The mammalian immune system both suppresses and tolerates tumors, so understanding this complexity should benefit the development of cancer therapies. Macrophages are proposed to play an important role in suppressing the immune response to cancer cells,
but it is not clear where these immune cells
come from or whether there are distinct
populations of macrophages with specific
roles in this setting. On page 921 of this issue, Franklin et al. (1) forge a more coherent view of macrophages that are associated
with tumor growth by assessing their origin, phenotype, and functions in an animal
model of breast cancer.
Tumor progression can be divided into
three phases—initiation, growth, and me-
tastasis (see the figure). The first phase is
characterized by the cell-autonomous accu-
mulation of genetic defects that leads to cell
transformation. This is followed by clonal
growth of transformed cells within the tis-
sue—the primary tumor site (2). Metastasis
results from the successful “engraftment”
of circulating tumor cells into secondary
locations where they proliferate after a
dormancy phase in which metastatic cells
remain quiescent (3). In both primary and
secondary tumor sites, the stroma, which
includes mesenchymal cells, macrophages,
and extracellular matrix (3), is thought to
play a role in the initial survival and prolif-
eration of transformed cells. However, as a
solid tumor grows and tumor cells acquire
the potential to escape the primary site, the
stroma becomes a more complex environ-
ment, with newly formed blood and lym-
phatic vessels and the recruitment and/or
proliferation of lymphoid and myeloid im-
mune cells (4). Immune cells are proposed
to prevent tumor progression via the elimi-
nation of immunogenic tumor cells by T
lymphocytes (CD8 subtype), a phenomenon
known as immunosurveillance (also called
immunoediting). During this process, tu-
mors that display either reduced immuno-
genicity or enhanced immunosuppressive
activity will escape elimination (5). Macro-
phages present in the tumor site can acti-
vate the immune response, but are mainly
thought to contribute to immunosuppres-
sion and tumor progression (6, 7), particu-
larly in the mammary gland (8). A high
density of macrophages in tumors is also
associated with worse overall survival in pa-
tients with gastric, urogenital, and head and
neck cancers, although it seems to be associ-
ated with better overall survival in patients
with colorectal cancer (7).
Franklin et al. carefully explore the contribution of macrophages to tumor growth
in mice that develop a mammary cancer
that is genetically driven by the expression of an oncogene. In investigating the
development and differentiation of macrophages in the normal mammary gland
and during the progression of a mammary
tumor, the authors identify a population of
macrophages that accumulates during tumor growth called tumor-associated macrophages (TAMs). These cells develop from
bone marrow–derived cells with the characteristics of inflammatory monocytes, which
are recruited to the tumor where they differentiate into macrophages and subsequently
proliferate. Franklin et al. observed that
when signaling by the protein Notch is prevented in these TAMs, their differentiation
is blocked. Interestingly, TAMs are distinct
from macrophages present in normal mammary tissue, which develop independently
of Notch signaling. Depletion of TAMs led to
a reduced tumor burden in the animal and
increased the cytotoxic potential of T lymphocytes present in the primary tumor site.
Thus, monocyte-derived Notch-dependent
TAMs are critical for tumor growth in this
mammary gland tumor model, at least in
Identifying the infiltrators
By Elisa Gomez Perdiguero and
Molecular characterization of macrophages reveals
distinct types during tumorigenesis
CANCER IMMUNOLOGY stress environment appear to be critical for
synthesizing this phase.
So why has this new transition not been
observed seismically? One possibility is that
the velocity change across the transition may
be too small and/or the boundary may undulate dramatically in its depth. Alternatively,
the temperature of the deep mantle may lie
below the temperature of the disproportionation reaction [which would require that the
mantle be a few hundred kelvin cooler than
currently inferred (12)—but this would also
imply that disproportionation could have
been important in the hotter past]. Another
option is that the oxidation state of iron in
the mantle may differ from those within the
experiments. The provocative aspects of this
discovery include not just changing the possible mineralogy of the deeper lower mantle,
but also that two phases of markedly different densities are produced. Whether these
phases could undergo partial segregation,
thus enriching or depleting regions in the
H-phase (particularly in an earlier, hotter,
less viscous, and possibly partially molten
mantle), is unknown. If such segregation did
occur, a natural explanation for the genesis
of LLSVPs might exist. Depending on its elasticity, an enrichment of H-phase within these
regions might provide an avenue to explain
their anomalous seismic signature.
Each of these experiments is the direct result of developments in high-pressure, high-temperature techniques and the availability
of high-intensity synchrotron sources. Probing the sensitivity of the pressure and temperature of melting and the phase transition
to variable oxygen fugacities, shifts in major
and minor elemental abundances, and volatile contents holds the prospect of mapping
out the likely chemical behavior of the lower
mantle. In doing so, the current void of information on the differentiation processes that
govern the chemical variations, structural
features, and evolution of Earth’s deepest
rocky reaches will be filled. ■
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10.1126/science.1254399 I L L U S