Evolutionary Medicine
Miriam Nývltová Fišáková
Department of Physiology
Cancer
Life History and its
Trade-offs
• Species have evolved their life histories
to maximize reproductive success. Many of
the traits underlying these life histories
involve the relative allocation of resources
among growth, reproduction, and
maintenance. Thus, some species have
evolved “fast” life histories that feature
rapid growth to small body size, high
reproductive effort, low levels of tissue
repair, and short lifespan, whereas others
have “slow” life histories with slow growth
to a larger body size, lower (but likely
prolonged) reproductive effort, investment
in tissue repair, and a long lifespan (see
Jones et al. 2014).
• Accordingly, species will have evolved tumor
suppressor mechanisms appropriate to their “chosen”
life history, in part explaining the similar rates of cancer
in small and large species. With some exceptions,
selection in general acts to maximize reproductive
success rather than longevity, and this declining force of
selection with age predicts that cancer suppression
mechanisms will be relatively less effective in ageing
organisms. This may explain in part the increased
incidence of cancer as human longevity is increased by
improved nutrition and more effective public health
interventions.
• Other more specific trade- offs may occur. For
example, tissue repair processes such as wound
healing require a supply of stem cells able to
proliferate and migrate to or within the injured site,
as well as the capacity to form new blood vessels,
and inflammation occurs at the site of the wound.
These capacities are reminiscent of some of the
hallmarks of cancer, and similar molecular
mechanisms appear to be involved (see Neves et al.
2015). It may be that species that have evolved
highly effective wound healing mechanisms, possibly
as a result of behaviors that risk physical injury, will
be more susceptible to the development of cancer.
Similarly, there may be correlations between
placental invasiveness and susceptibility to tumor
metastasis.
• There may also be trade- offs between
reproduction, ageing, and susceptibility to cancer.
One molecular mechanism mediating such trade- offs
involves the tumor suppressor gene p53, which
responds to cell damage by initiating cell cycle arrest
or apoptosis. We have already seen evidence that
larger and long- lived animals have more copies of this
gene. There is emerging evidence that p53 also has
roles in ageing (probably mediated by impaired tissue
repair) and reproduction (probably mediated in
mammals by effects on embryonic implantation).
Although p53 loss- of- function mutations are a major
cause of human cancers, the naturally occurring p53
polymorphisms, which seem to be the targets of
selection in some human populations (Shi et al. 2009),
appear to have more subtle effects; there are
differences between alleles at position 72 in their
relative capacities for tumor suppression (R72 allele >
P72 allele) and age ingrelated functions (P72 > R72).
The maternal P72 allele also appears to increase the
risk of twin births in humans and, intriguingly, cancer
incidence was also higher among the first- degree
relatives of these mothers (Tagliani- Ribeiro et al.
2012).
• Trade- offs between fertility and tumor suppression are
examples of antagonistic pleiotropy. A similar trade- off involving the
tumor suppressor gene BRCA1/2. Another demonstration of a
relevant life- history trade- off in humans comes from the
multigenerational Framingham study introduced, where the
negative correlation between female reproductive success and
ageing appeared to be mediated by genes linked to cancer
susceptibility (see Wang et al. 2013).
• Some neoplasms are directly linked to periods of particular
developmental plasticity, and this can explain the age distribution of
certain cancers. For example, tumors of tissues that primarily
proliferate in early life generally present as childhood tumors, such
as Wilm’s tumor of the kidney or rhabdomyosarcoma of muscle.
Osteosarcoma, a tumor of bone, generally appears during periods of
rapid peri- adolescent bone growth. In contrast, the risk of most
epithelial tumors such as colon cancer increases as an individual
ages because these tissues replicate through life and the risk of
multiple mutations increases with age
• Breast cancer, even in the absence of BRCA mutation, represents
an example where cultural change affecting life- history phasing in
the form of reproductive behavior has clearly played a role in
altering the risk of disease. It has been known for centuries that
celibate women are more likely to develop breast cancer (but have
less cervical cancer, which is induced by infection with the human
papillomavirus via intercourse). Celibate women are characterized
by an uninterrupted cycle of exposure to estrogen and progesterone
from menarche to menopause and by an absence of lactation. The
more children a woman has, the lower her risk of developing breast
cancer (see Ewertz et al. 1990). Whereas a hunter-gatherer woman
might only have 100– 150 menstrual cycles during her life because
of the interruptions of pregnancy and lactation, a modern Western
woman may be exposed to 500 cycles. Thus the nature of the
hormonal exposures is very different. The result is that the modern
woman has constant proliferative stress on the ductal epithelium
driven by estrogen and progesterone without any period of
intervening lactation. Lactation itself leads to a loss and renewal of
ductal epithelial cells, thus removing many cells with somatic
mutations. In one Chinese population where women tend to feed
only from the right breast, cancer is more common in the left breast,
showing that exudation of epithelial cells in milk is indeed protective
(see Ing et al. 1977).
