The goals of the proposed study will be to further purify and characterize a unique tumor-derived lipolysis promoting factor (LPF) and to define its role in the aberrations of lipid metabolism associated with cancer. The release of LPF into the extracellular environment by certain tumors was recently identified by our group, utilizing various established tumor lines, including the rat PA II prostate adenocarcinoma and human A375 melanoma. Although lipolytic components released by normal host cells have been implicated as a causative agent in cancer cachexia, this tumor-derived factor appears to be distinct from other previously described moieties. The in vitro lipolysis activity has been demonstrated to correlate with the ability of these tumors to induce in vivo lipid mobilization (in nude mice). The objectives of this study will include the purification of LPF from the conditioned media of PA II and A375 tumor cells by a series of chromatography steps. The mechanism(s) of LPF induction of lipolysis will be assessed, in terms of its binding and effect of lipase activation or expression, as well as the interaction of purified LPF with normal regulatory pathways of adipocytes. LPF will also be utilized to produce monoclonal (anti-PA II-LPF) or polyclonal (anti-A375-LPF) antibodies. These antibodies will be used to assay the presence of LPF in an animal model and cancer patients and to correlate LPF levels with manifestations of aberrant lipid metabolism. Using the PA-II animal model, the ability of monoclonal anti-LPF antibodies to neutralize LPF activity in vivo and in vitro will be examined, as well as the potential of retinoids to prevent LPF release or action of LPF on normal host cells. The immediate significance of this project is that the appearance of circulating lipolytic activity may represent an early diagnostic marker of certain tumors and that, since aberrations in lipid metabolism tends to be associated with a later indicator. The long range goal of this project is that prevention of the consequences of the tumor-derived lipolysis promoting factor, either by blocking its synthesis, release, or action on host lipid metabolism should reduce the weight loss and physical decline associated with these tumors, ultimately resulting in enhanced host survival by increasing their tolerance of and response to therapy.
| Gercel-Taylor, C; Doering, D L; Kraemer, F B et al. (1996) Aberrations in normal systemic lipid metabolism in ovarian cancer patients. Gynecol Oncol 60:35-41 |
| Taylor, D D; Gercel-Taylor, C; Jenis, L G et al. (1992) Identification of a human tumor-derived lipolysis-promoting factor. Cancer Res 52:829-34 |
