Electron microscopic observations on formation of pulmonary metastases.

The development of pulmonary metastases after local surgical control of malignant tumors has represented a major cause of treatment failure in a variety of neoplasms. The metastatic process has been a subject of considerable interest, investigation, and speculation for many years, but it remains as a poorly characterized and little understood phenomenon. The formation of blood-borne metastases is generally considered to involve several steps, including: (1) growth of a primary tumor with eventual shedding of viable malignant cells into the blood, either directly through vascular invasion or indirectly by lymphatic drainage; (2) transport of tumor cell emboli through the circulation to distant organs; (3) arrest of blood-borne malignant cells in distant vascular beds; (4) penetration of vascular walls by embolized tumor cells; and (5) growth of metastasized malignant cells in the parenchyma of target organs. Histologic investigations of the metastatic process were undertaken early [ 181. Various initial studies of experimental metastases in animal neoplasms indicated that once malignant cells shed from a primary tumor reach the venous circulation, they are carried to the capillary bed of target organs where the cells become arrested prior to invasion of the target organ parenchyma [ 11, 24,251. The initial attachment of circulating tumor cells to the capillary endothelium of distant organs has been regarded as a crucial step in metastasis [6, 131. Numerous investigations have suggested that circulating tumor cells embolize to target organs, where they arrest in vascular channels and attach to the endothelium prior to invading the surrounding tissue parenchyma [4, 5, 26, 271. Various workers have proposed that the attachment of embolized malignant cells to the vascular walls is largely dependent upon entrapment of the tumor embolus within a thrombus or fibrin meshwork [2, 8, 17, 28, 291. Such a thrombus might serve to stabilize the tumor emboli within the vessels until the cells are able to penetrate the endothehum and establish metastatic foci within the perivascular connective tissue. Despite active research efforts, there have been relatively small amounts of data concerning the mechanisms involved in the arrest of circulating tumor cells and their method of growth in metastatic sites [9, 16, 301. Recently, electron microscopic investigations have attempted to characterize events in metastasis formation through examination of embolic tumor cells arrested within vascular beds [12, 141. Jones and coworkers [12] investigated the sequence of events in experimental pulmonary metastases of the Walker 256 carcinosarcoma in rats, utilizing both electron microscopy and fibrin-specific immunofluorescence. These investigators demonstrated that after intravenous injection, tumor cells were arrested in pulmonary capillaries and were surrounded by a thrombus formed from ag-