Two different types of concomitant resistance induced by murine tumors: Morphological aspects and intrinsic mechanisms

Concomitant resistance (CR) is the phenomenon according to which a tumor-be aring host inhibits the growth of a secondary implant of the same tumor at a distant site. Confirming and extending previous results of our laboratory , histological studies have revealed that two temporally separate peaks of CR can be detected throughout tumor evolution. The first peak induced by im munogenic small tumors, in euthymic but not in nude mice, is associated wit h extensive necrosis of the secondary tumor implant and a profuse infiltrat ion of polymorphonuclear granulocytes and mononuclear cells resulting in it s final destruction; these features correspond to a typical immunological r ejection. The second peak of CR induced by both immunogenic and non-immunog enic large tumors, in euthymic as well as in nude mice, is characterized by a dormant tumor stage with scarce or null mononuclear infiltration, associ ated with a significant reduction of tumor mitotic index and of the number of PCNA+ cells along with an increase in apoptosis and an arrest in S phase . In previous reports we suggested that a 1000 D serum fraction from mice b earing large tumors could be responsible for the induction of this dormant tumor stage. In this study tumor cells incubated in vitro with that serum f actor mimicked the inhibition and cellular alterations observed in vivo in the secondary tumor inhibited by the second peak of CR. Moreover, the passi ve transfer of this factor by the intraperitoneal (i.p.) route induced an i n vivo inhibition of an i.p. tumor reproducing the image characteristic of the second peak of CR. This represents a direct proof that this serum facto r can restrain tumor growth in vivo and that it is, most probably, the effe ctor of the second peak of CR.