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Abstract While genetic changes are critical for the malignant transformation of
epithelial cells, the microenvironment in which the cells reside also governs car-
cinogenesis. Most tumors arise within a cellular microenvironment characterized
by suppressed host immunity, dysregulated inflammation, and increased produc-
tion of cellular growth and survival factors that induce angiogenesis and inhibit
apoptosis. The studies highlighted in this chapter indicate that the lung tumor and
its microenvironment interact, together informing the process of carcinogenesis.
Understanding the molecular mechanisms driving the contributions of the tumor
microenvironment to lung carcinogenesis may afford us the opportunity to develop
new drugs that target these reversible nonmutational events in the prevention and
treatment of lung cancer. Findings from recent microenvironment-related clinical
studies have implications for understanding the immunopathobiology of lung cancer,
for targeting surgery and adjuvant therapy, and for designing future trials of adju-
vant therapy. If the field is to progress and promising leads in the laboratory are
to translate into anticancer therapeutics, future trials targeting the tumor microen-
vironment must incorporate improved patient risk assessment and selection, in
addition to the continued evaluation of combination therapies using the optimal
biological dose of each compound being tested. Appropriately targeting the tumor
microenvironment in a highly selected patient population is a newly emerging
strategy that holds unique potential for advancing the current state of lung cancer
prevention and treatment.
Keywords
)
e-mail: [email protected]
Tumor Microenvironment
Tonya C. Walser, Jane Yanagawa, Edward Garon, Jay M. Lee,
and Steven M. Dubinett
Lung Cancer: Prevention, Management, and Emerging Therapies,
Introduction
While genetic changes are critical for the malignant transformation of epithelial
cells, the microenvironment in which the cells reside also governs carcinogenesis.
Most tumors arise within a cellular microenvironment characterized by suppressed
host immunity, dysregulated inflammation, and increased production of cellular
growth and survival factors that induce angiogenesis and inhibit apoptosis. The
pulmonary microenvironment, in particular, represents a unique milieu in which
inflammatory cells, endothelial cells, etc.) components of the microenvironment.
Understanding the molecular mechanisms driving the contributions of the tumor
microenvironment to lung carcinogenesis may afford us the opportunity to develop
new drugs that target these reversible nonmutational events in the prevention and
treatment of lung cancer.
described molecular signatures associated with progression. Identification of robust
biomarkers predictive of cancer progression and prognosis could have a clinically
biomarkers would aid in the appropriate selection of patients who would benefit
from therapy beyond surgery. The molecular signatures that have emerged from
these progression-associated gene sets are composed mainly of cytokine genes
involved in inflammatory and immune responses. In one such study by Bhattacharjee
adenocarcinoma specimens allowed the investigators to discriminate between
biologically distinct subclasses of adenocarcinomas, as well as primary lung adeno-
carcinomas versus metastases of nonlung origin ) study that closely followed came from Beer et al. 2) profiling to predict survival among patients with early stage lung adenocarcinomas.
low-risk stage I adenocarcinomas and poor or favorable predicted survival, respec-
identified, but, more importantly, the molecular profile that emerged predicted
predicted the poor survival of patients with stage I adenocarcinomas ). And
). Together, these
-
ing and clear evidence that molecular signatures composed mainly of inflamma-
tion- and immune-related cytokines correlate with important clinical parameters.
A recent investigation of the role of the lung tumor microenvironment in pro-
). To inquire whether gene
Tumor Microenvironment
as a biomarker to predict cancer progression and prognosis, this group conducted a
patients with adenocarcinoma. Many of the genes identified were part of a unique
inflammatory and immune response signature that this group previously observed
). Ultimately, however, they
prognosis. The results of this well designed trial demonstrate that molecular signa-
tures associated with the tumor microenvironment can serve as robust biomarkers
predictive of cancer progression and prognosis.
Though not in lung cancer, a recent publication by Farmer and colleagues was
the first to report a major contribution of stromal genes to drug sensitivity in the
7)
group described a stromal gene signature that predicts resistance to preoperative
tumor microenvironment-associated gene signatures, and it encourages the devel-
opment of antistromal agents as a new method by which to overcome resistance to
chemotherapy.
).
By coculturing a K-ras mutant lung adenocarcinoma cell line with one of three lung
profiling the secreted proteins, they developed an in vitro model for evaluating the
mechanisms by which stromal cells regulate the biological properties of lung ade-
nocarcinoma cells. The group confirmed that the in vitro model robustly recapitu-
lates many of the features of their K-ras mutant murine model and, most importantly,
microenvironment. By two different proteomic approaches, the investigators profiled
the secretome of the tumor cells and evaluated its regulation by the stromal cells.
