Executive
Summary of Inflammation and Cancer
Think Tank
Inflammation
is a response to acute tissue damage, whether resulting from physical injury,
ischemic injury, infection, exposure to toxins, or other types of trauma. It can play a role in tumor suppression by
stimulating an antitumor immune response, but more
often it appears to stimulate tumor development. Epidemiologic and clinical research indicates
an increased risk of certain cancers in the setting of chronic
inflammation. For example, two inflammatory bowel diseases, ulcerative
colitis and Crohn’s disease,
predispose to cancers of the intestinal tract. Basic research, in turn,
has shown that many of the processes involved in inflammation (e.g., leukocyte
migration, dilatation of local vasculature with increased permeability and
blood flow, angiogenesis), when found in association with tumors, are more
likely to contribute to tumor growth, progression, and metastasis than to
elicit an effective host anti-tumor response.
Interestingly,
inflammation functions at all three stages of tumor development: initiation,
progression and metastasis. Inflammation
contributes to initiation by inducing the release of a variety of cytokines and
chemokines that alert the vasculature to release
inflammatory cells and factors into the tissue milieu, thereby causing
oxidative damage, DNA mutations, and other changes in the microenvironment,
making it more conducive to cell transformation, increased survival and
proliferation.
Chronic
inflammation appears to contribute to tumor progression by establishing a
milieu conducive to development of different cancers. However the precise
mechanism by which it does so remains to be determined. Infection is a common cause of inflammation,
and evidence indicates that the presence of microbes can be a cofactor in
the tumor promoting effects of inflammation.
Tumor
cells produce various substances that attract inflammatory cells, which then
secrete an array of soluble mediators.
These further stimulate proliferation of the initiated cell, tissue
disruption in the stroma, and tumor growth. Leukocyte infiltration, and particularly
macrophages, can lead to enhanced angiogenesis, which is associated with a poor
prognosis in some tissues.
The
role of inflammation in metastasis is less well defined than its roles in
cancer initiation and progression. The
soluble mediators secreted by tumor-associated leukocytes promote cell
motility, and induce angiogenesis, vascular dilation and extravasation
of tumor cells. Particularly interesting is the recent finding that metastatic cells leave the tumor as microcolonies,
containing lymphocytes and platelets as well as the tumor cell. Inflammation
continues to play a role at metastatic sites by
creating a cytokine milieu conducive to tumor growth.
Although
there is a strong association between chronic inflammation and cancer,
investigators have not yet uncovered all the molecules, pathways, and
mechanisms involved, and numerous questions remain to be resolved about the
mechanisms and targets of pro-inflammatory mediators of tumor development. These are articulated in the body of the
report and the recommendations that follow.
Furthermore, to understand the role of inflammation in tumor formation
and progression, we also need to understand its role in maintaining homeostasis
and responding to damage in normal tissue.
An appreciation of the importance of inflammation has already led to
clinical trials of anti-inflammatory drugs (e.g., COX-2 inhibitors) for cancer
prophylaxis and treatment. The results
obtained will provide clues to the dominant mechanisms at work, and will help
in the design of a new generation of interventions.
Introduction
Inflammation
involves a complex set of interactions between soluble mediators and immunocytes, triggered in response to tissue injuries that
include trauma, infection, toxic agents and autoimmune responses. Such injuries trigger a cascade of cellular
infiltrations and cytokine releases that result in local cellular proliferation
and repair of tissue damaged. While
sustained proliferation alone is insufficient to initiate cancer, a functional
relationship between inflammation and cancer has been recognized for a long
time. The current discussions centered
on our current understanding of the role of inflammation in cancer initiation,
progression and metastasis and highlighted areas in which there are major,
unresolved questions.
I. Inflammation and Cancer Initiation
Although
inflammation is a necessary response to clear viral infections, to repair
tissue insults - either chemical exposure or injury- and suppress tumor
initiation/progression, chronic inflammation is also clearly correlated with
increased risk of developing cancer. Inflammation may become chronic either because
an inflammatory stimulus persists or because of dysregulation
in the control mechanisms that normally turn the process off. Many of the cells, cytokines and systems (e.g.,
leukocyte migration, dilatation of the local vasculature and angiogenesis)
involved in inflammation are also found in a variety of tumors. Chronic inflammation caused by intestinal
flora leading to the inflammatory bowel diseases, ulcerative colitis and Crohn’s disease, is clearly linked with a higher incidence
of colon cancer. The use of mouse models
has furthered our understanding of the contributing cellular and molecular
factors in colon cancer. Similarly,
dietary intake of proinflammatory carcinogens has
been associated with prostate cancer.
