Tumors that metastasize do so to preferred target organs. To explain this apparent specificity, Paget, > 100 years ago, formulated his seed and soil hypothesis; i.e., the cells from a given tumor would "seed" only favorable "soil" offered by certain organs. The hypothesis implies that cancer cells must find a suitable "soil" in a target organ-i.e., one that supports colonization-for metastasis to occur. We demonstrate in this report that ability of human colon cancer cells to colonize liver tissue governs whether a particular colon cancer is metastatic. In the model used in this study, human colon tumors are transplanted into the nude mouse colon as intact tissue blocks by surgical orthotopic implantation. These implanted tumors closely simulate the metastatic behavior of the original human patient tumor and are clearly metastatic or nonmetastatic to the liver. Both classes of tumors were equally invasive locally into tissues and blood vessels. However, the cells from each class of tumor behave very differently when directly injected into nude mouse livers. Only cells from metastasizing tumors are competent to colonize after direct intrahepatic injection. Also, tissue blocks from metastatic tumors affixed directly to the liver resulted in colonization, whereas no colonization resulted from nonmetastatic tumor tissue blocks even though some growth occurred within the tissue block itself. Thus, local invasion (injection) and even adhesion to the metastatic target organ (blocks) are not sufficient for metastasis. The results suggest that the ability to colonize the liver is the governing step in the metastasis of human colon cancer.A metastatic colony is the end result of a complex series of processes resulting from tumor-host interactions (1, 2). These include angiogenesis and intravasation of tumor cells (3), circulation and extravasation (4), and adhesive interactions with other cells, including endothelial and target cells (5-7), as well as colonization of the target organ. Adhesion molecules and proteolytic enzymes seem to play a role in this process (5-8). However, only some tumors metastasize and there is no clear understanding of the key properties and events that lead to metastatic colony formation.Tumors can have enormously different characteristic metastatic rates. In contrast to the variability in rates, there is a surprising degree of specificity in the target organs colonized by metastases from a particular type of tumor (e.g., colon tumors most often target the liver). Over 100 years ago, Paget (9) noted the highly nonrandom spread of cancer to specific target organs. From these observations, he formulated the "seed" (primary cancer) and "soil" ("target organ") hypothesis of metastasis. A corollary of this hypothesis is that cancer cells must find a suitable "soil" in a target organ, one supporting colonization, for metastasis to occur. We demonstrateThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement"...
COL-2-JCK, a human colon cancer xenograft line able to be transplanted into nude mice, was implanted in the subserosal layer of the cecum, either as cancer tissue or as a single cell suspension. When cancer tissue was used for the cecal implantation, 100% extensive local tumor growth and a high incidence of metastases to the regional lymph nodes, peritoneum, liver, and lung was observed. In contrast, when the cell suspension of this line was injected into the cecal wall, no metastases were observed, with significantly reduced local tumor growth. The use of cancer tissue maintaining the original cancer tissue structure is therefore considered imperative for allowing full expression of the biological characteristics of cancer cells. This nude mouse model using the cecal implantation of cancer tissue should thus prompt further study on the biology of human colon cancer.
We have established a metastatic model of human gastric cancer using orthotopic transplantation of histologically intact tissue in nude mice, and have used this model to evaluate the effects of immunochemotherapy using OK-432, 5-fluorouracil (5-FU) and mitomycin C (MMC) against SC-I-NU, a human stomach cancer line. One-quarter or one-half maximum tolerated doses (MTDs) of 5-FU or MMC resulted in a significant reduction of stomach tumor growth, while liver metastases were not reduced, possibly due to suppression of natural killer (NK)-cell activity by both drugs. On the other hand, when combined with OK-432, half MTDs of 5-FU and MMC significantly reduced liver metastases, with synergistic reduction of stomach tumor growth, possibly reflecting a rescue of NK-cell activity by treatment with OK-432. This metastatic model of human stomach cancer shows that locally growing and metastatic tumors may have different chemosensitivities, and provides the opportunity to test both with various treatment regimens.
The synergistic antitumor activity of mitomycin C (MMC) and cisplatin (DDP) against the gastric cancer cell lines MKN-28 and MKN-45 was assessed in vitro using the MTT assay. The synergism of the two agents was evaluated in terms of the interaction index (I.I.). The sequence of MMC followed by DDP showed higher antitumor activity than the reverse sequence against MKN-28 and MKN-45, and the intracellular concentration of platinum was significantly increased in MKN-45 by preincubation with MMC, suggesting that MMC modulates cellular permeability to DDP or the ability of DDP to intercalate DNA. Since these two antitumor agents show different types of toxicity clinically, i.e., myelotoxicity by MMC and nephrotoxicity by DDP, this combination chemotherapy could be advantageous by providing synergistic antitumor activity without increased toxicity.
We have developed a liver metastatic model of human colon cancer using severe combined immunodeficient (SCID) mice. Liver metastases were observed in all the SCID mice on day 28 after intrasplenic injection with 5 x 10(6) dissociated tumor cells of COL-2-JCK, a human colon cancer strain serially transplanted in nude mice. When this model was applied for chemotherapeutic experiments, 5-fluorouracil (5-FU) demonstrated significant antitumor effects in preventing liver metastases, whereas the efficacy of 5-FU was limited in the currently used sc-ip chemosensitivity assay in nude mice. When the human LDH-5 isozyme was evaluated in the homogenized metastatic liver tissue of SCID mice, a good correlation was obtained between the liver tumor weights and LDH-5 isozyme, suggesting that it could be a promising quantitative indicator for metastases. This model would be useful for further studies on the treatment of liver metastases of colon cancer.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.