They concluded that stromal cells in the tumor microenvironment do alter the tumor
cell secretome, including proteins required for tumor growth and dissemination.
in angiogenesis, inflammation, cell proliferation, and epithelial–mesenchymal transi-
These findings suggest that stromal cells drive the aggressiveness of tumor cells via
-
tions between tumor cells and the tumor-adjacent stroma holds significant potential
in the search for novel cancer therapeutics.
-
nologic status of the host. The studies highlighted in this chapter indicate that the
lung tumor and its microenvironment interact, together informing the process of
carcinogenesis. Appropriately targeting the tumor microenvironment in a highly
selected patient population is a newly emerging strategy that holds unique potential
for advancing the current state of lung cancer prevention and treatment.
Macrophages and Mast Cells
Macrophages and mast cells are components of the innate immune cell infiltrate
present in nearly every malignancy. In basic, translational, and clinical research
investigations, these particular immune effector cells have been found to both
– 2)
for a correlation to favorable prognosis and support for a correlation to poor prog-
nosis –2 ) reflect differences in the number, grade, stage, and size of tumors included in each
study, all of which varied considerably across the studies. The lack of consensus
both within and between tumor types may also be related to the diverse approaches
-
leagues, tumor-associated macrophage density correlated with poor prognosis in
counted together ). Toomey and colleagues found no association between
those in the adjacent stroma were again counted together 2 ).
-
tive, and the number of cases evaluated was relatively small ). The original study
to demonstrate the importance of the microanatomical location of macrophages as
-
leagues specifically counted macrophages within gastric carcinoma tumor cell
were associated with increased survival ) rate was significantly increased in patients with a high number of macrophages in
the tumor islets when compared to those with a low number of macrophages in the
p tumor-infiltrating macrophages was an independent predictor of patient survival by
p -
histochemical staining data, these results led the investigators to conclude that
aggregation of macrophages within gastric tumors has a beneficial effect on host
-
).
Tumor Microenvironment
location of macrophages and mast cells associated with a tumor must be taken into
account when considering their correlation to prognosis. Because the microenvi-
ronment is a key determinant of immune cell phenotype and function, the authors
suspected that it might also influence the nature of the immunocyte–tumor interac-
macrophages and tryptase
macrophage density as
p
p p
p p
When the data were divided into two groups above and below the median cell count
value, additional associations with survival became clear. Tumor islet macrophage
p p -
group below the median. In contrast, with a stromal macrophage density above
the median, survival was reduced by half when compared with the group below the
-
ences in survival with respect to macrophage and mast cell counts were also evident
within each tumor stage. In fact, survival of patients with stage IIIa disease and
greater than the median tumor islet macrophage density was increased when com-
pared with survival of patients with stage I or stage II disease and less than the
median tumor islet macrophage density. Further, where surgical resection data
were available, patients with a high tumor islet macrophage density had a signifi-
p tumor islet macrophage count limits disease progression. These findings also
indicate that the location of immune cells within the tumor microenvironment is
critical in determining their relationship to prognosis. The importance is demon-
strated most clearly by the strong direct relationship between survival and tumor
islet macrophage density and the strong inverse relationship between survival and
stromal macrophage density.
-
tigated the prognostic value of tumor-associated macrophages with a focus on their
location within the tumor microenvironment )
p tumor islet macrophage density was an independent prognostic factor for survival
p -
cantly correlated with survival, nor was the stromal macrophage density when
p
More recently, Kawai and colleagues evaluated the number of macrophages and
mast cells in tumor islets and the adjacent stroma in pretreatment biopsy specimens
-
bination chemotherapy 27) than in the adjacent stroma had significantly better median survival than patients
p -
tion of tumor-infiltrating macrophages when compared with stromal macrophages
p Mast cell density in the tumor islets and in the adjacent stroma was also evaluated,
but neither correlated with the clinical outcome of this patient population.
Additionally, there was no correlation between chemotherapy response and mac-
rophage or mast cell density within the tumor islets or adjacent stroma. These find-
ings suggest that the number of macrophages in tumor islets and the adjacent
treated with chemotherapy, without being a predictor of chemotherapy response
beyond its response to chemotherapy. They further suggest that the transfer of mac-
rophages to tumor islets or elimination of macrophages from tumor-adjacent stroma
prognosis.
likely two types of macrophages within the tumor microenvironment, now referred
to as the “macrophage balance theory” 2) stromal macrophages contribute to tumor stroma formation and angiogenesis, thus
-
ing tumor growth. Macrophages in tumor-adjacent stroma secrete several growth
factors and proteases involved in angiogenesis. A recent study demonstrated that
interaction between lung cancer cells and these particular macrophages promotes
) mast cells produce histamine, basic fibroblast growth factor, heparin, chymase,
and tryptase, all of which have been shown to promote cancer progression
2)
tumor-killing mechanisms ). Tumor-infiltrating macrophages can also act as
take part in the activation of T cells and subsequent tumor cell destruction ).
Tumor Microenvironment
2).
