This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yuan, J. Articles by Glazer, P. M. Search for Related Content PubMed PubMed Citation Articles by Yuan, J. Articles by Glazer, P. M.

Diminished DNA Repair and Elevated Mutagenesis in Mammalian Cells Exposed to Hypoxia and Low pH¹

Departments of Therapeutic Radiology, Genetics, and Molecular, Cellular, and Developmental Biology, Yale University School of Medicine, New Haven, Connecticut 06520-8040

The tumor microenvironment is characterized by regions of fluctuating and chronic hypoxia, low pH, and nutrient deprivation. It has been proposed that this unique tissue environment itself may constitute a major cause of the genetic instability seen in cancer. To investigate possible mechanisms by which the tumor microenvironment might contribute to genetic instability, we asked whether the conditions found in solid tumors could influence cellular repair of DNA damage. Using an assay for repair based on host cell reactivation of UV-damaged plasmid DNA, cells exposed to hypoxia and low pH were found to have a diminished capacity for DNA repair compared with control cells grown under standard culture conditions. In addition, cells cultured under hypoxia at pH 6.5 immediately after UV irradiation had elevated levels of induced mutagenesis compared with those maintained in standard growth conditions. Taken together, the results suggest that cellular repair functions may be impaired under the conditions of the tumor microenvironment, causing hypermutability to DNA damage. This alteration in repair capacity may constitute an important mechanism underlying the genetic instability of cancer cells in vivo.

This article has been cited by other articles:

				A. M. Niemela, P. Hynninen, J.-P. Mecklin, T. Kuopio, A. Kokko, L. Aaltonen, A.-K. Parkkila, S. Pastorekova, J. Pastorek, A. Waheed, et al. Carbonic Anhydrase IX Is Highly Expressed in Hereditary Nonpolyposis Colorectal Cancer Cancer Epidemiol. Biomarkers Prev., September 1, 2007; 16(9): 1760 - 1766. [Abstract] [Full Text] [PDF]

				Y. Shimoyama, Y. Akihara, D. Kirat, H. Iwano, K. Hirayama, Y. Kagawa, T. Ohmachi, K. Matsuda, M. Okamoto, T. Kadosawa, et al. Expression of Monocarboxylate Transporter 1 in Oral and Ocular Canine Melanocytic Tumors Vet. Pathol., July 1, 2007; 44(4): 449 - 457. [Abstract] [Full Text] [PDF]

				R. S. Bindra, S. L. Gibson, A. Meng, U. Westermark, M. Jasin, A. J. Pierce, R. G. Bristow, M. K. Classon, and P. M. Glazer Hypoxia-Induced Down-regulation of BRCA1 Expression by E2Fs Cancer Res., December 15, 2005; 65(24): 11597 - 11604. [Abstract] [Full Text] [PDF]

				S. L. Gibson, R. S. Bindra, and P. M. Glazer Hypoxia-Induced Phosphorylation of Chk2 in an Ataxia Telangiectasia Mutated-Dependent Manner Cancer Res., December 1, 2005; 65(23): 10734 - 10741. [Abstract] [Full Text] [PDF]

				S. Shahrzad, L. Quayle, C. Stone, C. Plumb, S. Shirasawa, J. W. Rak, and B. L. Coomber Ischemia-Induced K-ras Mutations in Human Colorectal Cancer Cells: Role of Microenvironmental Regulation of MSH2 Expression Cancer Res., September 15, 2005; 65(18): 8134 - 8141. [Abstract] [Full Text] [PDF]

				A. Mayer, M. Hockel, A. Wree, and P. Vaupel Microregional Expression of Glucose Transporter-1 and Oxygenation Status: Lack of Correlation in Locally Advanced Cervical Cancers Clin. Cancer Res., April 1, 2005; 11(7): 2768 - 2773. [Abstract] [Full Text] [PDF]

				E. Obermueller, S. Vosseler, N. E. Fusenig, and M. M. Mueller Cooperative Autocrine and Paracrine Functions of Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor in the Progression of Skin Carcinoma Cells Cancer Res., November 1, 2004; 64(21): 7801 - 7812. [Abstract] [Full Text] [PDF]

