Tuning in Tumor Metabolism: The Cost of Being a Cancer Cell

Abstract

The genetic origin of cancers has been now accepted as a central principle of oncogenesis and the continued discovery of oncogenes and tumor suppressor genes is expanding the labyrinths of complexity in cancer biology [1][2][3]. Molecular pathway analyses of the critical oncogenes and their aberrant genetic modificationshave given a wealth of information on the deregulation of these pathways in cancer and how this knowledge can be exploited for designing drugs for cancer treatment. It is still not clear how these individual pathways interact between each other to yield a global cancer geno/phenotype. Common wisdom in the field dictates that it is not prudent to focus only on a few gene targets or a few molecular pathways to obtain a comprehensive understanding of cancer. This realization has led to the advent of large scale, systems approach to cancer such as genomewide association study (GWAS) without providing useful clues on the underlying molecular mechanisms. Despite all these advancements, a comprehensive understanding of cancer(s) is still a dream. Genetic heterogeneity that is commonly observed in human cancers is a robust example of why gene target-based drugs never attain 100% efficacy even within a cohort of patients with apparently similar tumor type. The problem at hand is therefore not of finding more "new" gene targets but of finding the missing piece in integrating our current repertoire of cancer-specific molecular pathways. We hypothesize that focusing on tumor metabolism could potentially rope-in diverse tumor genetics pathways thereby providing a common metabolic denominator for understanding deregulation of energy metabolism in cancer. Energy Metabolism in a Cancer CellDespite the tremendous progress for the past few decades (discovery of oncogenes, tumor suppressors, cancer signaling pathways), cancer related mortality and morbidity are still high as we are uncovering the labyrinths of complexity of cancer cell transformation. An intriguing puzzle is how tumor genetics and tumor metabolism collectively determine the cancer phenotype and the clinical manifestations. A number of alterations in cellular metabolism accompany cancer cell transformation [4][5][6][7]. These could range from altered glucose metabolism to coordinated changes in cell cycle deregulation and multiple facets of energy metabolism. Mutations in oncogenes and/or tumor suppressor genes and other carcinogenic events could transform a normal cell to a cancer cell. The question is : "What does it take to sustain and to propagate this cancer cell in the host environment ?". From a single cell perspective, mitochondria are the major bioenergetic organelles in eukaryotic cells that perform two critical functions namely, the ATP production and the programmed cell death (apoptosis). A sensitive balance between these "life" and "death" functions of the mitochondria is vital to cellular survival and eventually, to the physiological health. Mitochondrial DNA mutations have been implicated in organismal aging, neurological disorders su...