Transcellular Cell Movement and the Formation of Metastases

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Abstract
TRANSCELLULAR CELL MOVEMENT AND THE FORMATION OF METASTASES PETER P. H. DE BRUYN* The biological factors underlying the cytoplasmic mechanisms of the malignant behavior of transformed cells remain insufficiently understood . However, there are available for scrutiny a considerable number of observations and experimental data that permit reasonable conjectures for an analysis of some of the salient processes of malignant tumor behavior. For the purposes ofthe present discussion, it is useful to distinguish two separate pathophysiological components in tumor malignancy. One of these is a cell proliferation, which does not respect anatomical boundaries and which results in the invasion and destruction of neighboring tissues and organs by the malignant cells. The second component of malignancy is the establishment ofsecondary tumors distant from the primary tumor, that is, the formation of metastases. In the formation of metastases, there are two sequential phases: a primary phase, which is the entry of malignant cells into the circulation through the passage of malignant cells through the walls of the vessels of the tumor, and a secondary phase, which represents the actual clinical manifestation of metastases formation. This phase has also a transmural constituent in the sense that the malignant cells leave the circulation at the site of the future metastatic tumor and then proliferate there extravascularly . The second component of malignancy—metastases formation through transmural cell passage and vascular dissemination followed by metastatic growth—militates against the benefits of surgical removal of the primary tumor and in this respect constitutes the most pernicious aspect of malignancy. While the ultimate therapeutic goal in the control of malignancy remains the general selective destruction of malignant cells, a control ofmetastases formation would be an important adjunctive measure. Of the two phases of metastases formation, the The author's cited work is supported by NIH grant CA 05493 awarded by the National Cancer Institute. ?Department of Anatomy, University of Chicago, Chicago, Illinois 60637.© 1983 by The University of Chicago. All rights reserved. 003 1-5982/83/2603-0342101 .00 Perspectives in Biology andMedicine, 26, 3 · Spring 1983 | 441 primary one is the essential ingredient in the establishment of secondary tumors since the secondary phase is clearly dependent on the occurrence of the primary phase. Regarding the mechanisms and biological factors governing metastases formation, the transmural cell passage is of special biological importance . In the first place it is to be noted that the transmural entry of malignant cells into the circulation is selective. Normal stromal or parenchymal cells are not able to penetrate the vascular wall. This gives evidence that diere is a special form of interaction between malignant cells and the abluminal aspect of the vascular endothelium (or unilateral action ofone cell type on the other) that permits the malignant cell to enter the vascular lumen. With respect to the nature of this selective interaction , knowledge of the pathway through the endothelial lining is of importance. The following questions are to be asked: Do the malignant cells enter the circulation by local destruction ofthe vascular wall such as occurs in the destructive invasion of neighboring tissues and organs by the malignant ceUs? Or does the malignant cell enter the circulation through a structurally intact vascular wall as takes place in the transmural cell passage defined as diapedesis, and if so, does the malignant cell move through intercellular clefts between the endothelial cells as happens in the diapedesis ofblood cells in the inflammatory process [I]? Or does the malignant cell move through the vascular wall by penetrating the cytoplasm ofthe endothelial cell body, in which case the entry of malignant cells into the circulation would be a transcellular process? Each of these possible pathways through the endothelium requires a different form of interaction between malignant cell and endothelium and thus would characterize differentiy the nature of ceUular malignancy as it relates to metastases formation. Observations on the pathway of malignant cells through the endothelial lining of tumor vessels are available on three tumors transplanted and growing subcutaneously: the allogeneic Shay acute myelogenous leukemia [2], the syngeneic rat Wistar/Furth acute myelogenous leukemia, and the syngeneic mouse B16 melanoma [3]. AU three tumors invade and destroy neighboring tissues and produce metastases. Light microscopic and electron microscopic sections show that the...

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