				P. Vaupel The Role of Hypoxia-Induced Factors in Tumor Progression Oncologist, November 1, 2004; 9(suppl_5): 10 - 17. [Abstract] [Full Text] [PDF]

				R. S. Bindra, P. J. Schaffer, A. Meng, J. Woo, K. Maseide, M. E. Roth, P. Lizardi, D. W. Hedley, R. G. Bristow, and P. M. Glazer Down-Regulation of Rad51 and Decreased Homologous Recombination in Hypoxic Cancer Cells Mol. Cell. Biol., October 1, 2004; 24(19): 8504 - 8518. [Abstract] [Full Text] [PDF]

				N. Kokkonen, A. Rivinoja, A. Kauppila, M. Suokas, I. Kellokumpu, and S. Kellokumpu Defective Acidification of Intracellular Organelles Results in Aberrant Secretion of Cathepsin D in Cancer Cells J. Biol. Chem., September 17, 2004; 279(38): 39982 - 39988. [Abstract] [Full Text] [PDF]

				J. Okami, D. M. Simeone, and C. D. Logsdon Silencing of the Hypoxia-Inducible Cell Death Protein BNIP3 in Pancreatic Cancer Cancer Res., August 1, 2004; 64(15): 5338 - 5346. [Abstract] [Full Text] [PDF]

				V. T. Mihaylova, R. S. Bindra, J. Yuan, D. Campisi, L. Narayanan, R. Jensen, F. Giordano, R. S. Johnson, S. Rockwell, and P. M. Glazer Decreased Expression of the DNA Mismatch Repair Gene Mlh1 under Hypoxic Stress in Mammalian Cells Mol. Cell. Biol., May 1, 2003; 23(9): 3265 - 3273. [Abstract] [Full Text] [PDF]

				F. A. Rogers, K. M. Vasquez, M. Egholm, and P. M. Glazer Site-directed recombination via bifunctional PNA-DNA conjugates PNAS, December 24, 2002; 99(26): 16695 - 16700. [Abstract] [Full Text] [PDF]

				L. B. Harrison, M. Chadha, R. J. Hill, K. Hu, and D. Shasha Impact of Tumor Hypoxia and Anemia on Radiation Therapy Outcomes Oncologist, December 1, 2002; 7(6): 492 - 508. [Abstract] [Full Text] [PDF]

				A. Kondo, R. Safaei, M. Mishima, H. Niedner, X. Lin, and S. B. Howell Hypoxia-induced Enrichment and Mutagenesis of Cells That Have Lost DNA Mismatch Repair Cancer Res., October 1, 2001; 61(20): 7603 - 7607. [Abstract] [Full Text] [PDF]

				M. M. Mueller, W. Peter, M. Mappes, A. Huelsen, H. Steinbauer, P. Boukamp, M. Vaccariello, J. Garlick, and N. E. Fusenig Tumor Progression of Skin Carcinoma Cells in Vivo Promoted by Clonal Selection, Mutagenesis, and Autocrine Growth Regulation by Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor Am. J. Pathol., October 1, 2001; 159(4): 1567 - 1579. [Abstract] [Full Text]

				A. Lal, H. Peters, B. St. Croix, Z. A. Haroon, M. W. Dewhirst, R. L. Strausberg, J. H. A. M. Kaanders, A. J. van der Kogel, and G. J. Riggins Transcriptional Response to Hypoxia in Human Tumors J Natl Cancer Inst, September 5, 2001; 93(17): 1337 - 1343. [Abstract] [Full Text] [PDF]

				D. C. Malins, P. M. Johnson, T. M. Wheeler, E. A. Barker, N. L. Polissar, and M. A. Vinson Age-related Radical-induced DNA Damage Is Linked to Prostate Cancer Cancer Res., August 1, 2001; 61(16): 6025 - 6028. [Abstract] [Full Text] [PDF]