Taken together, the highlighted clinical studies also suggest that tumor-associ-
ated macrophages and mast cells are multifaceted and functionally versatile, and
they emphasize the importance of microenvironmental stimuli in the regulation of
has emerged since investigators began incorporating an evaluation of the microana-
tomical location of immunocytes into their study design. Findings from these recent
clinical studies have implications for understanding the immunopathobiology of
for surgery since those with high tumor islet macrophage density often do better
when considering adjuvant therapy, it would be useful to target patients most likely to
minimally overall, so the majority of patients do not benefit from the potentially
treatment would be beneficial. These findings may also be useful in the design of
future clinical trials, as those who are already predicted to do well based on their
-
useful clinically, the microanatomical location of these cell types must be consid-
ered routinely, counting methods must be standardized, and a clinically practical
cutoff value other than the median number must be established. In addition to quan-
tifying macrophage and mast cell numbers, use of activation markers would likely
development and as predictors of prognosis.
Dendritic Cells and Ectopic Lymph Nodes
The potential for the immune system to induce tumor regression has stimulated
much research into development of vaccines that unmask tumor antigens and lead
to a specific host immune response against the tumor )
deficit of transporter-associated antigen processing, and lack of costimulatory
molecules have rendered most such immunotherapeutic efforts ineffective ).
In addition, tumor cell-derived inhibitory factors and immune suppressive cells,
-
– ).
immune responses )
chemokines into the tumor microenvironment that attract antigen-specific T cells
in vivo. These properties, combined with efficient capture of antigens by immature
specific naïve T cells )
eradication of tumor cells ) -
-
notherapy – ) combined with the identification of specific tumor antigens have allowed initiation
– ) been demonstrated to be a safe approach in clinical studies – 7).
ex vivo
– ) -
gens or immunomodulatory proteins – ) -
spontaneous and Fas-mediated cell death, suggesting their utility in delivering
immunotherapy more efficiently and robustly ) ). In addi-
tion, enhanced local and systemic antitumor effects have been demonstrated when
)
) ).
-
promoting cognate T cell activation ) murine cancer models were previously reported – ) antiangiogenic activities in mice, thus strengthening its immunotherapeutic
potential in cancer 2)
evaluated.
diseases and chronic inflammation, the concept of ectopic lymph nodes or tertiary
lymphoid structures has recently made a resurgence. As described in a review by
populations, and well differentiated stromal cells and high endothelial venules ).
livers of geriatric mice, subsequently characterizing them as ectopic lymphoid
structures ). As described by Timmer and colleagues, ectopic lymphoid struc-
tures are also present in the synovial tissues of rheumatoid arthritis patients,
Tumor Microenvironment
). While ectopic lymph nodes are often
identified in association with local pathology resulting from chronic infection or
disease states is still the subject of debate, however. Accumulating evidence that
adaptive immunity can be initiated independent of secondary lymphoid organs,
likely via induction of these tertiary lymphoid structures, suggests that ectopic
lymph nodes may contribute to local protective immune responses in certain
7).
of ectopic lymph nodes within the tumor microenvironment and support their role
-
ated immune response independent of secondary lymphoid tissue ). The authors
observed tertiary lymphoid tissues composed of compartmentalized T cell and B
cells zones and elevated numbers of tumor-specific T cells to which they ascribed
within the tumor mass, resulting in tumor-specific T cells and subsequent tumor
regression ). In clinical samples of infiltrating ductal carcinoma of the breast,
-
). Bell and
)
that ectopic lymph node status may be a favorable prognostic indicator in ovarian
carcinoma ) -
72). While not evaluating
n n )
-
tively identified ectopic lymph nodes or tertiary lymphoid structures and demon-
strated that there is a correlation between their cellular content and clinical outcome
7 ). The structures, called tumor-induced bronchus-associated lymphoid tissue
to those in secondary lymphoid follicles of the lymph nodes. The density of
also poorly infiltrated by immune-reactive T cell subpopulations, again suggesting
-
-
ably sized and often aggregated, their cellular composition was instead character-
and B cells were strongly correlated to each other within the tumor. Additionally,
B cell follicles charac-
proliferat-
and B cells organized in a fashion reminiscent of secondary lymphoid organs to
-
p
The ectopic lymphoid structures described in the preceding study were not
observed in sites distant from the tumor, suggesting that they were induced in
response to the tumor microenvironment. The B cell areas included proliferating
in ectopic lymphoid structures of idiopathic lung fibrosis, indicating that
-
-
-
mor immunity.
While the highlighted studies suggest that ectopic lymph nodes composed pri-
-
ining clinical outcome are available. Why these structures arise, how they are
generated, and how they impact the host are questions still being evaluated. The
answers to these questions may be very different depending upon the cellular
microenvironment in which the ectopic lymph nodes are being investigated. For
Tumor Microenvironment
). These mice have few T reg cells in their lymph nodes
suggest that poor T reg cell activity or low T reg cell numbers result in the forma-
appear to play multiple and contradictory roles in the formation and function of
ectopic lymph nodes.
