Tumor cell motility.

Tumor cell motility is required for invasion and metastasis. The locomotory machinery of the cell includes cell projections called pseudopodia which are regulated by a complicated linkage between cell surface receptors or sensors and the internal cytoskeleton. Recently a new class of motility stimulating cytokines have been identified. These cytokines can function as autocrine motility factors and require a pertussis toxin sensitive G protein pathway to transduce a random motile response.

Cell motility, a principal requirement for metastasis.

In studying the role of motility in the metastasis of tumor cells, we have described an autocrine motility factor. This agent, which stimulates random motility, probably contributes to the initial dissociation of the cells from the primary tumor mass. Extracellular matrix components, via several different mechanisms, may facilitate the crossing of biological barriers by the cells prior to the entry into the circulation. In locating at new sites, the tumor cells may be induced to exit from the circulation in response to attractants such as IGFs that could emanate from the target organ. These same growth factors could then stimulate cellular proliferation for another metastatic cycle. It is quite probable that detection of AMF may provide a new tool in cancer diagnosis. The complete characterization of AMF may also yield valuable therapeutic approaches: design of low molecular size antagonists of the attractants and antibodies that might be effective therapeutically as well as diagnostically. It seems clear, in any event, that immobilizing the tumor cell may be a crucial step in inhibiting metastasis.

Insulin-like growth factors stimulate chemotaxis in human melanoma cells.

Insulin and insulin-like growth factors stimulate motility in the highly metastatic human melanoma cell line, A2058. Insulin-like growth factor-I (IGF-I) is the most potent with a maximal response at a concentration of 10 nM compared to the activities of insulin and insulin-like growth factor-II (IGF-II) which peak at 300-400 nM. Using checkerboard analysis, the responses to IGF-I and insulin are predominantly chemotactic, although insulin had a significant chemokinetic component. Pertussis toxin does not inhibit the response to any of these polypeptides. However, in previous studies, it was shown that the motile response to autocrine motility factor from these same A2058 cells was markedly inhibited by pertussis toxin. 125I-labelled IGF-I binds saturably and specifically to the A2058 cells. Scatchard analysis indicates a high binding affinity (Kd approximately 3 x 10(-10) M) and an estimated 5000 receptors/cell. These studies indicate that in addition to their mitogenic properties, certain growth factors may profoundly enhance metastasis of tumor cells by their ability to induce motility.

Prostacyclin inhibits 5-hydroxytryptamine release but stimulates thromboxane synthesis during cardiopulmonary bypass.

The antiaggregating agent prostacyclin (PGI2) was infused into ten dogs during cardiopulmonary bypass (CPB) to minimize thrombocytopenia and platelet dysfunction. The animals were anesthetized, placed on mechanical ventilation and underwent thoracotomy. After heparinization with 300 u/kg, animals were assigned to control (n=5) or PGI2 treated groups (n=5). Thoracotomy and then CPB decreased platelet numbers to below 30,000/mm3 (p less than 0.05) and fibrinogen to less than 150 mg/dl (p less than 0.05). PGI2 at 100 ng/kg.min was infused for the 2 h period of CPB. PGI2 infusion did not prevent these changes, but did prevent platelet serotonin release. In the control group after CPB, platelet serotonin fell from the baseline value of 1.11 microgram/10(9) to 0.35 microgram/10(9) platelets (p less than 0.05). In contrast, PGI2 treatment resulted in a serotonin increase to 2.27 micrograms/10(9) platelets (p less than 0.05). Thromboxane B2 concentrations of platelets and plasma rose during CPB (p less than 0.05). Surprisingly, PGI2 infusion accentuated this rise in platelet and plasma thromboxane B2 (p less than 0.05). These data indicate that during CPB, an infusion of PGI2: 1) does not prevent thrombocytopenia; 2) increases platelet serotonin uptake despite, 3) an associated rise in platelet and plasma thromboxane B2.