• In men, the incidence of prostate cancer
increases strongly with age and shows wide
geographical variation. The proliferation of this
tumor is frequently testosterone dependent, and
therapy involves anti-androgenic medication.
There is evidence that the risk of prostate cancer is
related to lifetime exposure to testosterone, and in
turn testosterone levels are influenced by age, by
energy intake, and (as well demonstrated in animal
studies) by behavioral factors related to
aggressiveness. This suggests that human
populations characterized by good nutrition
and/or a high level of social interaction requiring
aggressive behavior should have high testosterone
levels in young men and a high incidence of
prostate cancer in older men. Such a relationship
has been demonstrated by a study showing that
testosterone levels of young men are significantly
associated with population disparities in the
incidence of prostate cancer in older men,
providing evidence for a life-history trade-off
mediated by testosterone between early
reproductive effort and later health (see Alvarado
2013).
Coevolution
with
Microbes
Some 15 to 20% of human cancers are thought be the result of infections. Examples of these causative organisms include viruses (e.g., herpesvirus-related
Kaposi’s sarcoma, hepatitis C virus and liver cancer, papillomavirus and cervical cancer), bacteria (Helicobacter pylori and gastric cancer), and parasites
(schistosomiasis and bladder cancer). The causal nature of these organisms is clearly demonstrated by the rapid drop in incidence of their associated cancers
after the introduction of vaccination or eradication programs. Why do infections lead to cancer? One explanation is that the inflammation associated with
infection drives oncogenesis, for example by increasing levels of mutagens (such as reactive oxygen species produced by neutrophils) or proliferative signals
(growth factors) or by increasing tissue permeability allowing tumor invasion. It is likely that cancers associated with bacterial (e.g. Helicobacter) and some viral
(hepatitis C) infections arise in this way. But some tumor viruses act more directly on the host genome by inserting oncogenic genes that dysregulate cellular
signaling systems, leading to loss of endogenous control over cell replication and proliferation. For example, human papillomavirus can integrate into the host
genome, and the resulting oncogene products inactivate host tumor suppressor proteins (see Nguyen et al. 2014).
Why has evolution failed to develop mechanisms to avoid infection-related cancers? Since only a small proportion of infections with causative organisms lead to
oncogenesis, we can conclude that infection is necessary but not sufficient for oncogenesis and that other host or environmental factors are required.
Additionally some tumor-causing viruses, such as adenovirus, are oncogenic in some species but cause only mild infections in others. Oncogenesis mediated
through the inflammatory pathway is arguably one of the costs of this defensive mechanism. Therefore, infection-related oncogenesis
can be considered as an aspect of virulence or infection-related morbidity.
Kaposis sarcoma_herpes virus
Implications of
an Evolutionary
Approach for
the Prevention
and Treatment
of Cancer
• Prevention
• How can evolutionary perspectives on
cancer inform our approaches to prevention
and treatment?
• First, appreciation of the role of
environmental and life-history factors can
help to prevent the development of the
disease: examples include avoidance of
causative environmental factors (e.g.,
smoking) and modification of exposure to
life-history factors (e.g., use of estrogen
receptor antagonists such as tamoxifen to
modulate exposure to estrogen in high-risk
women). An appreciation of the role of
inflammation in carcinogenesis and
metastasis helps us to understand the
apparent protective effect of long-term use
of anti-inflammatory medications such as
aspirin and non-steroidal anti-inflammatory
drugs (NSAIDs) against the development of
colorectal cancer and possibly also breast
cancer. Finally, knowledge that the efficacy
of tumor suppressor mechanisms differs
across species according to theirevolved life
history can prompt research into new
modalities to prevent malignant
transformation or tumor metastasis in
humans.
