tumor angiogenesis and disease progression
by stimulating adipocyte production of vas-
cular endothelial growth factor–A (VEGF-A)
(8). In the pancreas, obesity is associated with
increased desmoplasia and inflammation,
which enhances IL-1b production by adipocytes. In cancer, this increase in IL-1b promotes the recruitment of immunosuppressive
neutrophils to the pancreatic TME, which accelerate tumor growth (5). In prostate cancer,
periprostatic adipocyte secretion of C-C motif chemokine ligand 7 (CCL7) drives invasion
of tumor cells into the surrounding stromal
tissue (9). Collectively, these studies demonstrate that systemic inflammation resulting
from obesity can perturb homeostatic communication between different organs, including WAT, bone marrow, and primary TMEs,
to mediate enhanced malignancy.
Obesity is also associated with increased
stage at diagnosis for breast cancer (1). Although this has been attributed in part to
impaired cancer screening efficacy, there
is emerging evidence that the systemic effects of OAI can also affect cancer metastasis (see the figure). Indeed, protumorigenic
metabolites, cytokines, and growth factors
can reprogram the systemic (i.e., blood or
circulation) environment to improve metastatic proficiency of the host. For instance,
in preclinical diet-induced obesity models,
obesity increases circulating concentrations
of IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF), leading to
altered myelopoiesis, enhanced neutrophil
trafficking to the lungs, and increased metastatic seeding of breast cancer cells compared
with lean controls (10). In preclinical models
of hypercholesterolemia (a comorbidity of
obesity), elevated circulating concentrations
of cholesterol metabolites also promote lung
metastasis of estrogen receptor–positive
(ER+) breast cancer through enhanced epi-thelial-to-mesenchymal transition, a cellular
process associated with invasion and metastasis (11). Given that metastasis is responsible
for the vast majority of breast cancer deaths,
these observations are consistent with epidemiological data showing increased breast
cancer mortality in association with obesity
in humans (1).
From a translational perspective, there
is considerable evidence that resolution of
energy imbalance and inflammation may
mitigate the protumorigenic effects of obe-
sity. “Obesity addiction” could expose new
cancer dependencies that may be vulnerable
to intervention. Notably, preventing weight
gain using caloric restriction can resolve
obesity-associated WAT inflammation in
mice (12). Weight loss is also associated with
a reduction in IL-5, GM-CSF, and circulat-
ing neutrophils, resulting in a reversal of the
prometastatic effects of obesity in preclinical
breast cancer models (10). These studies and
others suggest that weight loss may be an ef-
fective strategy to reverse energy imbalance
and WAT inflammation, thereby ultimately
improving cancer outcomes.
Additional lifestyle interventions that do
not necessarily require reduction in adipose
tissue, such as exercise and fasting, have
also demonstrated an ability to improve immune function (13, 14). Fasting is associated
with a reduction of immunosuppressive T
regulatory cells within breast tumors and
increased lymphopoiesis, which together
result in higher numbers of cytotoxic CD8+
tumor-infiltrating lymphocytes, and may
thus promote antitumor immune responses
(13). Exercise and epinephrine lead to activation of natural killer cell–mediated immuno-surveillance, and suppress tumor incidence
and growth in multiple cancer models (14).
These interventions, however, have not been
rigorously investigated in the obesity context;
therefore, further preclinical investigation
is required to fully understand their poten-
tial application in patients. Furthermore,
pharmacological approaches to target the
immune system in obese individuals have
yielded unpredictable results. For example,
certain immunotherapy regimens in aged
obese mice have led to lethal inflammatory
reactions (15), reinforcing a critical need to
reexamine what is known about tumor im-
munology in the obesity setting.
It is essential to understand how cancer
biology differs between obese and lean patients, and develop personalized approaches
to treat these distinct diseases accordingly.
Although pieces of the “cancer-obesity” puzzle are beginning to come together, given the
prevalence of obesity in developed countries,
we must emphasize the need to incorporate
preclinical obesity models and appropriate
clinical analysis in all cancer investigations.
Obesity is likely to emerge as the dominant
pathological state of the future, with considerable implications for patient care. j
1. E. E. Calle et al., N. Engl. J. Med. 348, 1625 (2003).
2. O. Osborn, J. M. Olefsky, Nat. Med. 18, 363 (2012).
3. N. Stefan et al., Cell Metab. 26, 292 (2017).
4. B.R.Seo et al., Sci. Transl. Med. 7,301ra130(2015).
5. J. Incio et al., Cancer Discov.6, 852 (2016).
6. R. Li et al. , Cell Metab. 19, 702 (2014).
7. M. Bordonaro, D. Lazarova, J. Cancer6, 825 (2015).
8. R. Kolbetal. , Nat.Commun. 7, 13007 (2016).
9. V. Laurent et al. , Nat. Commun. 7, 10230 (2016).
10. D. F. Quail et al. , Nat. Cell Biol. 19, 974 (2017).
11. E. R. Nelson et al. , Science342, 1094 (2013).
12. P. Bhardwaj et al., Cancer Prev. Res. (Phila) 6, 282 (2013).
13. S. Di Biase et al., Cancer Cell 30, 136 (2016).
14. L. Pedersen et al. , Cell Metab. 23, 554 (2016).
15. A. Mirsoian et al. , J. Exp. Med. 211, 2373 (2014).
which stifens extracellular
matrices and enhances
cancer cell growth.
myeloid cells drives
increased IL-1b signaling
in the tumor.
VEGF-A in response to
IL-1b, increasing tumor
(EM T) in cancer and
Neutrophils accumulate in the
lung and promote seeding and
outgrowth of disseminated
in response to
increased GM-CSF. Post-EM T breast cancer cells
express GM-CSF and
1 DECEMBER 2017 • VOL 358 ISSUE 6367 1131
Obesity and cancer progression
The effects of obesity on cancer progression are depicted using breast cancer as a representative example,
based on studies from mice and humans. Obesity promotes both primary tumor growth and metastatic
progression through systemic alterations that affect tissue homeostasis.