Systemic Metabolism, Its Regulators, and Cancer: Past Mistakes and Future Potential

Abstract

There has been a resurgence of interest in cancer metabolism; primarily in the resetting of metabolism within malignant cells. Metabolism within cells has always been a tightly regulated process; initially in protozoans due to metabolic enzymes, and the intracellular signaling pathways that regulate these, being directly sensitive to the availability of nutrients. With the evolution of metazoans many of these controls had been overlaid by extra-cellular regulators that ensured coordinated regulation of metabolism within the community of cells that comprised the organism. Central to these systemic regulators is the insulin/insulin-like growth factor (IGF) system that throughout evolution has integrated the control of tissue growth with metabolic status. Oncological interest in the main systemic metabolic regulators greatly subsided when pharmaceutical strategies designed to treat cancers failed in the clinic. During the same period, however the explosion of new information from genetics has revealed the complexity and heterogeneity of advanced cancers and helped explain the problems of managing cancer when it reaches such a stage. Evidence has also accumulated implying that the setting of the internal environment determines whether cancers progress to advanced disease and metabolic status is clearly an important component of this local ecology. We are in the midst of an epidemic of metabolic disorders and there is considerable research into strategies for controlling metabolism. Integrating these new streams of information suggests new possibilities for cancer prevention; both primary and secondary.

Keywords: cancer; diabetes; lifestyle; metabolism; obesity; post-genomic; prevention.

Figure 1

Overview of the IGF system. In the body the IGFs are constantly present at very high levels due to their binding to the IGFBPs, with IGF-II levels 3 to 4-fold higher than IGF-I. Following meals insulin is secreted from the pancreas but is the rapidly cleared, resulting in episodic transient exposure to the tissues. At the cellular level these ligands interact with a family of signaling tyrosine kinase receptors: the IGF-IR and the insulin receptor, which exists in two alternatively spliced isoforms. The IRB predominantly only binds insulin whereas the IRA also binds IGF-II, which due to its abundance is the most likely ligand. These receptors initiate intracellular signaling, principally the PI3K/Akt and Ras/Raf/MAP kinase pathways, that set in train processes that culminate in increased cell proliferation, survival and metabolism. In addition to maintaining levels of IGFs and restricting their interaction with cell surface receptors; the IGFBPs also have independent actions. Via interaction with integrin receptors IGFBP-2 suppresses PTEN, the phosphatase that counteracts the activity of PI3K and therefore IGFBP-2 can release the brake on IGF signaling. In addition to IGFBPs controlling the availability of IGFs there is also a cell surface IGF-IIR that limits the availability of IGF-II by targeting it for lysosomal degradation.

Figure 2

With aging the epithelial cells that have continuously divided throughout life naturally accummulate large numbers of mutations and some of these result in small occult neoplastic lesions, the “seeds.” In normal individuals such lesions develop slowly and rarely progress to clinical cancer. In obese individuals the internal milieu, or “soil,” is characterized by high levels of glucose, insulin, IGFs, inflammatory cytokines and adipokines and this environment increases the risk that latent neoplastic lesions progress more rapidly and develop into clinical cancers.