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Mechanisms Responsible for the Origin and Distribution of Blood-borne Tumor Metastases: A Review^*

( Department of Pathology, University of Pennsylvania, School of Medicine, Philadelphia 4, Pa.)

Combining the results of the investigations reviewed in this paper, the following concepts relative to the dissemination of malignant tumors within the body are tentatively advanced:

The local invasiveness of cancer cells is primarily dependent upon loss of the mutual adhesiveness of the cells, which loss is associated with, if not due to, local calcium deficiency. The easily detached single cancer cells, or even small clusters of them, are actively ameboid and are thereby enabled to penetrate the adjacent normal tissues.

Distant dissemination of cancer cells, as a sequel to local invasiveness, is largely dependent upon entrance of cells into vascular channels through which they are carried to other parts of the body. Many embolic cells, however, are unable to establish secondary growths in their new location.

Duration of growth of the primary tumor bears a positive relationship to the number of metastases, whereas the size of the primary tumor is less effective in influencing the number of metastases than are other factors as yet undetermined.

The venous distribution of metastases is largely dependent upon the anatomical arrangement of the venous channels (including the vertebral veins) into which emboli are commonly released. This accounts for the frequency of metastatic involvement of the lungs, the liver, and the bones of the spine, pelvis, and skull.

The arterial distribution of metastases is also dependent upon the number of embolic cells reaching the various organs, and in addition depends upon whether the embolic cancer cells lodge in capillaries and sinusoids or in thick-walled arterioles. These phenomena are variable from organ to organ, and evidently account in large measure for the relative infrequency of metastasis to some organs (spleen, muscle) and the frequency of metastasis to other organs (adrenals, kidney).

The lungs, however, although frequently the site of metastatic tumors, apparently afford relatively adverse conditions for tumor growth. This may be attributable to the peculiar physical structure, functions, and circulatory mechanisms of the lungs. The immediate transpulmonary passage of embolic tumor cells is perhaps more common than has been thought in the past.

It is further indicated that single embolic cells or tiny clusters, rather than large clumps, give rise to most metastases because these cells are able to reach the capillary bed where conditions are most favorable for the development of secondary tumors. Larger clumps lodge in arterioles, a situation unfavorable for the establishment of metastatic growths.

In the attempts herein reviewed to reveal "soil" factors as affecting the distribution of metastases, it would appear that they consist chiefly of physical or mechanical circulatory differences rather than of chemically favorable or unfavorable environments for the growth of tumor cells. In view of the results obtained in the experiments here reviewed, it is suggested that before hypothetical "chemical soil" factors are offered in explanation of the distribution of metastatic tumors, simple "mechanical-circulatory" factors affecting the frequency distribution of embolic tumor cells must be eliminated for each tumor and host studied.

^* Support from the National Cancer Institute of the National Institutes of Health, U.S. Public Health Service, and from the Anna Fuller Fund is gratefully acknowledged.

Received 12/12/52.

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