Elevated Glycine Metabolism in Cancer
Although the key alterations in cellular metabolism that occur in cancer cells are beginning to be better understood, much remains unknown regarding precisely how transformed cells consume and utilize different metabolites. Jain and colleagues used a high-throughput mass spectrometry approach to measure the consumption and release profiles of 219 metabolites from 60 cancer cell lines in an effort to systematically characterize which metabolic pathways are active among various cancer types. Surprisingly, the authors identified the nonessential amino acid glycine as preferentially consumed by rapidly proliferating cancer cell lines. To accompany the metabolic profiling data and to uncover a molecular basis for the altered metabolic profiles of cancer cells, they measured the gene expression of 1,425 metabolic enzymes by microarray analysis in each of the 60 cancer cell lines. Consistent with metabolic profiling results, expression of enzymes involved in mitochondrial glycine synthesis was elevated in rapidly proliferating cancer cell lines. The authors also tested in these cells the functional consequences of exogenous glycine deprivation in media and knockdown of SHMT2, a key biosynthetic enzyme in the mitochondrial glycine biosynthesis pathway. Both approaches showed that decreased glycine availability led to slower proliferation and increased time in the G1 phase of the cell cycle. Tracing experiments using radiolabeled glycine mechanistically revealed that rapidly proliferating cancer cells utilized glycine as a carbon donor for nucleotide biosynthesis in a mode independent of the glycine cleavage system. Interestingly, high expression of the mitochondrial glycine synthesis enzymes was associated with greater mortality in several independent data sets of patients with early-stage breast cancer who were followed for survival. Taken together, these data highlight an important role for glycine metabolism in cancer and identify novel therapeutic targets for highly proliferative cancers.
Crazy Cancer Stem Cells
Drugs that block cancer stem cells, in principle, may block the engine that drives tumor growth and relapse. To identify such drugs, Sachlos and colleagues analyzed loss of pluripotency in teratomas derived from human pluripotent stem cells (hPSC) and showed that pluripotency was correlated with expression of OCT4 and SOX2. They then developed a GFP-based screen, enabling the screening of small-molecule inhibitors that led to decreased expression of these markers (as surrogates for driving differentiation) in normal and neoplastic hPSCs. Screening of 600 annotated clinical compounds led to identification of thioridazine and mefloquine, with thioridazine the more potent compound upon secondary screening and both compounds showing a therapeutic index in acute myelogenous leukemia (AML) versus normal hematopoietic stem cells. Thioridazine is known to antagonize dopamine receptors. Examination of normal blood cells showed dopamine receptors only on AML cells and on some normal monocytes and granulocytes, and not on erythroid, megakaryocytic, or lymphoid cells. Triple-negative breast cancer stem cells showed elevated levels of dopamine receptors and very low-level expression in normal breast tissues. Treatment of AML cells with thioridazine and other dopamine receptor antagonists led to reduced numbers of AML cells in vitro, cooperated with AraC in vitro, and blocked engraftment of human AML cells but not normal human hematopoietic stem cells in xenograft experiments. These data suggest dopamine receptors as functional targets driving cancer stem cells in breast and hematopoietic malignancies and suggest that antipsychotic drugs may be useful as differentiation agents against cancer stem cells.
Clinically Relevant Molecular Subtypes of Urothelial Cancer
Urothelial cancer, comprising predominantly bladder cancer, is among the most common cancer types in men. Current pathologic classification schemes are imprecise with respect to prediction, as up to 25% of patients with low-stage, non–muscle-invasive tumors eventually develop invasive tumors and/or metastasis. Accordingly, a need exists for biologically based markers to complement pathologic classification as a means to improve prediction of tumor behavior. To address this need, the authors examined 308 tumors using expression profiling. Unsupervised clustering analyses initially revealed 7 subclasses. These subclasses were then examined for gene ontologies and mutational status of key genes (FGFR3, PIK3CA, and TP53) and condensed into 5 groups, termed urobasal A, genomically unstable, urobasal B, squamous cell carcinoma–like, and an infiltrated (by nonneoplastic tissue) class. Keratin family members, cell-cycle genes, EGFR, and ERBB2 were differentially expressed among the subtypes, with differences validated on the protein level by immunohistochemistry. The authors showed that molecular subtypes of tumors were relatively independent of tumor grade and stage. Molecular subtype was correlated with patient outcome, with the urobasal B and squamous cell carcinoma–like subtypes exhibiting the worst prognosis. Examination of potential drug targets identified subtype-specific targets that could inform the design of future clinical trials. Taken together, these results provide a framework for a biologically based classification system of urothelial cancer with the potential to improve outcome prediction for patients with these tumors.
Does Parkin Function as a Tumor Suppressor in Glioma?
The PARKIN gene, located within a known chromosomal fragile site (FRA6E), encodes a ubiquitin ligase. This gene is a primary determinant of Parkinson disease, where it is frequently mutated. PARKIN also appears to play a tumor-suppressive role in various human malignancies. Yeo and colleagues report a significant reduction of Parkin expression in glioma cells, overexpression of which reduces tumor growth of U87 cells in vitro and in vivo. The decrease in tumor growth was accompanied with decreased expression of cyclin D1, Akt, and VEGF receptor 2 (VEGFR2). In contrast, Parkin-null fibroblasts, derived from Parkin-null mice, exhibited increased proliferation accompanied with enhanced expression of cyclin D1, Akt and VEGFR2, authenticating the cause-and-effect relationship of these molecules in regulating tumor growth. Moreover, the Parkin gene signature (i.e., elevated levels of AKT 1, AKT 2, and KDR) was correlated with improved outcome of patients with gliomas. In these contexts, PARKIN appears to be a potential tumor suppressor targeting key tumors, correlating with decreased expression of molecules such as Akt, cyclin D1, and VEGFR2. Delineation of the role of PARKIN in glioma and other cancers could be useful for developing novel disease detection and monitoring strategies. This gene might also provide an appropriate target for novel therapeutic approaches to treat patients with gliomas.
Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.
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