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      Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukemia

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          Abstract

          Tissue stromal cells interact with leukemia cells and profoundly affect their viability and drug sensitivity. Here we show a biochemical mechanism by which bone marrow stromal cells modulate the redox status of chronic lymphocytic leukemia (CLL) cells and promote cellular survival and drug resistance. Primary CLL cells from patients exhibit limited ability to transport cystine for glutathione (GSH) synthesis due to a low expression of Xc- transporter, while bone marrow stromal cells effectively import cystine and convert it to cysteine, which is then released into the microenvironment for uptake by CLL cells to promote GSH synthesis. The elevated GSH enhances leukemia cell survival and protects them from drug-induced cytotoxicity. Furthermore, disabling this protective mechanism significantly sensitizes CLL cells to drug treatment in stromal environment. This stromal-leukemia interaction is critical for CLL cell survival and represents a key biochemical pathway for effectively targeting leukemia cells to overcome drug resistance in vivo.

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          Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.

          Arun Sreekumar, Laila Poisson, Thekkelnaycke M Rajendiran … (2009)
          Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human tumours, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer and metastatic disease. Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly increased during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells. Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Here, by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity.
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            Analysis of the adult human plasma metabolome.

            Matthew W. Mitchell, Benjamin Evans, Michael V. Milburn … (2008)
            It is well established that disease states are associated with biochemical changes (e.g., diabetes/glucose, cardiovascular disease/cholesterol), as are responses to chemical agents (e.g., medications, toxins, xenobiotics). Recently, nontargeted methods have been used to identify the small molecules (metabolites) in a biological sample to uncover many of the biochemical changes associated with a disease state or chemical response. Given that these experimental results may be influenced by the composition of the cohort, in the present study we assessed the effects of age, sex and race on the relative concentrations of small molecules (metabolites) in the blood of healthy adults. Using gas- and liquid-chromatography in combination with mass spectrometry, a nontargeted metabolomic analysis was performed on plasma collected from an age- and sex-balanced cohort of 269 individuals. Of the more than 300 unique compounds that were detected, significant changes in the relative concentration of more than 100 metabolites were associated with age. Many fewer differences were associated with sex and fewer still with race. Changes in protein, energy and lipid metabolism, as well as oxidative stress, were observed with increasing age. Tricarboxylic acid intermediates, creatine, essential and nonessential amino acids, urea, ornithine, polyamines and oxidative stress markers (e.g., oxoproline, hippurate) increased with age. Compounds related to lipid metabolism, including fatty acids, carnitine, beta-hydroxybutyrate and cholesterol, were lower in the blood of younger individuals. By contrast, relative concentrations of dehydroepiandrosterone-sulfate (a proposed antiaging androgen) were lowest in the oldest age group. Certain xenobiotics (e.g., caffeine) were higher in older subjects, possibly reflecting decreases in hepatic cytochrome P450 activity. Our nontargeted analytical approach detected a large number of metabolites, including those that were found to be statistically altered with age, sex or race. Age-associated changes were more pronounced than those related to differences in sex or race in the population group we studied. Age, sex and race can be confounding factors when comparing different groups in clinical studies. Future studies to determine the influence of diet, lifestyle and medication are also warranted.
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              Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1.

              A. M. Dell'Aquila, T J Kipps, Andreas Burger … (2000)
              A subset of blood cells from patients with B-cell chronic lymphocytic leukemia (CLL) spontaneously differentiates in vitro into large, round, or fibroblast-like adherent cells that display stromal cell markers, namely vimentin and STRO-1. These cells also express stromal cell-derived factor-1 (SDF-1), a CXC chemokine that ordinarily is secreted by marrow stromal cells. Leukemia B cells attach to these blood-derived adherent cells, down-modulate their receptors for SDF-1 (CXCR4), and are protected from undergoing spontaneous apoptosis in vitro. Neutralizing antibodies to SDF-1 inhibit this effect. Moreover, the rapid deterioration in the survival of CLL B cells, when separated from such cells, is mitigated by exogenous SDF-1. This chemokine also results in the rapid down-modulation of CXCR4 and activation of p44/42 mitogen-activated protein-kinase (ERK 1/2) by CLL B cells in vitro. It is concluded that the blood of patients with CLL contains cells that can differentiate into adherent nurse-like cells that protect leukemia cells from undergoing spontaneous apoptosis through an SDF-1-dependent mechanism. In addition to its recently recognized role in CLL B-cell migration, SDF-1-mediated CLL B-cell activation has to be considered a new mechanism involved in the microenvironmental regulation of CLL B-cell survival. (Blood. 2000;96:2655-2663)
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 100890575
                Journal ID (pubmed-jr-id): 21417
                Journal ID (nlm-ta): Nat Cell Biol
                Journal ID (iso-abbrev): Nat. Cell Biol.
                Title: Nature cell biology
                ISSN (Print): 1465-7392
                ISSN (Electronic): 1476-4679
                Publication date Nihms-submitted: 12 January 2012
                Publication date (Electronic): 19 February 2012
                Publication date PMC-release: 01 September 2012
                Volume: 14
                Issue: 3
                Pages: 276-286
                Affiliations
                [1 ]Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77054, USA
                [2 ]The First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Nanchang, Jiangxi, 330006, China
                [3 ]Faculty of Dentistry, Thammasat University, Pathum-thani 12121, Thailand
                [4 ]The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA
                [5 ]Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA
                [6 ]Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Medical Center, Columbus, OH 43210, USA
                [7 ]Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA
                Author notes
                [8 ]Correspondence should be addressed to: Peng Huang, Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Unit 951, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-834-6044; Fax: 713-834-6084; phuang@ 123456mdanderson.org
                Article
                Manuscript ID: NIHMS349014
                DOI: 10.1038/ncb2432
                PMC ID: 3290742
                PubMed ID: 22344033
                SO-VID: e90d3c1d-08f9-4412-8b02-8a8ad3233f5f
                License:

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA100428-09 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA085563-09 || CA
                Categories
                Subject: Article

                ScienceOpen disciplines: Cell biology
                Keywords: microenvironment,leukemia,stromal cells,glutathione,drug resistance
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: microenvironment, leukemia, stromal cells, glutathione, drug resistance

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