Browsing by Author "Dr. Marlene Hauck, Committee Member"

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Glucose and Lactate Consumption by the R3230 Mammary Adenocarcinoma.
(2006-07-27) Richardson, Rachel Ann; Dr. Mark W. Dewhirst, Committee Co-Chair; Dr. Donald Thrall, Committee Co-Chair; Dr. Marlene Hauck, Committee Member; Dr. James Raleigh, Committee Member
Tumors need to follow a simple plan to survive and grow. They need to: (1) take up energy substrates, (2) metabolize these substrates to produce ATP, and (3) remove metabolic wastes. The way in which different substrates are used depends on the specific tumor and its microenvironment. The two main factors that influence tumor metabolism are oxygen concentration and altered metabolic pathways/enzymes. Hypoxia, a common condition in tumors, (pO2<10mm Hg) is important for two reasons. Hypoxia influences clinical behavior of tumors, increasing their biologic aggressiveness, while decreasing their response to therapy. Additionally, hypoxia influences energy production in tumors because metabolism of most substrates is oxygen dependent, except glucose. Glucose can be metabolized in the presence (oxidative phosphorylation) or the absence of oxygen (glycolysis). Although hypoxia has a major influence on tumor metabolism, it is not the only factor. Altered metabolic pathways also play a role. Normally, the presence of oxygen inhibits glycolysis. In many tumors the presence of oxygen does not inhibit glycolysis (Warburg effect). Additionally, it has been observed that tumors given excess glucose will preferentially metabolize glucose by glycolysis even in the presence of oxygen and that this process decreases tumor respiration (Crabtree effect). Therefore, it was hypothesized that hyperglycemia treatment could be used to increase tumor pO2. The purpose of the research was to determine why hyperglycemia did not efficiently induce the Crabtree effect in the rat R3230 mammary adenocarcinoma (R3230Ac). Based on previous work done in the laboratory, three hypotheses were proposed: (1) glucose was not proceeding through the first step of glycolysis efficiently, (2) glucose was being utilized by oxidative phosphorylation despite the presence of high glucose concentrations, and (3) lactate was being used as an energy source. Both glucose metabolism and lactate metabolism were investigated in R3230Ac. The experiments investigating glucose consumption indicated the first two hypotheses to be unlikely and hinted that the third hypothesis was correct. The experiments investigating lactate consumption and metabolism of lactate by R3230Ac confirmed the consumption of lactate by this tumor. High lactate levels in human tumors have been shown to be correlated with both increased likelihood of metastases and negative clinical outcome. Increased lactate concentrations in tumors increased the likelihood of metastases in rectal carcinomas, cervical tumors, and head & neck tumors. In cervical and head & neck tumors, high lactate levels were also correlated with negative impacts on disease free survival (DFS) and overall survival (OS). The negative impact of high lactate levels in tumors is usually either contributed to the ability of tumors to rapidly consume glucose via glycolysis or the effects that lactate has on the tumor's microenvironment (e.g. inducing angiogenesis). Another possibility for the negative effect of lactate on clinical outcome has been demonstrated by my thesis, and that is lactate consumption by tumors. It is possible that different subsets of tumor cells, depending on their oxygenation status, either produce or consume lactate. A symbiotic relationship between these different cells may provide an advantage for the tumor. The ability to metabolize lactate needs to be investigated in other tumors to determine if this is a common trait among tumors. Additionally, a method to categorize tumors as lactate producers vs. lactate consumers should be pursued because the ability of tumors to metabolize lactate could have clinical implications and be a new target for cancer therapy.