Differential production of angiostatin by concomitant antitumoral resistance‐inducing cancer cells

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Abstract
The phenomenon by which tumor‐bearing hosts are capable of inhibiting secondary tumor implants or metastases, known as concomitant antitumoral resistance (CAR), is presumably due to antiangiogenesis at places distant from the primary tumor. Although angiostatin, a potent inhibitor of angiogenesis, has been reported to be one of the factors responsible for suppressing the growth of secondary tumors in mice bearing previous tumors, it has not been definitively proven yet. With the aim of investigating whether CAR‐inducing cancer cells display a differential angiostatin production and to support the role ascribed to that molecule concerning the inhibition of secondary tumor implants, 5 tumor models with different CAR‐inducing capacities were studied herein. One of the 2 human lung cancer cell lines analyzed revealed a strong CAR against secondary s.c. tumor implants in nude mice, and 2 of 3 of the murine mammary tumors used exhibited inhibitory effect on secondary s.c. and i.v. tumor inoculations in syngeneic hosts. Since angiostatin is a proteolytic fragment from plasminogen, we examined by Western blot the ability of all conditioned media collected from the tumor cells studied to convert plasminogen to angiostatin. An association between in vivo generation of CAR and in vitro conversion of plasminogen into angiostatin was found. Since different enzymatic mechanisms were described to explain the generation of angiostatin, we also studied gelatinase and urokinase‐type plasminogen activator secretion in conditioned media by zymography. The conversion of plasminogen into angiostatin by conditioned media was mainly inhibited by broad‐spectrum serine proteinase inhibitors, suggesting a possible role for 1 or more enzymes of that group in the process. These findings suggest the existence of a differential angiostatin generation by CAR‐inducing cancer cells, providing additional support to previous data obtained by other authors.