What Applied Physical Chemistry Can Contribute to Understanding Cancer: Toward the Next Generation of Breakthroughs

Living systems, whether healthy or diseased, must obey the laws of chemistry. The purpose of this review is to identify the interpretive limits of cellular biochemistry using, largely, the tools of physical chemistry. We illustrate this approach using two major concepts in cancer: carcinogenicity and cancer recurrences. Cells optimize the chemical performance of enzymes and pathways during cancer recurrences. Biology has been primarily concerned with the analysis of high affinity interactions, such as ligand–receptor interactions. Collective weak interactions (such as van der Waals forces) are also important in determining biosystem behaviors, although they are infrequently considered in biology. For example, activity coefficients determine the effective concentrations of biomolecules. The in vivo performance of enzymes also depends upon intracellular conditions such as high protein concentrations and multiple regulatory factors. Phase separations within membranes (two dimensions) and nucleoli (three dimensions) are a fundamental regulatory factor within cells, as phase separations can alter reactant concentrations, local dielectric constants, and other factors. Enzyme agglomeration also affects the performance of biochemical pathways. Although there are many examples of these phenomena, we focus on the key steps of cancer: carcinogenicity and the biochemical mechanism of cancer recurrences. We conjecture that oxidative damage to histones contributes to carcinogenicity, which is followed by nucleolar phase separations and subsequent DNA damage that, in turn, contributes to the redistribution of enzymes mediating metabolic changes in recurrent breast cancer.