Abstract Recent progress in understanding the role of the tumor microenvironment in cancer progression was the subject of the 2nd International Tumor Metabolism Summit entitled “Exploiting the Tumor Microenvironment for Therapeutics,” a meeting held at Palazzo Ducale in Genoa, Italy, October 7 to 8, 2005. One of the major conceptual advances in oncology over the last decade has been the appreciation that all major aspects of cancer biology are influenced by the tumor microenvironment. Two important means by which cancer cells adapt to their microenvironment are by reprogramming cellular glucose/energy metabolism to use pathways that generate ATP in the absence of O2 and by stimulating angiogenesis to increase O2 delivery. These responses are principally mediated at the transcriptional level by hypoxia-inducible factor-1. This meeting emphasized the complexity of the tumor microenvironment and opportunities for therapeutic intervention by targeting transcriptional and metabolic pathways that are activated during cancer progression. A better understanding of the crosstalk between signaling pathways and metabolic alterations that contribute to the cancer phenotype may provide insights leading to the development of novel therapeutic strategies. (Cancer Res 2006; 66(9): 4558-60)
Abstract The molecular pathophysiology of carcinogenesis is based to a great ex tent on somatic mutation. Through a process of clonal selection, tumor cells accumulate mutations that increase their ability to proliferate. These mutations are of two general types: (1) activating mutations in growth promoting genes known as oncogenes and (2) inactivating mutations in growth-restricting genes known as tumor suppressor genes. The vast majority of these mutations occur within the tumor cells only, either spontaneously or in response to an environmental mutagen. In the case of the tumor suppressor genes, however, rare germline loss-of-function mutations can result in a hereditary predisposition to cancer, as de scribed for the WTl gene in the WAGR syndrome (see Chapter 6). In these cases, the affected individual is heterozygous for an inactivating mutation in all cells of the body. When a somatic mutation occurs on the second allele within a target cell, both alleles have been inactivated and the process of oncogenesis is initiated, in accordance with the “two hit” model originally proposed by Knudson (1971; Knudson et al., 1975). For these affected individuals, the risk of developing a cancer (such as Wilms tumor in patients heterozygous for deletion of WTl) is greatly increased, approaching 100% in some cases. In addition to an extremely high incidence of tumorigenesis, the tumors appear at an earlier age, are bilateral in paired organs, and multifocal.
Hypoxia-inducible factor 1 (HIF-1) is a basic helix-loop-helix-PAS domain transcription factor that is expressed in all metazoan organisms and is composed of HIF-1α and HIF-1β subunits. Under hypoxic conditions, HIF-1 regulates the transcription of hundreds of genes in a cell type–specific manner. The HIF-1α subunit is regulated by O 2 -dependent hydroxylation of proline residue 402, 564, or both, by prolyl hydroxylase domain protein 2 (PHD2), which promotes binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation; and O 2 -dependent hydroxylation of asparagine residue 803 by factor inhibiting HIF-1 (FIH-1), which blocks the binding of the 300-kilodalton coactivator protein (p300) and CREB binding protein (CBP). The hydroxylation reactions, which utilize O 2 and α-ketoglutarate as substrates and generate CO 2 and succinate as by-products, provide a mechanism by which changes in cellular oxygenation are transduced to the nucleus as changes in HIF-1 activity. Hydroxylase activity is inhibited in the presence of low concentrations of O 2 , high concentrations of tricarboxylic acid cycle intermediates (isocitrate, oxaloacetate, succinate, or fumarate), or chelators of Fe(II). Receptor for activated C kinase 1 (RACK1) competes with heat shock protein 90 (HSP90) for binding to HIF-1α and mediates O 2 -independent ubiquitination and proteasomal degradation. A growing number of proteins and small molecules have been identified that regulate HIF-1 activity by modulating the physical or functional interaction of PHD2, VHL, FIH-1, RACK1, or HSP90 with HIF-1α.
