This proposal seeks to define and understand the mechanisms by which progressive tumor growth can alter macronutrient metabolism and contribute to the syndrome of anorexia, weight loss and tissue wasting termed cancer cachexia. In animal tumor models, a central feature of the metabolic alterations associated with cancer is that changes in liver protein metabolism serve to distinguish tumor-associated cachexia from uncomplicated starvation. The mechanisms which bring about specific changes in hepatic protein metabolism in the tumor-bearing state in humans are unknown. However, it has been proposed that endogenous cytokines elaborated as a part of the host immunologic response to malignancy also contribute to the metabolic abnormalities of cachexia. Evidence exists in rodent tumor models that the cytokines interleukin-6 and tumor necrosis factor may be responsible in large part for a variety of abnormalities in protein, lipid and carbohydrate metabolism in host tissues. While there is growing evidence for a physiologic role for IL-6 and TNF in patients with a variety of disease states (e.g. arthritis, meningitis, burns, gram negative sepsis), there is no direct evidence linking these or other cytokines with changes in host metabolism in humans with cancer.
The aim of the present proposal is to define abnormalities in hepatic protein, carbohydrate and lipid metabolism in homogeneous cohorts of patients with metastatic colorectal cancer, and to correlate these changes with the tissue-specific expression of metabolically important cytokines known to be capable of regulating hepatic metabolism in animals. The long- term goal is to establish a rational basis for therapeutic intervention in patients with cancer cachexia.
The specific aims of this proposal are as follows: 1. To characterize alterations in hepatic protein synthesis, hepatic amino acid uptake, gluconeogenesis and lipogenesis in patients with localized or metastatic colorectal carcinoma, compared to non-tumor bearing controls, using stable isotope methodologies. 2. To determine whether gene expression of cytokines known to be capable of modulating hepatocyte acute phase protein production in culture (IL-6, TNFalpha) is enhanced in vivo in tumor bearing humans. 3. To determine whether exogenous administration of rhIL-6 to humans can, reproduce the hepatic protein, carbohydrate and lipid changes characteristic of the tumor bearing state, and to compare the effects of rhIL-6 with the effects of exogenous rhTNF in humans.
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