The mononuclear phagocyte (MNP) system plays a fundamental role in inflammatory responses and defense against microorganisms. Its role in the tumor-bearing host is less well defined. Most, if not all, human and animal tumors contain MNP at various levels and a wide range of potential functions has been ascribed to them. The regulation of MNP functions is controlled by several physiological pathways, including one mediated by the monocyte-macrophage colony-stimulating factor (CSF-1 or M-CSF). This growth factor binds primarily to MNP regardless of their stage of differentiation or maturation via its receptor encoded by the c-fms protooncogene. Preliminary data have indicated that rhCSF-1 primes unstimulated resident mouse peritoneal, but not elicited, MNP for rapid cytokine gene transcription most successfully if priming occurs before the MNP adhere. Several typical inflammatory genes such as IL-1alpha, IL- 1beta, IL-6 and GM-CSF are rapidly transcribed but only IL-6 is secreted. The expression of the c-fms gene is down-regulated. Interestingly, TNFalpha gene expression was not induced by CSF- 1-priming in vitro but was induced following intraperitoneal injection of CSF-1. Given their location, tumor-associated MNP are ideally situated for participation in inflammatory responses and several reports have indicated that such MNP do express IL-1, TNF and IL-6. This application is focused on the proposition that CSF-1, produced at the tumor site or systemically, plays a key role in the movement,of MNP from the circulation into the tumor site, where their strategic location may play an important role in the fate of the tumor. The three Specific aims are: (l) to test the hypothesis that primed MNP bind to vascular endothelial cells (EC) by the interaction of adhesion molecules, whose expression is regulated by cytokines released by both primed MNP and activated EC; (2) that after the initial, transient contact with and release from EC, the activated MNP react with extracellular matrix proteins associated with the tumor mass resulting in superinduction of cytokine gene expression and secretion. We propose that, at this point, the cascade of reactions reaches its peak but ultimately leads to MNP quiescence; (3) To evaluate the biological role and the potential therapeutic benefit of CSF-l-primed MNP in tumor-bearing mice and analyze the mechanisms of action induced by CSF-l. This proposal will enable us to obtain a better understanding of the role of CSF-l in the inflammatory process, how primed and subsequently activated MNP interact with tumor cells and the potential mechanisms by which CSF-l administration is likely to benefit the tumor-bearing host.
Showing the most recent 10 out of 30 publications
