Orthotopic implantation of human colon
carcinoma cells is useful for studying the behavior of metastatic subpopulations. We observed that the parental line and variants of human colon
carcinoma KM12 cells were all tumorigenic following implantation into the subcutis or cecal wall of BALB/c nude mice. Their ability to metastasize to distant organ sites varied, however, with the site of growth. Subcutaneous (SC)
tumors did not produce visceral
metastases, whereas cecal
tumors metastasized to the regional mesenteric lymph nodes and to the liver. To examine the influence of organ environment on the extracellular matrix-degrading activity of the
tumors, we inoculated human colon
carcinoma cells into the subcutis or cecal wall and after 7 weeks isolated and cultured the
tumors in serum-free medium. The
conditioned media of SC
tumors contained very low levels of type IV
collagenase (
gelatinase) and
heparanase (
heparan sulfate-specific
endo-beta-D-glucuronidase), whereas the media of the cecal wall
tumors contained high levels of both. Zymograms of the media revealed that the intracecal human colon
carcinomas secreted more than three times the amount of latent and active forms of 92-kd type IV
collagenase than did the SC
tumors. Moreover, only the
conditioned media of intracecal
tumors contained latent and active forms of 64-kd type IV
collagenase. Histochemical analysis using rabbit antiserum raised against the synthetic
peptides of 72-kd
procollagenase type IV showed type IV
collagenase in the intracecal
tumors; human colon
carcinoma growing SC, however, were not stained significantly. These results suggest that factors in the organ environment may affect production and secretion of
tumor extracellular matrix-degrading
enzymes, and these factors may modify the metastatic behavior of human colon
carcinoma cells in nude mice.