Codependency of Metabolism and Epigenetics Drives Cancer Progression: A Review.

Cancer is widely considered to be a set of genetic diseases that are currently classified by tissue and cell type of origin and, increasingly, by its molecular characteristics. This latter aspect is based primarily upon oncogene gains, tumor suppressor losses, and associated transcriptional profiles. However, cancers are also characterized by profound alterations in cellular metabolism and epigenetic landscape. It is particularly noteworthy that cancer-causing genomic defects not only activate cell cycle progression, but regulate the opportunistic uptake and utilization of nutrients, effectively enabling tumors to maximize growth and drug resistance in changing tissue and systemic microenvironments. Shifts in chromatin architecture are central to this dynamic behavior. Further, changes in nutrient uptake and utilization directly affect chromatin structure. In this review, we describe a set of recent discoveries of metabolic and epigenetic reprogramming in cancer, and especially focus on the genomically well-characterized brain tumor, glioblastoma. Further, we discuss a new mode of metabolic regulation driven by epigenetic mechanisms, that enables cancer cells to autonomously activate iron metabolism for their survival. Together, these underscore the integration of genetic mutations with metabolic reprogramming and epigenetic shifts in cancer, suggesting a new means to identifying patient subsets suitable for specific precision therapeutics.

Molecular Subtypes of Primary Glioblastoma Identified by Gene Expression Profiling

BACKGROUND: The over-expression of the epidermal growth factor receptor (EGFR) occurs in nearly 50% of primary glioblastoma multiforme (GBM). Disruption of multiple signaling pathways is a critical factor in regulating the biological and clinical behavior of GBMs. In the future, therapy that specifically targets these disrupted pathways may represent the best potential treatment for patients with GBM. Large scale gene expression profiling provides a powerful approach to identify these disrupted genetic pathways and to uncover previously unknown molecular subtypes. METHODS: We used 13 cases of primary GBM biopsy samples obtained from untreated patients and Affymetrix high-density oligonucleotide arrays to identify novel subsets of primary GBMs. RESULTS: We showed that the expression of 90 genes differentiate EGFR+ from EGFR non-expressing (EGFR-) de novo GBMs, including expression of a number of potentially targetable molecules that act as growth/survival factors for GBMs. We also demonstrated the presence of two additional molecular subtypes of primary GBMs, including one characterized by the coordinate upregulation of contiguous genes on chromosome 12q13-15, which has a distinct global gene expression profile and expresses both astrocytic and oligodendroglial genes. CONCLUSION: We have shown that there are EGFR+ primary GBMs, GBMs with coordinate upregulation of genes on chromosome 12q13-15, and primary GBMs lacking either alteration. Moreover, they have distinct transcriptional profiles. Our findings strongly suggest that the three GBMs are biologically different tumor types, despite their identical microscopic appearance, and provide an important first step in developing a molecular taxonomy of GBMs.