| Within lung
adenocarcinoma, histology is heterogeneous and
associated with tissue invasion and clinical outcomes.
The spectrum of intra-tumoral histological heterogeneity
in adenocarcinoma suggests invasiveness represents
a continuum of disease from noninvasive bronchioloalveolar
carcinoma (BAC) to adenocarcinoma mixed subtype
with BAC component to pure invasive adenocarcinoma.
The molecular events essential to this transition
in the lung are presently unknown. In this study,
we focus on invasion, a significant biological
and morphological characteristic of cancer with
direct clinical implications in terms of metastasis
and outcome. In preliminary gene expression profiling
experiments, we identified the type II TGF-ß
receptor (TGFßRII), which was expressed
at significantly lower levels in invasive tumors,
as one of the most interesting genes in the acquisition
of lung invasiveness classifiers. We hypothesize
that repression of TßRII in lung adenocarcinoma
is required to mediate tumor/stromal interactions
required for the acquisition of invasiveness and
metastasis in lung adenocarcinoma. In this grant
proposal, we will address the main hypothesis
in the following specific aims: 1. We will determine
the clinical significance of TßRII immunostaining
human lung adenocarcinoma by examination of a
large, clinically annotated tumor microarray;
2. We will determine the requirement for CCL5
(Rantes) in mediating invasiveness in TGFßRII
knock-down cells. CCL5 was identified as a potential
downstream mediator of TGF-ß signaling in
invasive tumors. In these studies, we will demonstrate
the importance of TGFßRII pathways in modulating
tumor epithelial/stromal interactions important
for the acquisition of invasiveness in lung adenocarcinoma
and we expect to identify the mechanisms of this
activity. The results of these studies will facilitate
the attainment of the 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.
|
