By Haiying Zhang and David Lyden
Cancer is a systemic disease. Tumor growth and malignant progression rely not only on the intrinsic aber- rant genetic and epigenetic makeup of tumor cells but also on the tumor- induced systemic factors that affect
cells in the primary tumor as well as distant microenvironments (1). Notably, bone
marrow–derived cells (BMDCs) have been
shown to contribute to primary tumor progression by promoting hallmark processes
such as inflammation, immunosuppression, vasculogenesis, and extracellular matrix remodeling. BMDCs are also involved
in establishing tumor-permissive microenvironments that form before the arrival of disseminated tumor cells at future
metastatic sites (known as premetastatic
niches) and promote metastatic outgrowth
(2–5). In addition to the direct effects of
tumor-secreted factors on BMDC recruitment to tumors, on page 1147 of this issue
Engblom et al. (6) report that osteoblasts,
which reside in the bone, can be remotely
activated by secreted factors from lung adenocarcinoma, which in turn mobilize a
specific subset of BMDCs—neutrophils—to
foster tumor growth.
Using mouse models of lung adenocarci-
noma, the authors showed that in the ab-
sence of metastasis, primary lung tumors
promote the production of osteoblasts
expressing osteocalcin (OCN+), increas-
ing bone mass and density (osteopetrosis)
and altering osteoblast gene expression.
Remarkably, deletion of OCN+ cells re-
duced mature osteoblast numbers and led
to significant tumor suppression, indicat-
ing that these OCN+ cells are function-
ally required for lung adenocarcinoma
progression. Interestingly, Engblom et al.
showed that this tumor suppressive phe-
notype can be rescued through parabiosis
(a surgical process to join two animals that
allows the sharing of blood circulation) of
OCN+ osteoblast–deficient mice with OCN+
osteoblast–sufficient mice, which suggests
that the phenotype is mediated by circu-
lating factors stimulated by these immobi-
lized bone-residing osteoblasts.
Indeed, the authors found that a specific subset of neutrophils that express
CD11b and Ly6G was recruited to the
primary tumor in an OCN+ osteoblast–
dependent manner. Consistently, antibody
depletion of CD11b+ Ly6G+ neutrophils in
tumor-bearing mice harboring increased
numbers of OCN+ osteoblasts significantly
suppressed tumor growth. Further analysis revealed that OCN+ osteoblasts induced
a particular subset of neutrophils that
highly express the cell surface adhesion
receptor sialic acid–binding immunoglobulin-like lectin F (SiglecFhigh neutrophils).
This subset of neutrophils exhibited protumorigenic properties, promoting tumor
growth in vivo.
Engblom et al. provide new insight on the
systemic effects of osteoblasts during lung
adenocarcinoma progression (see the figure). Osteoblasts and osteoclasts cooperate
to control bone homeostasis, which is typically disrupted by cancer metastasis. The
role of osteoblasts in establishing a favorable microenvironment for bone metastasis
is documented in many cancers (7). Negative regulation of osteoblasts (that is, loss
of proliferative phenotype and increased
terminal differentiation) in osteolytic premetastatic lesion formation has also been
reported (8). Here, Engblom et al. reveal a
mechanism by which tumor-driven osteoblasts support primary lung tumor growth
by supplying a specific subset of neutrophils
remotely to the primary tumor. A similar
remotely control tumors
Tumor-driven systemic activation of osteoblasts in
the bone promotes lung tumor growth
Children’s Cancer and Blood Foundation Laboratories,
Departments of Pediatrics, and Cell and Developmental
Biology, Drukier Institute for Children’s Health,
Meyer Cancer Center, Weill Cornell Medicine, Ne w York,
NY 10021, USA. Email: email@example.com;
DNase in the double–DNase-deficient mice
could completely protect the animals from
the effects of neutrophilia, indicating a redundant function. These observations also
indicate that neutrophils have a tendency to
produce NETs if there is a high concentration of neutrophils, and this happens even
in the absence of a specific infectious trigger. Thus, NETosis needs to be counterbalanced to maintain the integrity of the body
and avoid autoimmunity (see the figure).
TMAs are a well-known pathology in humans who suffer from massive infectious
complications such as sepsis. Interestingly,
Jiménez-Alcázar et al. showed that serum
from patients in the acute phase of a systemic bacterial infection could not degrade
NETs, and autopsy material from victims of
generalized sepsis showed high numbers of
NET-associated clots in the fine blood vessels of the lungs. Also, in double–
DNase-deficient mice, infection with a bacterial
pathogen or exposure to bacterial products
led to a highly aggressive disease similar to
sepsis in humans. The ability to control the
overwhelming production of NETs is therefore an essential protective measure in mice
and humans that counterbalances the function of neutrophils during inflammation.
Jiménez-Alcázar et al. show how endogenous DNases protect individuals from the
autoimmune side effects resulting from hyperactive neutrophils. Future work needs
to clarify whether this can be exploited for
human therapy, for example, by providing
DNases to patients suffering from TMAs due
to sepsis, SLE, cancer, or drugs (12). Both
DNase1 and DNase1L3 were found to be involved in the pathogenesis of human SLE (6,
11). It should also be investigated whether
there are additional mechanisms to protect hosts from NETs. For example, only a
minority of neutrophils in culture undergo
NETosis (13). Do the remaining neutrophils
have sensors for NETs that stop them from
producing more? In any case, the discoveries of Jiménez-Alcázar et al. bring us a step
closer to the first therapeutic applications
of the ever-increasing knowledge about
NETs and their function in host defense. j
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support primary lung
tumor growth by supplying
a specific subset of
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