End Organ Arrest Organ Directed Metastasis

Postintravasation, tumor cells migrate to the sites of metastasis. Clinical and experimental observations suggest that metastatic destinations are selective for specific tissues159; for example, among others, breast and prostate cancers preferentially metastasize to bone,160 colorectal cancer to the liver,161 and skin cancer to the lung.162

Mechanisms proposed to account for directed metastasis are controversial. The British surgeon Stephen Paget retrospectively investigated the metastatic destinations of a variety of cancers by examining autopsy records and documented organ-specific metastasis patterns.163 He attributed this proclivity for organ-specific metastasis to a salutary interaction between the metastasizing cell and the end organ. He likened the metastasizing cell to a seed that thrives in the growth-promoting "soil" of the target organ.

An alternative mechanism explaining directed metastasis was proposed in the early 20th century by another surgeon, James Ewing. Ewing also documented a nonrandom pattern of metastatic cancer spread; in contrast to Paget, however, Ewing suggested that metastatic patterns could be attributed to an anatomic, circulatory bias164; that is, metastasizing cells tend to lodge and secondarily proliferate at the first vascular bed distal from the primary tumor site.

Analyses of patterns of metastatic spread provide support for Ewing's hypothesis. Weiss et al., in extensive studies of colon cancer metastasis, observed generalized proximal organ metastasis correlating with the magnitude of target organ flow.165 Weiss' analyses, however, do not wholly vitiate the "seed and soil" hypothesis of Paget. To the contrary, in these same studies, Weiss observes that patterns of secondary metastasis do not perfectly correlate with the magnitude of blood flow. In some organs, the tendency for metastasis is greater than or less than what would be predicted solely on the basis of the magnitude of blood flow. These findings suggest that some specific interaction between the circulating metastatic cell and the target organ influences the likelihood of that cell metastasizing to that organ. Additional observations corroborate this notion; patients with ovarian cancer frequently develop malignant abdominal ascites, necessitating placement of peritoneovenous shunts. In these circumstances, malignant cells are drained from the abdomen back into the circulation via the jugular vein whence they pass through the capillary bed of the lungs. Ewing would predict that these patients would develop pulmonary metastases, and yet autopsy results reveal an overwhelming absence of such growths.166,167

Hart and Fidler examined the organ biases of B16 melanoma metastases. In the whole animal, B16 cells spontaneously form metastases within the lung and ovaries. The investigators intravenously injected B16 cells into mice bearing syngeneic pulmonary, ovarian, and renal subcutaneous implants.168 Hart and Fidler found that B16 tumors do not develop randomly; rather, they formed selectively within the implanted lung and ovarian tissue, and not within the kidney tissue. Thus, it would seem that some special interaction between circulating B16 cells and the pulmonary and ovarian tissue dictates the metastatic bias.

A number of recent investigators, including Binacone et al., have sought to elucidate the mechanistic basis of organ-selective metastasis.169 E-selectins are adhesion molecules expressed on the surface of endothelial cells. Binacone demonstrated that the destination of metastasizing B16 cells could be efficiently directed by controlling cell-surface expression of E-selectin. This demonstration suggested that organ-directed metastasis may be defined, in part, by an interaction between proteins expressed on the surface of the target organ endothelium and those expressed on the surface of metastasizing cells. In support of this hypothesis, the metastatic destination of Chinese hamster ovary cells can be altered by transfecting these cells to express a4p1 integrin on their surface.170

In agreement with the idea of metastasizing cell-organ endothelium interactions providing a basis for organ-selective metastasis, a number of different lines of evidence have suggested the uniqueness of organ endothelia.171-173 Ruoslahti and his coworkers have suggested that the uniqueness of the organ endothelia derives from signature endothelial cell-surface proteins that comprise an address system and ensure delivery of the metastasizing cell to a designated target tissue.174-176 For example, specific proteins have been identified that mediate the binding of metastatic breast and prostate cancer cells to lung tissue177 179 and colon cancer cells to the liver.180

Taken as a whole, the evidence supports both a circulatory, anatomic bias, as proposed by Ewing, and unique endorgan properties, as theorized by Paget, underlying the ultimate site of metastasis. Recent investigative initiatives have sought to further define the molecular basis and relative contributions of the circulatory, anatomic, and "seed and soil" mechanisms toward organ-directed metastasis.

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