INSIGHTS | PERSPECTIVES
Obesity and the tumor
By Oakley C. Olson,1 Daniela F. Quail,2
Johanna A. Joyce1
Obesity is a growing global epidemic and rivals smoking as the leading prevent- able risk factor for cancer incidence and mortality, being responsible for an estimated ~20% of cancer-related eaths in adults (1). Obesity underlies a
number of distinct but interconnected health
conditions that have profound consequences
for physiology, including hypernutrition, dys-biosis, hypercholesterolemia, metabolic syndrome, and chronic inflammation. Although
each of these health conditions may affect
cancer pathogenesis, inflammation, in particular, is known to be a potent driver of cancer
initiation and progression through its ability
to cultivate a microenvironment that is permissive to neoplastic transformation. Thus,
as immuno-oncology continues to gain clinical importance, understanding
the relationship between cancer and various inflammatory
conditions, including obesity,
Adipose tissue is found in
several anatomical locations,
including various subcutane-
ous and visceral regions, and
in bone marrow. Within these
depots, the metabolic status
of adipose tissue can vary: Brown adipose
tissue (BAT) is highly specialized, energy-
consuming, thermogenic fat that supports
glucose homeostasis and insulin sensitiv-
ity. By contrast, white adipose tissue (WAT)
stores energy and is relatively more abun-
dant. Clinically, WAT is crudely estimated
by using the body mass index (BMI; body
mass/height2 in kg/m2), where overweight is
defined as a BMI between 25 and <30, and
obesity as a BMI of 30 or higher (1). In obese
individuals, increased and deregulated WAT
contributes to chronic, systemic inflamma-
tion and metabolic syndrome (2). Interest-
ingly, ~20% of lean adults display metabolic
“obesity,” characterized by WAT inflamma-
tion, higher proportions of visceral WAT, and
insulin resistance (3). Conversely, roughly
50% of obese individuals remain metaboli-
cally healthy (3). Although obesity and WAT
inflammation are strongly correlated on a
population level, BMI alone cannot accu-
rately capture immunometabolic dysfunc-
tion within a given individual. Therefore,
preclinical studies that define the causal re-
lationships between WAT inflammation and
cancer will potentially have clinical relevance
for patients across all weight categories.
Obesity-associated inflammation (OAI)
can dramatically alter tissue composition,
thereby creating a fertile soil for cancer
development; it is conceivable that these
changes may lower mutational and epigenetic barriers to tumorigenesis. For instance,
in breast (4) and pancreas (5), OAI is associated with altered extracellular matrix
composition that facilitates
transformation of premalig-nant cells. In the colon, epigenetic alterations that occur in
cancer are observed in normal
epithelial cells in the context of
obesity (6), thus lowering the
mutational threshold that is
required for malignant transformation (7). These studies
suggest that OAI “primes” both
the tissue microenvironment and premalig-nant epithelial cells to facilitate oncogenic
transformation. Indeed, obesity is often associated with specific molecular subtypes
of cancer (7), which may reflect a selective
pressure exerted by the obese microenvironment resulting in the altered fitness of
specific oncogenic mutations. Accordingly,
tumors that evolve within an obese microenvironment may exhibit “obesity addiction”
whereby they are driven by a dependency on
hypernutrition and inflammatory cytokines.
OAI can also contribute to disease progression at the primary tumor site by perturbing
the homeostatic balance of cytokines in the
systemic milieu. In breast cancer, tumor-infiltrating myeloid cells producing inter-
leukin-1b (IL-1b), an inflammatory cytokine,
are elevated in the obesity-associated tumor
microenvironment (TME), and can promote
1Ludwig Institute for Cancer Research, University of Lausanne,
Switzerland. 2Goodman Cancer Research Centre, Department
of Physiology, McGill University, Montreal, Canada.
Email: firstname.lastname@example.org; email@example.com
tic gene expression and nutrient gradients in
the model ocean.
The authors found that although the
emergent microbial community differed
between model runs, metabolic capacity
and thus ocean biogeochemistry remained
stable. In other words, the specific activities
of microbes mattered more than their species identity.
Many ecologists have been trained to address two key questions: Who is there, and
what are they doing? Perhaps, in the ocean,
one only needs to know the latter. But before fully embracing this notion, we need
to better understand how natural selection
acts on marine microbes and how rapidly
mutations for new variants arise. These
questions could be addressed in Coles et al.’s
model by allowing for different rates of mutation and selection to occur within a physically and biologically dynamic ocean model.
Future efforts can build on the foundation of the model. Coles et al.’s results provide guidance for future improvements of
ocean physics models by indicating where
the physics in those models is too coarse
to resolve the impact of microbial activities. For example, some aspects of nutrient
gradients in the Coles et al. model differ
from observations in the North Atlantic
and are more likely due to poor resolution
in the physical model than to errors in the
parameterization of biological activities.
Future iterations of the model could begin
to incorporate symbioses. These ubiquitous
multispecies and even multikingdom interactions have been fine-tuned over evolutionary time (12) and influence rates and
magnitudes of nutrient transformations in
the global ocean. Last, because the model
output can be compared with in situ gene
expression, there is a new opportunity to
extend the model and integrate global-scale
surveys of genes and transcripts, such as
the Tara Oceans expedition (3), with global-scale biogeochemical models. j
1. P. G. Falkowski, T. Fenchel, E. F. Delong, Science 320, 1034
2. V. J. Coles et al., Science 358, 1149 (2017).
3. S.Sunagawa et al., Science 348,1261359(2015).
4. L. Zinger et al., PLOS ONE 6, e24570 (2011).
5. A. Z. Worden et al., Science 347, 1257594 (2015).
6. B.B. Ward, Proc. Natl. Acad. Sci. U. S. A. 99,10234(2002).
7. J. S. Bowman, H. W. Ducklow,PLOSONE 10, e0135868
8. H.Alexander, B.D.Jenkins, T.A.Rynearson,S. T.Dyhrman,
Proc. Natl. Acad. Sci. U.S.A. 112, E2182 (2015).
9. V. J. Coles, R. R. Hood, in Aquatic Microbial Ecology and
Biogeochemistry: A Dual Perspective, P. M. Glibert, T. M.
Kana, Eds. (Springer International Publishing, 2016),
10. T.Mock et al., Global Change Biol.22,61(2016).
11. M. J. Follows, S. Dutkiewicz, S. Grant, S. W. Chisholm,
Science 315, 1843 (2007).
12. S.A.Amin etal.,Nature522,98(2015).
Obesity-associated inflammation promotes
tumor growth and metastatic spread
1130 1 DECEMBER 2017 • VOL 358 ISSUE 6367