori 2011). Like animal populations well adapted to their environments, cell populations with high fitness should be resistant to change: The chance that a mutation improves fitness will be much less when there is little room for improvement. Highly effective competition in a young, healthy stem cell population should serve to maintain the status quo, preventing somatic cell evolution. In other words, non-conformist cells are suppressed via competition by their fit neighbors (Fig. 1, top), just as a healthy lawn can limit weed growth.
But when general cellular fitness is reduced, such as with aging or following damaging carcinogen exposure, certain oncogenic mutations can be adaptive (restoring fitness; Fig. 1, bottom). An oncogenic mutation could be adaptive by circumventing or fixing problems caused by the damage and may be adaptive in a cell under one set of conditions but not another. For example, if a carcinogen causes widespread cell death in a tissue, there will be increased selection for oncogenic mutations that promote cell survival. Damage to the niche, which also occurs with aging or carcinogen exposure, can also increase selection for adaptive mutations. In some ways, these concepts are analogous to the acquisition of antibiotic resistance in gut flora: Antibiotic treatment will select for mutant bacteria resistant to the antibiotic and will also destroy competing bacteria and substantially alter the niche.
So just as evolution of species is driven by mutation and selection, cancer evolution is also driven by both oncogenic mutations and alterations in selective pressures, both of which can result from aging and carcinogenic exposures. For example, smoking not only exposes your lungs to DNA-damaging chemicals that can cause oncogenic mutations (Hecht 2002) but also should dramatically alter selective pressures within the lung: Normal lung stem cells are highly damaged (reducing their fitness), and the environment that these cells are in (their niche) is highly perturbed (remember the black lungs in a jar that you were shown to keep you from smoking?). Damage to the landscape of the lung also leads to compensatory proliferation to fill empty niches (Takahashi et al. 2010), providing increased opportunities for cancers to develop. Massive destruction of the landscape, such as after the gigantic meteor hit off the Gulf of Mexico at the Cretaceous–Tertiary (K–T) Boundary ∼65 million years ago, can lead to new speciation as organisms adapt to the new environment (Raup 1986). The same probably applies within an individual, although somatic cell evolution within an individual is inherently dangerous, as it can lead to cancer.
So what lessons can we take from these evolutionary considerations of cancer? For starters, we cannot simply focus on the cancer but need to consider its environment within the body. We need to learn how to attack the cancer and at the same time support the immune system, boost normal cell fitness, and restore a more normal niche. For cancer prevention, maintaining fit tissues by doing all of the things we already know are good for us (eat well, don't smoke, exercise, etc.), should help prevent cancer by maintaining fit cells within a tissue, making it harder for a rogue early cancer cell to outcompete normal cells and expand. The following sections will continue our discussion of cancer as an evolutionary process: How do cells that acquire oncogenic mutations eventually evolve into complex and invasive cancers? How can an evolutionary viewpoint help explain carcinogen-induced cancers? How can an evolutionary understanding of cancer improve therapeutic approaches to combat cancer?