Project: Research project

Project Details


TGF-beta may potentially be successful in the treatment of colon cancer
since it inhibits the proliferation of responsive human colon carcinoma
cells and elicits differentiation-like effects. However, approximately 50%
of colon carcinoma cells tested were unresponsive to TGF-beta. The overall
goal of this proposal is to expand a previously-established model system
for TGF-beta resistance in human colon carcinoma cells, and to utilize this
model system to identify possible mechanisms underlying TGF-beta
resistance. The result obtained from this proposal will identify targets
for the development of drugs which will either mimic the inhibitory effects
of TGF-beta on epithelial colon tumors or which will eliminate the
development of resistance to growth regulation by TGF-beta. Areas of
investigation aimed at elucidating mechanisms of action of and/or of
resistance to TGF-beta include: (1) Characterization of receptor binding
and receptor subtypes in the resistant and sensitive clones, (2)
Investigation of the involvement or alteration of G proteins and of ras
oncoproteins in transduction of cellular signals generated by TGF-beta (G
proteins appear to be involved in TGF-beta-induced mitogenesis in
fibroblast cells), and (3) Investigation of alterations in the regulation
of expression of the nuclear proto-oncogenes c-myc, c-fos, and c-jun (and
their protein products) to identify any alterations in these molecular
links between signal transduction and transcriptional regulation. Previous
work indicated that 3/4 of initially-identified TGF-Beta-resistant clones
over-expressed c-myc, an event which has been shown to alter TGF-Beta
responsiveness in other cells.

Additional experiments will be focused on the cellular environment as a
mediator of altered TGF-beta responsiveness. Overproduction of, or
responsiveness to, growth stimulatory autocrine factors in the resistant
clones may outweigh any potential inhibitory effects of TGF-beta.
Therefore, involvement of EGF, TGF-alpha and the EGF receptor in TGF-beta
resistance will be addressed.
Effective start/end date1/1/9011/30/95


  • National Cancer Institute


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