Transplantation of 2 chemically (DMBA, MCA)-induced tumors into syngeneic female or male DA strain rats elicited hormonal changes during tumor growth. Plasma levels of 7 different hormones were studied. Tumor cells in syngeneic recipients produced a biphasic decrease in insulin, an early increase in prolactin, and a late-phase decrease in thyroxine. Corticosterone decreased in female tumor bearers but increased in males. This difference may reflect differences in the tumors transplanted. Male rats had a decrease in testosterone during the late phase of tumor growth, while females had a biphasic decrease in progesterone and a late-phase increase in growth hormone. The tumors used were moderately immunogenic in syngeneic recipients. However, tumor transplantation to allogeneic recipients produced an early decrease in growth hormone and no change in insulin, corticosterone or thyroxine. Further, transplantation of normal liver cells to syngeneic or allogeneic recipients produced no hormonal abnormalities. This study demonstrates that hormonal changes which are not observed with normal cells or allogeneic tumor transplantation can occur within 2 days of syngeneic tumor transplantation. Progressive tumor growth is characterized by a worsening endocrine imbalance which involves multiple hormone systems.
EL-4 lymphoma cells transplanted to syngeneic C57BL/6J mice induced a biphasic decrease in inflammation and a bi-phasic increase in serum levels of corticosterone. In addition, this tumor altered serum levels of 3 other hormones, resulting in a biphasic decrease in insulin, an early decrease in prolactin, and a terminal severe deficiency in thyroxine. Early changes occurred 16 to 48 hr after tumor transplantation and were of variable duration, while late-phase defects developed during the last few days of life. Soluble factors associated with tumor growth may mediate certain hormonal changes since serum levels of corticosterone increased and insulin decreased following injection of tumorous ascites into normal mice. Further, injection of cell-free tumor culture supernatants increased corticosterone levels. Hormonal changes following injection of soluble factors occurred after a delay of 16 hr indicating that the factors acted indirectly. Surgical adrenalectomy blocked the corticosterone increase induced by tumor transplantation or ascites injection and eliminated the anti-inflammatory effect of tumor transplantation while significantly decreasing the effect associated with injection of tumorous ascites. Thus, the physiologically induced increase in serum levels of corticosterone reached anti-inflammatory levels. Further, elevated levels of corticosterone are a major contributing factor to anti-inflammation induced by tumorous ascites injection and constitute the principal mechanism of anti-inflammation following tumor transplantation.
Appropriately stimulated lymphocytes and macrophages produce factors in vitro that increase serum corticosterone levels when injected in vivo. In this study, we used euthymic and congenitally athymic mice on a BALB/c background to explore the role of T cells in controlling corticosterone levels and the leukocyte response to inflammation. Adult athymic mice had more intense inflammatory reactions than euthymic mice despite higher basal corticosterone levels. This latter condition may be due to interleukin-1 (IL-1) since macrophages from athymic mice when stimulated in vitro by lipopolysaccharide produced more IL-1 than macrophages from euthymic mice. In response to mitogen stimulation, however, splenocytes from athymic mice produced a factor (not IL-1), which, upon injection, increased corticosterone levels and suppressed inflammation. Production of this factor was enhanced by T cells since splenocyte supernatants from euthymic mice were more potent in eliciting both effects. Evidence for in vivo participation of T cells in regulating corticosterone levels was obtained by tumor transplantation. Injection of syngeneic tumor cells or cell-free tumorous ascites rapidly increased corticosterone levels in euthymic but not athymic mice. Anti-inflammation correlated with increased corticosterone levels but was observed also in athymic mice receiving syngeneic tumor transplants. These studies demonstrate that T cells enhance production of a lymphokine that increases corticosterone levels and are required for the corticosterone response to tumor transplantation. In addition, the data suggest two pathways of anti-inflammation in tumor-bearing hosts: a corticosterone-independent, T cell-independent mechanism and a T cell-dependent mechanism that involves a lymphokine-mediated increase in corticosterone blood levels.
Histiocytic lymphomas develop spontaneously in about 80% of SJL/J mice between the ages of 8 and 14 months. These animals were used for the determination of whether spontaneously arising cancers compromise monocyte function similar to the monocyte defects described during growth of transplanted tumors. SJL/J mice with tumors accumulated significantly fewer macrophages than did age-matched animals without tumors either on sc implanted filters or in peritoneal exudates induced by phytohemagglutinin. There was no corresponding defect in polymorphonuclear neutrophil responses. Whereas no apparent correlation existed between tumor size and degree of inhibition, animals without demonstrable tumors had no inflammatory defects. Aging did not alter the inflammatory response to implanted filters but increased both the resident peritoneal macrophage population and the total macrophage yield to phytohemagglutinin provocation. When given transplants of histiocytic lymphomas, young SJL/J mice developed similar inflammatory defects. This study represents the first demonstration that spontaneous tumors, in addition to transplanted tumors, produce abnormalities in monocyte inflammatory responses.
Autochthonous and transplanted tumors induced by 3-methylcholanthrene-impregnated paraffin pellets in DA rats and C57BL/6 mice were analyzed for effects on macrophage inflammatory responses. Tumors emerged in 40% of carcinogen-treated rats with a mean latency of 8.1 months. During the latent period, rats treated with carcinogen versus rats treated only with paraffin had a higher frequency of depressed macrophage responses, which, however, did not alter either tumor latency or incidence. Tumors emerged in 70% of carcinogen-treated mice with a mean latency of 110 days. Prior to tumor emergence, mice treated with carcinogen or paraffin had a higher frequency of depressed responses than untreated control mice, and such abnormalities in the presence of carcinogen were positively associated with tumor development. Macrophage responses were not altered in rats or mice bearing large autochthonous tumors, although emerging tumors in rats but not in mice were associated with a modest inhibition in macrophage responses. Autochthonous tumors that did not induce macrophage abnormalities did so in syngeneic recipients upon tumor transplantation.
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