In greater than 80% of colon
tumors and established cell lines, the specific activities of the
protein tyrosine kinases pp60(c-src) and pp62(c-yes) are increased with respect to normal colonic epithelial cells. However, no mutations in either gene have been identified in colon
tumors. Therefore, the possible
biological consequences of activations of these
protein tyrosine kinases in colon
tumors have been unclear. To determine if
pp60(c-src) activation affects growth and tumorigenicity of established colon tumor cell lines, an antisense expression vector that specifically reduces
pp60(c-src) expression was constructed. The vector was transfected into HT 29 cells, an established colon tumor cell line in which both
pp60(c-src) and pp62(c-yes) are activated. Two stable subclones were isolated in which
pp60(c-src) but not pp62(c-yes) expression and activity were reduced. These established cell lines proliferated more slowly than parental cells proportionately to reduction in
pp60(c-src) expression. When injected into nude mice, antisense transfected cells formed slow-growing
tumors; however, the rate of
tumor growth was reduced far greater than would be predicted from decreased proliferation rates in tissue culture. In contrast, stable subclones transfected with a comparable "sense" expression vector were unaltered in growth rates in tissue culture and in nude mice with respect to parental HT 29 cells. These data demonstrate that the activation of
pp60(c-src) alone contributes to the tumorigenicity of HT 29 cells, a cell line widely used as a model for
biological properties of colon
carcinoma. Furthermore, because
pp60(c-src) and pp62(c-yes) appear redundant to the growth regulation of normal colonic epithelial cells, the data suggest that src-specific inhibitors might be of therapeutic value for
colon cancer.