Mechanisms of TGFbeta Production in Human Cancer Cells

Project: Research project

Project Details


DESCRIPTION: (Application Abstract) Although TGFb is an endogenous growth
inhibitor for epithelial cells, this growth inhibitory response is often lost
in solid tumors. Cancer cells displaying altered expression of TGFb receptors
are among those that no longer display growth inhibitory sensitivity. However,
the TGFb-resistant cells are still able to produce large quantities of the
polypeptide. Since the paracrine effects of TGFb are largely tumor-enhancing,
once the tumor epithelial cells have become refractory to TGFb-mediated growth
inhibition, it would seem advantageous to shut off tumor cell TGFb production.
This approach should reduce the paracrine, tumor-promoting effects of TGFb and
could provide a novel alternative to strategies designed to restore TGFb growth
inhibitory sensitivity to the resistant tumor cells. Our preliminary studies
have revealed many of the signaling components which mediate TGFb1 production.
The results of the proposed studies will define more subtle mechanisms which
contribute to production of TGFb1, and will elucidate the production cascades
for the TGFb2 and TGFb3 isoforms. We hypothesize that specific proteins in the
TGFb production cascades are over-expressed or over-activated in late-stage
tumors that have lost autocrine negative TGFb regulation due to TGFb receptor
defects. We will examine the relevant signaling components in human colon
carcinoma cells (HCCCs) in vitro and in colon, breast, and prostate cancer
samples from patients. The latter molecular profiling studies will be performed
with pure populations of cells procured by laser capture microdissection. We
will also stably express antisense or wild-type versions of the relevant
signaling components in HCCC model systems to determine the effect on the
tumorigenic potential of the cancer cells in vitro and in vivo. Thus, the major
objectives of this proposal are to delineate the components of the TGFb
production cascades which are altered in human cancer cells in vitro and in
vivo, and to determine whether blockade of these specific components will
reduce tumor cell TGFb production, its paracrine effects on stromal cells, and
its tumorigenic potential in vivo. Accordingly, the studies proposed in this
application will demonstrate the potential utility of TGFb-based therapeutics
against epithelial cancers which have progressed to the point of TGFB growth
inhibitory insensitivity.
Effective start/end date4/1/015/31/14