Biological stoichiometry in human cancer

Abstract

Background: A growing tumor in the body can be considered a complex ecological and evolutionary system. A new eco-evolutionary hypothesis (the "Growth Rate Hypothesis", GRH) proposes that tumors have elevated phosphorus (P) demands due to increased allocation to P-rich nucleic acids, especially ribosomal RNA, to meet the protein synthesis demands of accelerated proliferation.

Methodology/principal findings: We determined the elemental (C, N, P) and nucleic acid contents of paired malignant and normal tissues from colon, lung, liver, or kidney for 121 patients. Consistent with the GRH, lung and colon tumors were significantly higher (by approximately two-fold) in P content (fraction of dry weight) and RNA content and lower in nitrogen (N):P ratio than paired normal tissue, and P in RNA contributed a significantly larger fraction of total biomass P in malignant relative to normal tissues. Furthermore, patient-specific differences for %P between malignant and normal tissues were positively correlated with such differences for %RNA, both for the overall data and within three of the four organ sites. However, significant differences in %P and %RNA between malignant and normal tissues were not seen in liver and kidney and, overall, RNA contributed only approximately 11% of total tissue P content.

Conclusions/significance: Data for lung and colon tumors provide support for the GRH in human cancer. The two-fold amplification of P content in colon and lung tumors may set the stage for potential P-limitation of their proliferation, as such differences often do for rapidly growing biota in ecosystems. However, data for kidney and liver do not support the GRH. To account for these conflicting observations, we suggest that local environments in some organs select for neoplastic cells bearing mutations increasing cell division rate ("r-selected," as in colon and lung) while conditions elsewhere may select for reduced mortality rate ("K-selected," as in liver and kidney).

Figure 1. Absolute and relative values for elemental composition in normal and malignant tissues of liver, kidney, colon, and lung.

A. and B. P content. C. and D. N content. The number of observations contributing to each mean is given by the number associated with each bar or point. Data in the right hand panels are expressed as the mean of the patient-specific ratios of malignant relative to normal tissue values (m/n ratio) for each parameter. The horizontal line shows an m/n ratio of one, indicating no difference between malignant and normal tissues. Error bars indicate±one standard error. Asterisks next to each symbol in the right hand panels indicate the results of the organ-specific t-test examining whether the m/n ratio differs from one for that organ (*** = p<0.0001; ** = 0.0001<p<0.001; * = 0.001<p<0.05; no asterisk = non-significant).

Figure 2. Absolute and relative (malignant/normal) values for N:P ratio and percentage of P in RNA for normal and malignant tissues of liver, kidney, colon, and lung.

A. Absolute values and B. relative values for N:P ratio. C. Absolute values and D. relative values for %P in RNA. Data are expressed as in Figure 1.

Figure 3. Absolute and relative (malignant/normal) values of biochemical parameters in normal and malignant tissues of liver, kidney, colon, and lung.

A. and B. RNA content. C. and D. DNA content. Data are expressed as in Figure 1.

Figure 4. Scatter plots of patient-specific data for paired observations of P content (% of dry mass) for malignant (y-axis) and normal (x-axis) tissues in the four organs studied.

The dotted line indicates the 1:1 relationship. A data point lying above the line indicates that P content is elevated in malignant tissues, relative to normal, in that patient.

Figure 5. Scatter plots of patient-specific data for paired observations of RNA content (% of dry mass) for malignant (y-axis) and normal (x-axis) tissues in the four organs studied.

The dotted line indicates the 1:1 relationship. A data point lying above the line indicates that RNA content is elevated in malignant tissues, relative to normal, in that patient.