| Adenocarcinoma
is the most common lung cancer histology and its
incidence is increasing. Approximately 68,000
incident cases are expected in 2005 with an estimated
five year survival rate of 30–40%. Within
lung adenocarcinoma, histology is varied and associated
with tissue invasion. The spectrum of intra-tumoral
histological variation in adenocarcinoma suggests
invasiveness represents a continuum of disease
from noninvasive bronchioloalveolar carcinoma
(BAC) to invasive adenocarcinomas. Invasion is
the first step of tumor metastasis and is directly
associated with clinical outcome.
In preliminary studies, we used DNA microarrays
to identify some of the molecular events essential
for this invasiveness transition in the lung.
One of the most interesting genes identified in
the acquisition of invasiveness classifiers was
the type II Transforming Growth Factor-ß
receptor (TGFßRII), which was expressed
at significantly lower levels in invasive tumors.
This finding was confirmed using several methods
and suggests the hypothesis that loss of this
gene is required for the acquisition of invasiveness
in lung adenocarcinoma.
The clinical implications of these observations
are highly significant. The prevalence of non-invasive
lung adenocarcinoma is increasing, presumably
as a result of increased detection by screening.
Clinical studies indicate that the prognosis of
non-invasive bronchioloalveolar carcinomas is
favorable and suggest that treatment approaches
in terms of surgical procedure and adjuvant chemotherapy
may be tailored to the biologic properties of
these tumors. Currently there are no validated
biomarkers that predict recurrence or survival.
The ascertainment and application of biologically
and clinically important molecular information,
such as the invasiveness signature, into clinical
decision analysis may further enhance the effective
allocation of treatment for patients with lung
carcinoma.
In the first aim of the study, we will directly
examine the clinical significance of our previous
observations. Specifically, we will evaluate the
correlation of tumor protein expression of TßRII
and related proteins with distinct clinical endpoints:
lymph node metastasis and survival. For this study,
we will take advantage of a lung tumor tissue
microarray we have developed that contains discrete
sections from tumors of 184 patients for which
clinical information has been acquired. Results
from our tissue microarray will be confirmed using
an independent set of tumors present on a microarray
developed by our collaborators.
The mechanisms responsible for the activity of
TGFßRII in lung adenocarcinoma invasion
are unclear. In recent preliminary studies using
microarrays, we have identified potential mediators
of this effect, which include a chemokine protein
for which inhibitors are available. We have confirmed
this finding and hypothesize that inhibition of
this chemokine will prevent invasion that ensues
after loss of TGFßRII. In this proposal
we will use cell lines and animal models to test
commercially available chemokine inhibitors to
determine if invasion is decreased. Positive results
of these studies will be translated to the “bedside”.
The proposed studies will facilitate the attainment
of our long-term goals, which are to develop clinically
available assays to predict invasive propensity
in adenocarcinoma tissue specimens and to develop
and test pharmacologic agents that will reduce
invasiveness in patients with lung cancer or prevent
the development of invasive tumors in individuals
at high risk for lung cancer.
|