Treatment
• The primary treatment strategy for cancers in humans is complete
or partial surgical removal of the tumor, where possible. This may be
precededand or followed by systemic chemotherapy with cytotoxic
drugs, or by localized radiotherapy, with the aims of reducing tumor
bulk before surgery and/or killing or depleting any tumor cells
remaining after surgery. Sometimes, particular aspects of the tumor
cell phenotype, such as surface receptor expression, are targeted
with specific agents (e.g., tamoxifen for estrogen-receptor-positive
breast cancer). All these approaches are usually effective initially,
although at the cost of considerable toxicity to the patient. However,
in most cases the tumor recurs in a form that is resistant to the initial
chemotherapy. Most tumors and their metastases are formed of
multiple subpopulations of cells with different suites of mutations,
and consequently different phenotypes, evolving according to the
spatially and temporally differing microenvironment across the
tumor. The initially predominant sub- clones can be viewed as those
having the highest fitness in their environment; since resistence to
chemotherapy has costs, such as diversion of metabolic effort to drug
detoxification, then it is likely that these fittest sub- clones will be
sensitive to therapy. However, exposure to cytotoxic chemotherapy,
while killing sensitive cells, will select for a population of resistant
cells that, although they may have been less dominant (i.e., had lower
fitness) in the original tumor environment, will expand to fill the
ecological niche left by the death of the original population of
sensitive cells.
• There are several implications of this evolutionary perspective. First, tumors
containing high sub- clone diversity will contain more genetic variation from which
resistance to therapy can be selected. This implies that, before treatment, multiple
biopsies are required to assess the phenotypes of the predominant sub- clones within a
tumor in order to optimize targeted chemotherapy, since a single biopsy may only
sample a fraction of the sub- clones. Indeed, the extent of genetic diversity (mutational
load) within a tumor can itself be used as a prognostic indicator for the development of
resistance and disease progression. Secondly, the genotypes and phenotypes of the
predominant tumor clones emerging after relapse from chemotherapy will be very
different from those before treatment. Understanding this can help guide subsequent
rounds of treatment. Thirdly, although the goal of most current cancer treatment is to
eradicate all tumor cells by using chemotherapy at the maximum dose intensity that can
be tolerated, it has been suggested that this may not be the best approach to balance
the course of the disease with the patient’s quality of life. Modeling and experimental
studies show that “adaptive therapy,” which uses continuously modulated schedules of
low-dose chemotherapy aiming to keep tumor size constant, results in stable disease
and prolonged survival with minimal therapy-related toxicity (see Gatenby et al. 2009).
Adaptive therapy aims to allow the survival of a significant number of chemosensitive
cells, and these “fitter” cells will suppress the growth of the population of resistant cells
by avoiding rapid proliferation of a treatment-resistant clone. The fourth point concerns
the treatment approach to metastatic cancer. Metastases will contain only a proportion
of the genetic diversity ofthe primary tumor, and metastasized tumor clones must adapt
to the host tissue environment. There is evidence that metastases from different
primary tumors adapt convergently to the environment of the new host tissue. For
example, liver metastases from different primary cancer sites appear to evolve towards
a common liver-adapted phenotype. These observations suggest that treatment of
metastatic disease should take account of the features of the host tissue as well as of
the tissue at the site of the primary tumor (see Cunningham et al. 2015)
Key Points
• Cancer is the uncontrolled growth and spread of abnormal cells. The cellular abnormalities that characterize cancer generally
represent dysfunction of the evolved control mechanisms that allow cooperative multicellularity.
• Cancer typically begins as a single clone of mutated cells, but the high mutation and proliferation rates of cancer cells result in
the formation of multiple sub-clones in the tumor with diverse suites of mutations that respond differently to selective pressures
within the tumor microenvironment (somatic evolution).
• This heterogeneity and the high genetic variation within tumors represent a challenge for chemotherapy in particular, because
treatment-resistant cells are invariably present and undergo rapid clonal expansion after sensitive cells are killed.
• The incidence of cancer appears to be increasing worldwide as populations age, although there are wide variations by tumor type,
geographical area, and demography.
• Lifetime cancer risk is modulated by evolutionary mechanisms such as environmental novelty, life-history traits, and burden of
infection.
• Application of these evolutionary insights may lead to new approaches to cancer prevention and treatment.
Cancer Palaeopathology
Thank you fo your attention!