Metastatic Model of Human Colon Cancer Constructed using Orthotopic Implantation in Nude Mice.

Abstract

Nude mice have been used to grow subcutis (s.c.) growing human colorectal tumors, but these tumors rarely metastasize. This is a problem for studies into the biological behavior of metastatic subpopulations of human colorectal cancers. We have followed the evolution of the parental line and of a variant of human colon carcinoma KM12 cells, that were both tumorigenic, following implantation into the s.c. or cecal' wall of nude mice. The tumors growing s.c. did not produce visceral metastases, whereas the cecal tumors metastasized to the regional mesenteric lymph nodes and to the liver. However, the incidence of liver metastases was different between the parental cell line KM12C cells and the in vivo selected cell line KM12SM cells after orthotopic inoculation. The morphological findings of KM12 cells proliferating in a monolayered sheet revealed that these two cell lines consisted of various cell populations. These results suggest that in the orthotopic colon cancer models, liver metastasis is defined by difference in subpopulations of metastatic phenotypes to the liver with early dominance of its growth in the implanted organ. As a result, our new model using orthotopic implantation of KM12SM cells, which produce a 50% incidence of liver metastasis, can help to provide a technique to study the biological behavior of metastatic subpopulations of human colon cancers.Key words metastatic animal model, human colon carcinoma, orthotopic implantation, liver metastasis, lung metastasis, mesenteric lymph node metastasis Received for publication December 15,1997C orresponding address and reprint requests to: Yutaka Ogata,

Tumor Progression of Skin Carcinoma Cells in Vivo Promoted by Clonal Selection, Mutagenesis, and Autocrine Growth Regulation by Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor

“…Thus, these cell lines confirmed a stable tumor progression from benign to highly malignant and metastatic cells in the in vivo environment. The selection of a more malignant phenotype in vivo has also been reported for other tumor systems such as prostate carcinomas, 49 colon carcinomas, 50 transitional cell carcinomas of the bladder, 51 and pancreatic carcinomas. 52,53 In these studies, in vivo passage of tumor cells resulted in increasingly malignant tumor cell populations with a higher metastatic potential than exhibited by the parental cell lines.…”

“…A-5RT cells induce an earlier and stronger activation of the tumor stroma and an enhanced angiogenic response, partly resulting from strong vascular endothelial growth factor expression (S Vosseler, M Skobe, and NE Fusenig, unpublished observations). In vivo selection of more malignant tumor cell populations with a higher metastatic potential has also been reported for prostate carcinomas, 49 colon carcinomas, 50 transitional cell carcinomas of the bladder, 51 and pancreatic carcinomas. 52,53 Tumor progression in these systems is also associated with the increased expression of angiogenic growth factors such as vascular endothelial growth factor and basic fibroblast growth factor and other cytokines such as interleukin-8.…”

Natural polyphenols facilitate elimination of HT-29 colorectal cancer xenografts by chemoradiotherapy: a Bcl-2- and superoxide dismutase 2-dependent mechanism

“…Similar experiments need to be repeated with at least two to three different colorectal cancer lines and also with both metastatic versions of a parental colorectal cancer line (e.g., KM12C poorly metastatic and KM12SM highly metastatic; ref. 61). If these experiments are successful, our strategy may possibly help to improve the poor prognosis in a significant number of patients bearing a malignant colorectal cancer.…”

Inhibition of Liver Metastasis from Orthotopically Implanted Colon Cancer in Nude Mice by Transfection of the TIMP-1 Gene into KM12SM Cells

“…25 Therefore, the expression of MMP-9 and TIMP-1 by the same cells or neighboring cells are postulated to be a critical factor in activating the proenzyme with the TIMP-1 complex. In our established nude mouse model of liver metastatic human colon cancer, 26 the balance between the expression of MMP-9 and TIMP-1 in the tumor cells influenced the occurrence of liver metastasis from orthotopically implanted colon carcinoma, but that in the stromal cells did not. 27 Thus, it is postulated that the downregulation of MMP activities in primary tumoral tissue may effect the inhibition of liver metastasis, and that an endogenous increase in TIMP activities in tumor cells would be more effective for inhibiting MMP activities and tumor metastasis.…”