Liver colonization competence governs colon cancer metastasis.

Abstract

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"...

Establishment of and Comparison between Orthotopic Xenograft and Subcutaneous Xenograft Models of Gallbladder Carcinoma

“…Scale bars=100um and its potential of metastasis. The findings of our study conform to the related reports of previous studies (Fidler 1991;Kuo et al, 1995). In the experiment we found the liver metastatic rate of the orthotopic model was even higher than that of clinical gallbladder carcinoma, which may be due to the cases that we chose.…”

In vivo Color-Coded Imaging of the Interaction of Colon Cancer Cells and Splenocytes in the Formation of Liver Metastases

“…The ''seed and soil'' hypothesis of Paget (1) assumes direct interaction of tumors and normal cells (i.e., ''the seeds growing in the soil''), the analogy of tumor cells growing in a distant organ. This hypothesis was confirmed by us in 1995 when we showed that colon tumors would metastasize to the liver only if the tumor tissue were able to grow when implanted directly on the liver (13). If colon tumor tissues were unable to grow when implanted directly on the liver, the tumors were also unable to metastasize.…”

Consistent Liver Metastases in a Rat Model by Portal Injection of Microencapsulated Cancer Cells

“…Matrigel, an extracellular matrix that contains several growth factors and cytokines, was used as a ''burst-supporting'' agent in the present study, although coculture with various growth factors, cytokines, extracellular matrix components, and fibroblasts might also augment cell proliferation and capsule burst. Regarding the second condition, some cancer cells have never been reported to proliferate in liver even after direct intrahepatic injection, indicating that the liver is not an appropriate soil for some cell lines (18,50). Application of the present microcapsule system to those cell lines might not generate liver metastases, even if they have the capacity to rupture the outer layer of microcapsules.…”

“…Alternative strategies for obtaining liver metastases with cancer cells of low metastatic potential include orthotopic implantation, by injecting cancer cell suspensions, or by surgical transplantation of tumor fragments (13)(14)(15). Obstacles in the latter strategy include the presence of undesired metastases and are moreover difficult to reproduce in terms of the frequency and extent of metastases (16)(17)(18).…”