Chronic inflammation resulting from esophageal reflux gives rise to gastroesophageal reflux disease (GERD) and Barrett’s
esophagus, also linked with a higher incidence of cancer. In the case of Barrett’s, chronic inflammation
leads to the production of TNF".
This, in turn, induces the nuclear translocation of $-catenin and transcriptional activation of proliferative signals.
The molecular
basis for the increased risk is thought to be two-fold: 1) generation by
inflammatory macrophages of reactive oxygen (ROS) and nitrogen (RNS) species
leads to DNA damage in the surrounding epithelial cells and 2) enhanced proliferative signals mediated by cytokines released by
inflammatory cells increase the number of cells at risk for mutations. In combination, DNA damage and proliferative signals create a circumstance conducive to
the development of cancer. ROS and RNS
can cause extensive damage to essential proteins (e.g., DNA repair enzymes), to
DNA and to the mitochondria through a series or cascade of reactions. Among the many possible mutations that may
result from oxidative DNA damage are the formation of single- and/or
double-stranded breaks and the stimulation of recombination events. Free-radical damage can be caused by the
pro-inflammatory prostaglandin enzyme, cyclooxygenase
2 (COX-2), which leads to the production of highly reactive peroxide
intermediates at high levels in a local tissue environment. Drugs that selectively inhibit the COX-2
enzyme, including NSAIDs, are being studied to
determine their impact on local tumor biology and development, and in clinical
trials. Recent studies have suggested protective effects of COX-2 inhibitors in
colorectal cancer and breast cancer. Several small studies of colorectal, non-small
cell lung cancer, breast, cervical and esophageal tumors have shown that
increased COX-2 levels are associated with poor clinical prognosis. Animal models for colorectal cancer show
similar patterns of COX-2 expression and response to COX-2 inhibitors as human neoplasias.
Inflammation
results in the recruitment of leukocytes secreting a variety of proliferative cytokines and angiogenic
factors to the site of tissue insult. These
cytokines, necessary for proper wound healing, stimulate epithelial
proliferation, which if unchecked could lead to dysplasias
and ultimately cancer. Paradoxically,
cytokine deficiency (e.g., GM-CSF, IL-2 and IFN() can also lead to tumor
development. Immune homeostasis consists
of a succession of pro- and anti-inflammatory signals. Loss of the anti-inflammatory signals leads to
chronic inflammation and proliferative signaling. The mechanisms involved in the interplay of
microbes and defective immune homeostasis is an area that requires further
delineation. Future steps will involve
clinical studies to determine whether individuals have polymorphisms or genetic
variations that affect specific cytokine pathways.
The discussion
highlighted the duality of inflammation in controlling and promoting tumor
development. While chronic inflammation
can establish conditions conducive to tumor initiation and progression,
compelling data also suggest that the presence of lymphocytic
infiltrates in a variety of tumors is associated with a good clinical outcome. The major challenge in this area is to
understand the balance between inflammatory tumor suppression and promotion and
how to control it.
II. Inflammation and
Cancer Progression
It is generally
accepted that chronic inflammation – triggered by toxins, microbes or
autoimmune reactions – plays a major role as a tumor promoter. However, the precise function of inflammation
in tumor progression remains to be elucidated.
Tumor cells produce various cytokines and chemokines
that attract leukocytes, which in turn produce cytokines and chemokines that stimulate further tumor cell proliferation;
the inflammatory tumor microenvironment is characterized by the presence of
host leukocytes both in the stroma and around the
tumor. A developing neoplasm can contain
a diverse leukocyte population, including neutrophils,
dendritic cells, macrophages, eosinophils,
mast cells and lymphocytes. These
inflammatory cells secrete an array of cytokines, interleukins, interferons and other soluble mediators and further induce
secretion of cytokines by resident stromal cells.
