INSIGHTS | PERSPECTIVES
mechanism of reciprocal interaction between primary tumor and osteoblasts was
described in prostate cancer (9).
Future work is needed to understand
the mechanism underlying osteoblast-induced neutrophil migration. For example,
(7). Could this discrepancy be
due to the tumor type–specific
molecular signals that target
osteoblasts and osteoclasts
(which break down bone)? Or
do other systemic effects [for
example, those that induce cachexia (muscle wasting)] that
indirectly lead to bone loss play
a role in osteoporosis? Furthermore, it is tempting to speculate that other cell populations
derived from the osteoblastic
niches could also be influenced
through osteoblast modulation
and systemically contribute to
tumor progression, a hypothesis
that can be supported by the
parabiosis experiment and antibody depletion of CD11b+ Ly6G+
cells carried out by Engblom et
al. Addressing these questions will help
elucidate the mechanisms underlying the
systemic regulation of cancer progression.
Neutrophils present in the tumor microenvironment contribute to tumor invasion,
angiogenesis, and progression; however,
whether neutrophils play strictly pro- or
antitumor roles remains controversial (10).
The dichotomous roles of neutrophils on
tumors have thus limited our ability to
therapeutically tackle tumor-associated
neutrophils. Engblom et al. identified a
specific neutrophil subset that is mobilized by tumor-instigated osteoblasts and
recruited to the primary lung tumor, where
they acquired a full protumorigenic gene
expression profile. The gene expression
profile of SiglecFhigh neutrophils has been
associated with poor prognosis in lung
cancer patients (6), suggesting that this
transcriptomic signature could serve as a
biomarker of poor prognosis.
Importantly, the molecular switch inducing the protumorigenic polarization of
SiglecFhigh neutrophils upon encountering
the primary tumor microenvironment remains unknown. Therefore, a better understanding of the mechanisms driving
neutrophil polarization is required to allow manipulation of neutrophils for therapeutic purposes. Furthermore, SiglecFhigh
neutrophils share similar phenotypic and
functional profiles with granulocytic myeloid-derived suppressor cells (MDSCs), a
major component of the systemic regulation of tumor progression via immunosuppression (11, 12). Because of the similar
cell-surface markers that have been used
to identify neutrophils and MDSCs, clarifying the molecular profiles that distinguish
these two subpopulations is required for
guiding precise therapeutic strategies.
Engblom et al. highlights the importance
of identifying messengers that mediate the
systemic cross-talk between tumor cells
and distant organs to open up new avenues
for therapeutic blockade of tumor progres-
sion. Notably, they showed that soluble
receptor for advanced glycation end prod-
ucts (sRAGE) was elevated in the serum of
lung tumor-bearing mice and that sRAGE
accounts, at least partially, for the osteo-
blast activation and subsequent egress of
neutrophils from bone marrow. The source
of sRAGE, its effects on osteoblasts, and
the identification of other potential factors
mediating such cross-talk warrant further
investigation. Indeed, to convey messages
to distant organs, tumor cells can use dif-
ferent “messengers,” including chemo-
kines, cytokines, cell-free nucleic acids,
and extracellular vesicles, all of which are
either secreted by or in response to tu-
mors. Exosomes in particular can educate
bone marrow cells to promote their mobi-
lization to premetastatic sites (13). Thus,
whether exosomes play critical roles in
mediating the systemic cross-talk between
tumor cells, osteoblasts, and neu-
trophils is worth exploring.
Engblom et al. add important
insights to our understanding of
cancer as a systemic disease. Do
these neutrophils also contribute
to metastatic disease (
premetastatic niche establishment and
metastatic colonization and outgrowth) of lung cancer in other
organs? Or are independent
mechanisms, or different subsets
of neutrophils, involved in lung
cancer metastasis? Are other
organs affected by the systemic
regulation of tumor progression?
Cancer has adverse nonmetastatic
effects, including cachexia and
paraneoplastic syndrome (when
tumor-induced factors cause
damage in the central and peripheral nervous system) (14, 15).
Does mobilization of neutrophils
promote functional and metabolic alterations in other organs
besides the lung to contribute
to such nonmetastatic complications? A better understanding of
the systemic cross-talk between
tumor cells and remote cells—
such as osteoblasts, which can influence
tumorigenic and nontumorigenic complications—should aid in developing novel therapeutic approaches. j
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2. Responsive systemic factors
Secondary organ–derived factors
Systemic factors could also
1. Tumor-secreted systemic factors
1128 1 DECEMBER 2017 • VOL 358 ISSUE 6367
Cancer is a
Primary tumor mediates
cross-talk with other organs via
systemic factors to promote
primary tumor growth and
metastasis, and elicits systemic
inflammation and a variety of
other nonmetastatic systemic
complications such as cachexia,
and paraneoplastic syndromes.