As previously noted, tertiary lymphoid structures have now been identified in
nonmalignant, autoimmune, chronic inflammatory, and malignant microenviron-
-
tory and the formation of nonmalignant- versus malignant-associated lung-related
lymphoid structures is warranted ). Additionally, they suggest that routine
lung sections from nonmalignant areas of patients with cancer and from patients
with nonmalignant conditions should be assessed to gauge the true nature of the
ectopic lymph nodes. The functional activity of lymphocytes residing within
ectopic lymph nodes in human solid tumors, their tumor specificity, and their
ability to predict clinical outcome are also heralded as the most pressing ques-
tions yet to be addressed.
T Regulatory Cells
Active immune suppression induced by tumors has been well documented in lung
cancer tissues, but fail to respond to the tumor ). A high proportion of these
high
T reg cells
). Tumor cells may promote immune suppression by directing surrounding
inflammatory cells to release suppressive cytokines into the tumor microenviron-
differentiation of effector lymphocytes into T reg cells ) -
cancer cells escape immune surveillance and inhibit antitumor immunity. Thus,
identification of T regs in cancer patients was a finding of great clinical impor-
).
T reg cells capable of inhibiting autologous T cell prolif-
eration )
77)
study. A subsequent evaluation of T reg cells in the peripheral blood of patients
n n = 22) indicated that T reg cells are
n ).
-
pared with healthy volunteers had significantly higher percentages of T reg cells
p p
)
-
induced apoptosis of the T reg cell population. While T reg cell function was
T cell subsets after
T reg cells in peripheral
– ).
These findings are consistent with studies in murine models demonstrating that
T reg cells can significantly augment the efficacy of
cancer vaccination ). Together, these data suggest that T reg cells are selec-
Though not in lung cancer, one of the first studies to link T reg cell recruitment
).
Where data were available, tumor T reg cell content was associated with reduced
n p p p p -
ards model, tumor T reg cells were a significant predictor of death hazard after
controlling for stage, surgical debulking, and other factors affecting survival
p -
nificant predictor of increased risk for death and reduced survival in ovarian cancer.
T cells,
which preferentially home to lymph nodes, T reg cells from patients with late stage
ovarian cancer preferentially homed to tumors and ascites and only rarely to drain-
ing lymph nodes. Additionally, tumor cells and tumor-adjacent macrophages were
tumor trafficking. While these data provide the basis for developing novel immune-
boosting strategies based on eradication of the T reg cell population in cancer
Tumor Microenvironment
patients, they also suggest that novel pathways regulating T reg cell biology and
trafficking are still being discovered and elucidated.
-
-
T reg cells and induces a regulatory
− T cells 7)
were separated by a transwell ) − T cells and significantly up-regulated its
−
T reg cells in murine lung cancer models was determined.
-
). Utilization of lymphocytes
-
These and other basic and translational research investigations have informed our
T reg cells in the lung cancer microenvi-
ronment, collectively suggesting that the development of clinical strategies to reduce
T reg cells include
clinical trials that utilize total lymphodepletion – )
T
reg cell population )
-
-
– ). These
pathways and malignant phenotypes may be inhibited by several different agents in
). Therefore, trials are
) will help further define the required interventions in this pathway and lead to more
specifically targeted agents to diminish T reg cell activities in cancer. These agents
could then be combined with other immune-based clinical therapies in an informed
manner.
Matrix Metalloproteinases
-
like growth factors and their receptors, cell adhesion molecules, cytokines, chemok-
– ).
those tumor cells to metastasize in animal models. Knock-out mice deficient in
-
associated with less aggressive tumor behavior and favorable prognosis. In addition
-
genesis by promoting angiogenesis, stimulating tumor growth, regulating innate
role in promoting cancer progression ).
a statistically significant survival advantage in most of the advanced stage malignan-
– ). Briefly, mouse models
with early stage disease, yet most clinical trials were initiated in patients with late
trials. Further, investigators started patients on a fraction of the dose proven effective
in mice, and that dose was reduced, or patients were given drug holidays, when
-
be eliminated to achieve an antitumor response.
Tumor Microenvironment
inhibitors with cancer prognosis. There has been a similar slow return to optimism
-
cessfully targeted therapeutically. Before that time, however, investigators must
-
type of each malignancy during each stage of that particular malignancy, and clini-
cal trials must be tailored to fit the knowledge gathered from these inquiries.
action in vivo is also essential if the most appropriate and most effective antitumor
-
-
diverse and sometimes opposite effects depending upon their source, their tissue
-
membrane protein present on the surface of numerous tumor cells. By stimulating
-
). Immunohistochemical staining of
p
stroma was more often associated with large cell carcinomas when compared with
p -
p p -
independent prognostic indicator of poor overall survival and disease-free survival
p -
determining which patients have the most aggressive disease.
overall survival ) -
-
p -
an independent predictor of patient survival for the adenocarcinoma group
p
)
were not evaluated as in the previous studies.
