Promotion of Tumor Growth In Vivo by Antimacrophage Agents 2

Abstract

ABSTRACT-Various attempts were made to assess the role of the mononuclear phagocyte system in tumor resistance of rats in vivo. The growth of sc inoculated, weakly immunogenic, carcinogen-induced, syngeneic tumor cells was modestly reduced by ip injection and, more impressively, by local injection of peptoneinduced, activated, nonimmune macrophages. A single iv injection of silica particles or carrageenan on the day of sc tumor cell inoculation greatly enhanced tumor growth. When these agents had been given a few days before or after tumor cell inoculation, the tumor-promoting efficiency was distinctly diminished or even cancelled. The enhancing effects of silica and carrageenan on tumor growth were nullified by the macrophage-stabilizing agent, poly-2-vinylpyridine N-oxide. To assess the in vivo consequences of silica administration, various cellular, biochemical, and functional macrophage parameters were determined at different intervals. Results indicated the complexity of events elicited after the mononuclear phagocyte system was damaged, which made the interpretation of such results difficult.-J Natl Cancer Inst 57: 1355-1361,1976. Many in vitro studies indicate that, in addition to the basic role that is assigned to lymphocytes (in tumor resistance), macrophages activated by specific or nonspecific means also contribute to tumor resistance (1). Since presently no direct or effective way exists of depleting the host of macrophages, their function in tumor resistance in vivo remains obscure. However, considerable evidence, admittedly indirect, implies such a capacity for the macrophage (2). For example, in the Nippostrongylus brasiliensis-infected rat, tumor growth can either be suppressed or enhanced, depending on the timing of inoculation of tumor cells in relation to the parasite infection (3). In this (4) and other in vivo model systems (5, 6), suppression of tumor growth seems attributable to AM, and enhancement of tumor growth seems due to a macrophage-inactivating factor arising after a nematode infection (7). Moreover, the use of adjuvants of microbial derivation such as BCG, Corynebacterium parvum, or Listeria monocytogenes has been considerably expanded, and recent evidence attests to intralesional injection of the adjuvant being particularly effective in producing regression of established syngeneic tumors (8)(9)(10)(11). As the responsiveness of tumors to these adjuvants does not parallel their immunogenicity, this effect is now considered more likely to reflect the extent to which tumors are infiltrated by macrophages. Still other observations imply an inverse relationship between the macrophage content of tumors and tumor regression (12) or metastases (13). Despite these distinctive approaches and the expanding magnitude of the effort, no convincing evidence exists that macrophages are directly involved in tumor resistance.The function of macrophages in tumor resistance is explored further in the present study. Various measures known to diminish the functional capacities of macrophages in vi...

Effect of carrageenan on the non-specific resistance of mice to injected syngeneic tumour cells, alone or in mixtures

“…This observation has been previously reported for both chemically induced (Keller, 1976;Nelson & Nelson, 1978) and virally induced (Lotzova & Richie, 1977) tumours. It is unlikely that the enhancement is due to a direct stimulatory effect of carrageenan on tumour growth, since carrageenan has been shown to be toxic for tumour cells in vitro (Pollack & Nelson, 1973), although products from damaged macrophages may have an enhancing effect (Keller, 1976). Carrageenan has many biological effects (Di Rosa, 1972) including anticoagulant activity (Anderson & Duncan, 1965) and inhibition of complement (Borsos et al, 1965), all of which may affect tumour growth.…”

“…Carrageenan is known to impair delayed hypersensitivity reactions in vivo (Bice et al, 1971;Schwartz & Leskowitz, 1969) and is a potent immunosuppressant of antibody formation (Aschheim & Raffel, 1972;Thomson et al, 1976). Keller (1976) and Thomson & Fowler (1977) have shown that carrageenan has an enhancing effect on the growth of relatively large tumour-cell inocula. Benjamini et al (1977) reported that mitomycin C treatment of syngeneic tumour cells prevented replication of such cells, which could still be used to induce specific cell-mediated immunity.…”

Macrophage-mediated natural cytotoxicity against various target cells in vitro. II. Macrophages from rats of different ages

“…As effector cells from normal tissues are far more heterogeneous than peritonealexudate cells (Keller, 1976b), a role for effector cells other than mononuclear phagocytes capable of mediating spontaneous cytotoxicity also merits consideration. In view of the recently recognized diversity of the cell populations manifesting natural killer capacity, the demonstration of consistent abrogation of the cytolytic effector-cell activity in vitro by silica (Keller, 1973(Keller, , 1978, an agent accepted as selectively toxic for macrophages (Kessel, Monaco and Marchisio, 1963;Allison, Harington and Birbeck, 1966;Keller, 1976a) may not be entirely conclusive. It is therefore essential clearly to identify and characterize the mononuclear phagocytes from other cell types manifesting spontaneous killer capacity.…”

“…After culture at 37°C in a humid atmosphere of 5% C02 and 95% air in RPMI-1640 (Keller, 1976a;Keller, 1978).…”

“…Prelabelled target cells were added to effec-tor-cell monolayers to an initial effector/target cell ratio of 10:1. After 48 h incubation, the percent isotope release was determined as previously described (Keller, 1976a) and the cytocidal capacity calculated as in Keller and Keist (1978). All tests were performed in triplicate, the mean and standard deviation being determined.…”