GROWTH REGULATION OF HUMAN COLONIC NEOPLASMS

A multidisciplinary group will characterize growth regulation in
human colon neoplasms to identify growth regulatory targets for
development of anticolon cancer therapeutic agents. The in
vitro model system will consist of the types of cells found in
normal colon; hyperplastic polyps, adenomatous polyps and
carcinomas. Comparative analysis of the biological
characteristics of each type of cell will be made and include
tumorigenicity, ability to grow with anchorage independence,
metastatic capability and analysis of differentiation markers. A
profile of expression of growth regulatory mechanisms will be
established for each growth phenotype. This profile will provide
for the characterization of the dependence of the growth of
cellular phenotypes on specific autocrine growth factors,
exogenous growth factors and oncogenes. Cellular phenotype
specific interrelationships among these three types of molecules
will also be characterized. These characterizations will identify
autocrine factors which if uncoupled (either by antibodies or
analogues) could lead to a significant change in the dependent
cell's biological characteristics toward a more benign phenotype
or perhaps cell death. Uncoupling of synergistic inter-
relationships among these types of molecules could also produce
the same result. It will be determined whether modulation of the
growth regulatory phenotype associated with a cellular phenotype
will also result in the modulation of the biological properties
associated with the phenotype. This will be accomplished by
developing appropriate transfection vectors for the
overexpression of growth regulatory associated autocrine factors
and oncogenes in benign cells. Successfully transfected cells will
be tested for alterations in biological and growth regulatory
phenotypes. Some oncogenes have been associated with the
expression of differentiated functions in colon and other systems.
These will also be tested in transfection systems to determine
whether their overexpression will modulate malignant phenotypes
to more benign states. It will also be determined whether a series
of putative differentiation or inhibitory agents can affect the
biological and growth regulatory phenotypes in a similar manner.
Of particular interest will be the effects of differentiation
promoting transfections and the inhibitory agents on the
expression of growth regulatory molecules and their relationships
since the development of agents to mimic these effects could
allow for effective therapeutic intervention.