)
activity in nontumor tissue was significantly different in patients later found with
recurrence when compared to those without recurrence, and it was associated with
-
tumor tissue can be used as a prognostic biomarker that predicts postoperative
suggest that it could be used to assist in deciding which patients are most in need
of postoperative adjunct chemotherapy.
-
variate analysis ) -
tence of bone marrow microinvolvement did not influence prognosis, patients
n p
to worse survival.
)
Tumor Microenvironment
p p
including prognosis )
p p -
p -
p
-
)
)
tumor specimens was significantly lower than in the control tissues. Additionally,
-
p
-
-
)
). This makes
tumor microenvironment.
weight inhibitors will likely continue to be the cheapest and the easiest to engineer,
produce, and deliver. As reviewed by Konstantinopoulos et al. ), broad spectrum
-
tings, such as stokes, before being used clinically in the setting of chronic condi-
), validating
-
gets requires the use of surrogate markers that can guide dose-escalation. Identifying
molecular markers that will predict response would also be useful. The reviewers
chemotherapeutic or molecularly-targeted agents must be evaluated preclinically.
If these suggestions are implemented, future clinical trials in carefully selected
patient populations with very specific malignancies at predetermined stages are
Cyclooxygenase-2 and Prostaglandin E2
2, a substrate for specific prostaglan-
-
-
tochemistry )
cytoplasmic staining in alveolar macrophages and occasionally in the bronchiolar
-
reviewed ) multifaceted role in conferring the malignant and metastatic phenotype of lung
cancer. Although multiple genetic alterations are necessary for lung carcinogene-
– ),
enhanced angiogenesis ), decreased host immunity ), and
enhanced invasion and metastasis 22). These newly discovered molecular
mechanisms in the pathogenesis of lung cancer provide novel opportunities for
cancer chemoprevention and therapy ).
microenvironment that is both an autocrine and paracrine mediator of immune
Tumor Microenvironment
regulation ), epithelial cell growth and invasion ), and epithelial survival
)
the most recent approaches to lung cancer chemoprevention and therapy have
leads to increased cancer cell growth and motility. Krysan and colleagues were
). These findings provide the rationale
-
predict shorter survival among patients with early stage disease ). The strength
p p
adenocarcinomas ). These reports, together with other studies documenting an
), a common polymor-
), and
epidemiological studies that indicate a decreased incidence of lung cancer in
patients who regularly take aspirin ) the pathogenesis of lung cancer.
-
-
preventative agent for lung cancer by administering heavy current smokers with a
-
choalveolar lavage and biopsy ) p
p that of cytoplasmic survivin. These findings support the hypothesis that oral
randomized placebo-controlled clinical trials are underway to determine the effi-
-
noma ).
)
similar to that observed with gefitinib alone. Agarwala and colleagues conducted a
similar study in an unselected population of chemotherapy naïve patients with
)
-
)
agent gefitinib. Finally, Fidler and colleagues recently evaluated the safety and
)
have a critical effect on efficacy.
)
Based on these results, a phase II trial is currently in progress to assess combination
-
). The
-
) -
)
Tumor Microenvironment
were associated with higher risk than lower doses ). These studies suggest that
-
mine safety profile. It is unclear if cardiac ischemia will occur at a higher rate with
-
pies or conventional chemotherapy.
impact of use of aspirin on the relative risk of colorectal cancer in relation to the
). The authors found that regular use of aspirin
II trial to assess whether there was benefit with dual eicosanoid inhibition or with
). These studies illustrate the
importance of a more individualized approach to therapy that ideally minimizes the
risk-benefit ratio and improves efficacy in future clinical trials.
Peroxisome Proliferator-Activated Receptor-Gamma
and 15-Prostaglandin Dehydrogenase
-
-
lism and clearance represents an alternative therapeutic approach to interfering with
-
microenvironment has the potential to inhibit tumor growth by lowering the con-
)
sensitizing drugs that includes troglitazone, ciglitazone, rosiglitazone, and pioglita-
), a ligand-activated nuclear receptor. While the role of
in regulation of metabolism and inflammation is well established, in recent
– )
-dependent and -independent
may be helpful in designing anticancer therapies.
agonist rosiglitazone on
) -
increased in gefitinib- and rosiglitazone-treated cells. These data indicate that the
ligands may serve as therapeu-
ligand, trogli-
).
