Inhibition of the arrest of hematogenously disseminated tumor cells

Abstract

Most metastases in patients occur as a result of hematogenous dissemination of tumor cells. This process of metastasis is complex and consists of several steps, foremost of which is the arrest of circulating emboli in capillary beds and the formation of a thrombus at that site. Thrombus formation in the metastasis of human cancer was described first by Billroth in 1878. It was reported that the organization of tumor cell emboli, and the subsequent penetration of tumor cells into the capillary wall, was the first stage of metastasis. Since then, many investigations and observations have been made clinically as well as experimentally to clarify the process (or mechanisms) of tumor cell arrest and how to inhibit it. Coagulative and fibrinolytic pathways were believed to have a main role in thrombus formation. However, other factors responsible for the relationship between tumor cells and the host must be also considered. Elegant and extensive studies by Fidler and Kripke demonstrated that development of metastasis is not a random process, but a selection process of specialized subpopulations of highly metastatic cells within the primary tumors. Biochemical constituents and ionic properties on cell surfaces, deformability or locomotive activities of tumor cells, as well as thrombo-plastic-fibrinolytic activities, are also important factors determining the arrest patterns of circulating tumor cells. On the other hand, host defense factors against tumor cells in the bloodstream have been attracting much attention recently in tumor immunology. Host defense factors relating the arrest of tumor cells to the establishment of metastatic foci seemed difficult to define, since many studies showed contradictory data concerning the influence of immune response on tumor cell arrest. Hemodynamic abnormality may also influence the arrest of tumor cells in the circulation. Hypercoagulability induced from host tissues is greatly associated with the arrest patterns. Platelet activities might affect thrombus formation. Nevertheless, exact explanations of the process or mechanisms inhibiting or enhancing the arrest of tumor cells after hematogenous dissemination have not been obtained. In any event, for cancer treatment, it is important to determine which substances inhibit the arrest of circulating tumor cells and how to prevent hematogenous metastasis. In this review, we will focus upon coagulative and fibrinolytic processes and then upon substances that inhibit the arrest of circulating tumor cells. Furthermore, some comments on the possible clinical applications of inhibitory substances for prevention of cancer metastasis are added.

Studies on rat mammary adenocarcinomas: a model for metastasis

“…It is thought that cell-associated fibrin generated by these activities may be an important determinant of the metastatic behaviour of blood-borne cells. In support of this idea is the finding that treatment of animals with anticoagulants often, but not always, results in decreased metastasis formation (51,55). Despite this there has been little work on the possible relationship between tumor cell PCA, expressed in vitro, and the ability of cells to form colonies after i.v.…”

Immunostimulating cell surface substance from Staphylococcus epidermidis strain ATCC-31432 prevents metastatic lung colonization in Balb/c-mice

“…It may be that cell-associated fibrin generated by these activities may be important for the metastatic process. This suggestion is supported by the observation that treatment of animals with anticoagulants such as heparin often, but not always, results in decreased metastasis formation [21,24]. For cancer treatment it is important to inhibit the arrest of circulating tumor cells (using anticoagulants) and to eliminate them (with the aid of immunostimulating or cytotoxic agents).…”

Shaping future strategies for the pharmacological control of tumor cell metastases

“…This is reflected in the current literature where the bulk of research studies on the pharmacology of metastases have focused almost exclusively on the mechanisms by which metastatic tumor cells spread rather than on the proliferative capacity of the same cells established in distant organs. In analyzing the metastatic cascade in animal tumor models several discrete stages in the metastatic process have been studied in detail (2,4,10,11) and several have been proposed as sites for therapeutic intervention (12)(13)(14). Many of these studies have been instrumental in examining the biology, pharmacology and biochemistry of tumor cell metastasis but the prospects of exploiting this information in the design of mechanism-based drugs which display improved activity against established metastases, are for reasons described above, remote, Compounds with proposed 'antimetastatic' activity like inhibitors of tumor cell invasion (protease inhibitors and disruptors of microtubule function) (15)(16)(17)(18)(19)(20)(21), antagonists of tumor cell-platelet interactions (prostacyclin thromboxane antagonists, calcium channel blockers) (22)(23) and blockers of tumor cell arrest (laminin fragments) (33, 34) may serve as useful tool compounds to yield insight into the pathogenesis of metastasis and may even find limited clinical utility in the prophylactic discouragement of tumor cell spread.…”