Hypertumors in cancer can be caused by tumor phosphorus demand

Abstract

In cancer, tumoral and peritumoral environmental conditions are controlled mostly by the unusual metabolism of malignant cells. For example, tumors typically demand much more phosphorus (P) than normal tissue does, primarily because tumor cells upregulate ribosome biogenesis. Here I use mathematical models to show that this unusual demand for P can lead to a hypertumor, which is a region of highly aggressive cells growing parasitically on the original tumor that can kill all or part of it. Previous work has suggested that hypertumors may develop when a tumor is invaded by an aggressive cell type that fails to secrete angiogenesis factors. In this talk I introduce an entirely different mechanism of hypertumor development. In this case, the aggressive strain upregulates phosphate transporters, leading to increased growth potential, which allows tumor cells to outpace growing blood vessels.When cancer is viewed as an ecological phenomenon-that is, a population of diverse entities (cells) competing with one another for scarce resources, as opposed to the traditional view of cancer as a derangement of molecular machinery inside cells-one recognizes that ribosomes may play an under-appreciated role in tumor biology. All cells use ribosomes to manufacture proteins. Since proteins are the machines that control essentially all cell activities, all cell processes therefore depend on ribosomes. This fact accounts for why a large fraction of a cell's biomass-up to 15% in eukaryotic cells [1]-is RNA. Ribosomes comprise four RNA (together designated rRNA) and 82 protein components. The necessity and composition of ribosomes in turn produce an important constraint on cell activities because ribosome biogenesis requires significant amounts of phosphorus (P). Compared to ribosomal protein, rRNA is highly P-enriched. For example, Sterner and Elser [1] note that P contributes about 9% of the mass of nucleic acids, compared to 0% for protein. As a result, P accounts for about 5% of a eukaryotic ribosome's mass. No other organelle requires as much P relative to carbon (C) and nitrogen (N), the two other major contributors to organic biomass. These observations led Sterner and Elser [1] to what they call the Growth Rate Hypothesis (GRH), which ". . . states that differences in organismal C:N:P ratios are caused by differential allocations to RNA necessary to meet the protein synthesis demands of rapid rates of biomass growth and development" [1, p144]. Applied to malignant neoplasia, the GRH suggests that aggressively growing cancer cells should be rich in P (relatively low C:P and N:P ratios) because they upregulate ribosome biogenesis [2][3][4][5]. Since cells pick up P from the interstitium primarily in the form of inorganic phosphate, the GRH also predicts that aggressively growing cancer cells should increase production of membrane phosphate transport proteins.To study the GRH's application to cancer in more detail, I modified an existing simple model of vascular tumor growth [6] to include P demand. Let P (t), x(t), y(t) and z(...

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