These in vitro studies demonstrated a synergistic interaction between troglitazone
-
ligands and chemotherapeutic agents in the treatment
). Mice
monotherapy or a combination of both drugs. Tumor burden and pathology, along
with cell proliferation and apoptosis, were evaluated. Tumor burden was unchanged
or increased in mice after monotherapy. In contrast, significant tumor inhibition
occurred in response to combination therapy. Immunohistochemical analysis revealed
that therapy was mediated by increased apoptosis and decreased tumor cell prolif-
eration. Importantly, the synergy between carboplatin and rosiglitazone did not
ligand and carboplatin combination is worthy
of further investigation clinically, particularly in those cancers that show primary
resistance to platinum therapy or acquired resistance to targeted therapy.
in primary human lung cancer specimens ). While
splice variant
-
-
splice
Tumor Microenvironment
variant may be one mechanism by which tumor cells become resistant to drug- and
chemical-induced cell death, suggesting that the splice variant may be linked to
tumor progression and poor clinical outcome.
-
increased risk of cardiovascular events associated with chronic rosiglitazone or
-
-
date drug molecules may be therapeutically effective, without leading to adverse
chemoprevention of lung cancer will require careful patient risk assessment and
selection that ideally minimizes the risk-benefit ratio and improves efficacy in
future clinical trials.
g prognosis in lung cancer patients ), and recent work has revealed multiple
g -
). The
g
effects of harmful prostaglandins without impacting production of critical cardio-
protective eicosanoids. More research is required to define these and other oppor-
downstream effects.
Inflammation and Epithelial–Mesenchymal Transition
Within the tumor microenvironment, inflammatory cells and their secretomes influ-
ence nearly every aspect of cancer progression ). The role of chronic inflam-
mation in carcinogenesis is well documented – ), such that Montavani recently
suggested that inflammation represents the seventh hallmark of cancer ).
The tobacco-induced pulmonary microenvironment, in particular, represents a
unique milieu in which carcinogenesis proceeds in complicity with surrounding
and deregulated inflammation – ). Among the cytokines, growth factors,
and mediators released in these lung diseases and the developing tumor microenvi-
) have deleterious properties that simultaneously inhibit cell-mediated
72– ).
Advances in risk assessment play a crucial role in the development of preventive
– ), and recent studies emphasize the integral role of inflammation as a
).This raises the intriguing possibility that agents used to limit
). By study-
assessments of emphysema and spirometric evaluation of airflow obstruction have
been correlated to lung cancer risk in this population, providing potential clinical
and imaging parameters for lung cancer risk assessment ) direct the appropriate attention and potential chemopreventive measures to the
people who need it most.
-
)
cancer initiation given the carcinogen-rich inflammatory milieu characteristic of
model of K-ras-induced malignancy ). Adair–Kirk et al. suggest other mech-
anisms, including activation of a proinflammatory cytokine cascade initiated
by the “inflammasome” ) )
the inflammatory response to cigarette smoke by lung epithelial cells. The dis-
). In a retrospective analysis
during treatment with inhaled corticosteroids and increased during treatment
epithelial cell stress. Additionally, Bulk and colleagues recently discovered that
n -
related proteins also represent potential biomarkers and novel therapeutic targets
Tumor Microenvironment
development of lung cancer and resistance to therapy 72, )
72, )
bronchial epithelial cell lines ). Factors that play a pathologic role across
the spectrum of carcinogenesis – from premalignancy to advanced disease – hold
after resection of early disease develop recurrence. In this population, targeting these
factors could potentially treat patients for any remnant of the cancer they already
have while simultaneously preventing the cancer they are at risk of developing.
).
)
-
-
– )
) ).
gain of epithelial stem cell properties ). Thus, in the pathogenesis of lung cancer,
carcinogenesis, therefore implicating the inflammatory pulmonary environment in both
)
NF-kB
B) pathway
is considered the central mediator of immune responses ). The pathway is
induced by many different stimuli in the developing tumor microenvironment, and
there are hundreds of downstream effector molecules ) B proteins
B is inhibited by
I B. When specific serine residues on I B are phosphorylated, I B is targeted for
degradation by the proteasome ). The I -
bers ). In response to stimulation, one action of this family is to phosphorylate
I B, leading to its degradation. A variety of agents targeting IKK family members
are currently being evaluated in early phase clinical studies. The proteasome is a
multisubunit protein, the role of which is destruction of proteins ). The protea-
some degrades many different ubiquinated proteins. The antineoplastic activity of
proteasome inhibition is hypothesized to be impaired destruction of I B, as ele-
vated levels of I B.
B is
considered one of the mechanisms of action. Bortezomib is the only agent under
B is considered its
inhibitor. It is a modified dipeptidyl boronic acid that reversibly inhibits the
)
).
single agent dose of bortezomib was established, the agent was evaluated in com-
bortezomib in combination with gemcitabine and carboplatin ) and in combi-
nation with gemcitabine and cisplatin ) 2 2 2
2 2
myelosuppression, the frequency of bortezomib was less in the cisplatin containing
study. A phase II study evaluated bortezomib in combination with gemcitabine and
tolerated, but the overall survival and progression-free survival were similar to
historical data ).