Interestingly,
both cytokines that promote and suppress proliferation of the tumor cells are
produced. As in the case of cancer
initiation, it is the imbalance between the effects of these two classes of
activity that results in tumor promotion. For example, in the presence of GM-CSF and
IL-4, monocytes differentiate into immature dendritic cells, which migrate into inflamed peripheral
tissue, capture antigens and then migrate to lymph nodes to stimulate T
lymphocyte activation. Deletion of GM-CSF
from Polyoma T transgenic mice reduces cancer progression.
This is correlated with reduced
macrophage infiltrates, which play a major role in the transition from adenoma
to carcinoma. GM-CSF vaccines that
stimulate dendritic cell and T cell responses are
being combined with anti-CTLA4 treatment in clinical trials to potentiate the anti-tumor response.
In contrast,
IL-6 and CSF-1 secreted by tumor cells can skew monocyte
differentiation towards the macrophage lineage. Although tumor associated macrophages can kill
tumor cells when activated by IL-2, IL-12 or interferon, they also produce a
host of compounds – angiogenic factors, growth
factors, proteases and cytokines – that either contribute to cancer progression
or blunt the anti-tumor response.
Macrophages generate a variety of proteases, including cathepsin B, which contribute to tumor growth. Stromal fibroblasts
and monocytes enhance this proteolysis. During tumor progression, the degradation of
the matrix and stromal fibroblasts appears to be focal, suggesting that widespread degradation may not be
necessary for tumor growth. In mammary
cancer models, a variety of leukocytes are found at the tumor-stroma interface. A
complex interaction between tumor, stroma and
inflammatory cells results in the secretion of protease and matrix degradation
and the entrapment and degradation of fibroblasts by the tumor.
Other studies
have indicated that hypoxia signaling pathways are engaged very early in cancer
development. Hypoxia stabilizes HIF-1"
which in turn induces VEGF secretion by epithelial cells that stimulates microvascularization and angiogenesis.
The spatial
relationship between inflammatory cells and tumors is now being investigated by
imaging of a range of live human tumor and associated cells. Examination of the interaction reveals that
although T cells will home to the tumor, they stay on the periphery and do not
enter. Real-time images of mammary
tumors in mice show that the tumor regions are metabolically active,
compared with surrounding stroma and fat cells. These
regions also have a much greater inflammatory response; associated immune
cells, particulary T cells, are very active and
mobile. In mammary cancer models, imaging reveals that tumor associated
macrophages preferentially line up along the lumenal
side of the tumor-associated vessels. Macrophages in this region are relatively
static, whereas those at the stromal interface are
very active and motile, suggesting differential behavior within the tumor. The
functional significance of this remains to be
determined.
Although the
role of inflammatory cells and soluble mediators in tumor progression is now
well documented, the details of the cellular and molecular interplay between stroma and tumor progression remain to be elucidated.
III. Inflammation and
Metastasis
Unlike tumor
progression, where the role of inflammation in promoting cancer cell
proliferation and stromal/matrix degradation is
reasonably well understood, the role of inflammation in metastasis is less well
defined, although appears to be important.
The cytokines and chemokines secreted by tumor
associated macrophages and leukocytes promote cell motility and induce
angiogenesis and the growth of tumor-associated vessels, providing an egress
route for metastatic tumor cells. The leukocytes also promote vessel dilation
and extravasation of tumor cells. Particularly intriguing is the observation
that metastatic cells leave the tumor as microcolonies, containing lymphocytes and platelets, the
latter allowing attachment to distal organ sites. Tumors that are unable to form such microcolonies are not malignant.
At the distal, metastatic sites, evidence suggests that inflammation
continues to play a role in the establishment of metastases. At the sites of prostate cancer metastases in
the bone, inflammation triggers the secretion of TGF-β by osteoclasts. TGF-β in turn induces the cancer cells to
secrete PDGF which further stimulates the osteoclasts,
leading to bone degradation and stimulation of cancer cell growth. PDGFR on tumor-associated endothelial cells
increases their levels of bcl-2 and bcl-xl, rendering
them resistant to apoptosis and chemotherapy. Similarly, in brain metastases of melanoma, astrocytic infiltrates upregulate
MDR (multiple drug resistance) in the tumor cells, making them more resistant
to chemotherapy.
Next Steps and Important
Questions
Tumor
immunotherapy approaches should include targeted intervention of
inflammation-mediated growth, pairing molecular information of inflammatory
infiltrates with that of specific tumors.
Therapy should be specifically directed to both the organ
microenvironment and the tumor.
Specific Recommendations for the NCI: