| It has been well established for over 70 years that malignant, invasive tumors preferentially use the glycolytic metabolic pathway for energy production (Warburg, 1930). This is but one consequence of a generally established regression of tumor cells to a primitive phenotype. In a sense, cells belonging to the transformed population, characterized by unchecked growth and the ability to invade surrounding normal tissue, have regressed to an earlier point in their evolutionary development. This regression is characterized not only by this non-oxidative metabolism, but also by a loss of intercellular communication and regulation that, in the case of normal cells, facilitate their cooperation in the community of a well functioning organ.; An often misunderstood feature of tumor growth, at least at the early stage, is that tumors grow at the expense of the surrounding normal tissue; the more familiar displacement by pressure of the expanding tumor on the surrounding normal tissue only occurring at the latest stage of development. It has been proposed that this altered tumor metabolism facilitates this growth (Gatenby, 1995) by establishing a microenvironment at the tumor-host interface that favors tumor cells at the expense of the adjacent normal cells due to a lowered extracellular pH. Based simply on this altered metabolism and its resulting acidic microenvironment, many features of tumor morphology and growth dynamics have been recapitulated by mathematical models (Gatenby and Gawlinski, 1996) and computer simulations (Patel, et al., 2001) of a cellular automaton.; It has been often observed that carcinomas (malignant tumors of epithelial tissue) arise as a consequence of a series of transformations beginning with hyperplasia (an excess growth of normal), followed by the development of an adenoma (a transformed, yet benign type of tumor), and ending with frankly malignant invasive carcinoma (Vogelstein, et al., 1989).; Most adenomas develop in the epithelial lining of the lumen of a duct functioning in a particular organ (digestive tract, hepatic duct, nephron, etc.). An evolutionary model of carcinogenesis in this setting has been proposed (Smallbone, 2006) to explain the adenoma-carcinoma transformation as a result of population genetics. In this model cells in the adenoma compete for glucose and oxygen substrates. However the adenoma, situated within the lumen, is distal from the vascular bed below the epithelial lining and is thus hypoxic. This hypoxia favors mutations which result in cells expressing the glycolytic phenotype, glycolysis being a metabolism not requiring oxygen.; In thesis we present a computer simulation of a hybrid cellular automaton model of this hypoxia induced adenoma-carcinoma transition in the realistic setting of a ductal lumen. Many features of the adenoma-carcinoma sequence and the resulting tumor growth and invasion are successfully reproduced in the results. |