2 ),
), and erlotinib ). All three have been evaluated in combination
Tumor Microenvironment
2 )
achieved a partial response, and seven achieved stable disease. The recommended
2 2
2 2 2
in a phase I trial )
2 2 2
study ). Although the combined therapy was well tolerated, the study was
demonstrated insufficient clinical activity in the combination arm.
has been evaluated as a single agent for the treatment of small cell lung cancer
) 2
were felt to be insufficient to proceed with the development of bortezomib for this
clinical situation.
Although a great deal of clinical data has been generated evaluating bortezomib
in lung cancer, at this time, there are no data that indicate a role of the agent in the
-
ting, but these responses have been rare. There is also no convincing data that the
addition of bortezomib to standard regimens improves the outcome. It is still pos-
sible that such differences could be detected in larger studies, or by identifying a
subgroup of patients with an increased likelihood of response to bortezomib. It is
also possible that other proteasome inhibitors in development will demonstrate
greater efficacy.
HGF and c-Met
c-Met is a receptor tyrosine kinase that is currently receiving considerable attention
)
signaling, including increased motility, invasion, proliferation, and angiogenesis ).
cancer ) ).
mutation of c-Met have all been observed ). In the setting of lung cancer, c-Met
amplification has recently received increased attention for its role in resistance to
). Although most of the work to establish such a
role for c-Met has been in vitro, there is newly available clinical data in which biop-
while biopsies at the time of resistance did show evidence of amplification. Although
data have spurred clinical studies to evaluate the role of c-Met inhibition along with
have not yet been completed. Based on the preclinical data described above, several
are used. Many agents are being evaluated in phase I testing as well.
the subject of clinical investigation 222). In addition to single agent studies, this
agent has been studied with other antiangiogenic agents, including bevacizumab, and
the investigational small molecule tyrosine kinase inhibitor, motesanib diphosphate
). These combinations were well tolerated and will be investigated further in
-
therapy or targeted agents in studies of nonthoracic malignancies. In one study cur-
Tyrosine kinase inhibition is another attractive approach to inhibiting c-Met
), and phase I
) -
). It is currently being
evaluated in phase II studies in several nonthoracic malignancies.
and small cell lung cancer. Agents targeting this pathway are currently under evalu-
ation, but it is still too early to know whether this will be a successful strategy in
clinical situations.
Angiogenesis
The induction of tumor vasculature, termed the angiogenic switch, is a required
on their microenvironment. Interaction between tumor and stroma leads to the
Tumor Microenvironment
elevation of proangiogenic factors and the inhibition of antiangiogenic factors,
-
nential growth and metastases 227). Tumor angiogenesis has been shown to play
an important role in the progression of a number of solid tumors, including lung
cancer, and potential therapies targeted to antiangiogenic pathways have been a
)
such therapies. In particular, they suggest a need for further preclinical studies that
of other therapies.
-
antiangiogenic therapies, studies have begun to focus on their combination with
other agents. It is believed that the early antiangiogenic effect is, in fact, a morpho-
logic normalization of poorly organized and inefficient tumor vasculature. The
-
stitial fluid pressure before continued suppression ultimately leads to decreased
perfusion ) agents, and a strong argument for the use of antiangiogenics in combination with
standard chemotherapy.
Although multiple clinical trials at all phases are currently evaluating targeted
focused on the addition of bevacizumab to standard chemotherapy. Bevacizumab is
-
)
doublet chemotherapy with or without bevacizumab ). Because of a prior phase
II trial that suggested patients with squamous cell lung cancer had an increased
patients with brain metastases, a history of gross hemoptysis, or those requiring
therapeutic anticoagulation. The results of the trial revealed superior response rate
and progression-free survival in the bevacizumab group. Importantly, the investiga-
tors found that the addition of bevacizumab conferred an advantage in overall sur-
no significant benefit was achieved in overall survival for women ) or the elderly
) included in the study. A second large multicenter phase III
there was no overall survival advantage associated with the addition of bevaci-
zumab in this study ).
The details of these clinical trials contribute important insights for the development
drug delivery, but also result from the manipulation of angiogenic effects specifi-
cally initiated by only certain chemotherapies ). The authors demonstrate how
progenitors, which home to viable tumor tissue and contribute to tumor recovery
after the administration of chemotherapy. They also provide evidence that this effect
the overall antitumor effect of chemotherapy. The fact that an improvement in overall
more focused preclinical data to elucidate the mechanisms of action for disease prog-
ression, interaction between drug therapies, and physiological treatment responses,
possibly addressing the questions raised by the results of these clinical trials.
effect in response to treatment as well as the fact that the same pathologic out-
comes can be reached by different avenues further supports the argument for using
and angiostatic peptides. Angiogenic peptides possess a glutamic acid–leucine–
contribute to inflammation, neovascularization, and neoplasia. Importantly,
).
inhibit premalignant alveolar lesions, in addition to inducing apoptosis of vascular
endothelial cells in these same lesions ). These effects are dependent on inter-
-
eradicating tumor-associated angiogenesis. The study further suggested that this
B activation with the
). In another study,
, which is produced by macrophages and
monocytes in the tumor microenvironment, can induce a variety of angiogenic
was reversible with blockade
the critical concept that studies for targeted therapies must evaluate their role in
Tumor Microenvironment
antiangiogenic factors or alternative angiogenic pathways may provide a more
dramatic clinical benefit.
Ultimately, the optimization of antiangiogenic therapies will require the
the benefit for those receiving bevacizumab appeared to be greatest in those
). In addition to specifying the populations that benefit with currently tested
therapy, efforts have already branched out to identify multimodality strategies to
) -
zumab with first- or second-line therapy in patients whose brain metastases from
investigating whether bevacizumab can be used safely in patients with squamous
cell histology if they have been pretreated with either chemotherapy or thoracic
radiation therapy.
The results of the advanced trials involving the combination of bevacizumab and
chemotherapy have already had an important clinical impact on how patients with
lung cancer are treated today. They also inspire further investigations regarding
-
ment. They have also contributed to defining appropriate patient selection, which
will continue to be a crucial subject of study. In addition to the ground-breaking
-
antiangiogenic therapy in earlier stages of lung cancer, and defining alternative
angiogenic pathways. In summary, the development of antiangiogenic therapies in
interaction between cancer and its microenvironment.
Conclusion
While genetic changes are essential for the malignant transformation of epithelial
cells, the tumor microenvironment plays an equally significant role in cancer pro-
gression and metastasis. Molecular signatures that are most often composed of
cytokines involved in inflammatory and immune responses correlate with important
clinical parameters. There is mounting evidence that these signatures serve as
robust biomarkers predictive of cancer progression, prognosis, and therapeutic
resistance. Molecular profiling studies that have assessed the tumor-adjacent
stroma and in vitro models of the tumor microenvironment have been particularly
suggestive that the secretome of the tumor microenvironment drives the aggressiveness
of tumors.
In the clinical studies highlighted in this chapter, macrophage, mast cell, and
-
eters, while ablation of immune-suppressive T reg cells is associated with a favor-
antitumor immune response and improved clinical outcome is the focus of numer-
inhibitors and better informed patient selection will yield more favorable out-
comes in the future.
Inflammation and angiogenesis are cancer-associated phenotypes clearly
aspects of the tumor microenvironment will also likely require patient selection and
-
able preclinical data. Taken together, further elucidation of the microenvironmental
and molecular mechanisms involved in lung carcinogenesis is required. Targeting
the reversible events in the microenvironment that contribute to tumor progression
continues to hold great clinical promise.
References
-
prognosis in hepatocellular carcinoma based on a unique immune response signature of the
-
Tumor Microenvironment
-
infiltrating macrophages: its correlation with tumor angiogenesis and patient survival in non-
cancer cell thymidine phosphorylase reactivity in non-small-cell lung cancer: impact on
-
and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-
enhance apoptosis in activated T lymphocytes through an I kappa B kinase-dependent mecha-
2-dependent regulation of cytokine balance in lymphocytes and macrophages: up-regulation
-
-
-
chemo-immunotherapy using autologous dendritic cells and activated killer cells from tissue cul-
-
-
leukin 7 gene-modified dendritic cells augments specific antitumor immunity and achieves
Tumor Microenvironment
therapeutic antitumor immunity by dendritic cells genetically modified with an adenoviral
tissue chemokine in human dendritic cells augments chemotactic activities for lymphocytes
modified dendritic cells reduces tumor burden in spontaneous murine bronchoalveolar cell
rheumatoid arthritis synovial tissues dissected by genomics technology: identification of the inter-
cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas.
tumor-infiltrating dendritic cells in human non-small cell lung carcinoma in relation to apop-
-
small cell lung cancer patients is significantly higher in tumor tissues than in normal tissues,
of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with
peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarci-
cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells
antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy.
Tumor Microenvironment
-
-
-
-
-
-
-
-
-
-
-
Tumor Microenvironment
and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the
-
-
-
-
-
-
-
-
immunosuppression in association with chronic immune activation. Int Immunol
pulmonary disease. A prospective, matched, controlled study. Ann Intern Med
-
costeroids and risk of lung cancer among patients with chronic obstructive pulmonary dis-
Tumor Microenvironment
-
meterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease.
-
mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor
determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer
-
-
and twice-weekly bortezomib in combination with gemcitabine and cisplatin in the first-line
vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously
versus best supportive care in patients with non-small-cell lung cancer previously treated
-
combination with bortezomib in previously treated advanced non-small cell lung cancer
-
-
Tumor Microenvironment
non small-cell lung cancer patients treated with bevacizumab in combination with carbopla-
-
lial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing
-
-
