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Full Text (PDF) Research Article Cancers as Wounds that Do Not Heal: Differences and Similarities between Renal Regeneration/Repair and Renal Cell Carcinoma Joseph Riss,1 Chand Khanna,2 Seongjoon Koo,8 Gadisetti V.R. Chandramouli,1 Howard H. Yang,3 Ying Hu,3 David E. Kleiner,4 Andreas Rosenwald,5 Carl F. Schaefer,3 Shmuel A. Ben-Sasson,11 Liming Yang,9 John Powell,9 David W. Kane,6 Robert A. Star,10 Olga Aprelikova,1 Kristin Bauer,1 James R. Vasselli,7 Jodi K. Maranchie,7 Kurt W. Kohn,6 Ken H. Buetow,3 W. Marston Linehan,7 John N. Weinstein,6 Maxwell P. Lee,3 Richard D. Klausner,1 and J. Carl Barrett1 1Laboratory of Biosystems and Cancer, 2Comparative Oncology Program, 3Laboratory of Population Genetics, 4Laboratory of Pathology, 5Metabolism Branch, 6Genomics & Bioinformatics Group, Laboratory of Molecular Pharmacology, 7Urologic Oncology Branch, Center for Cancer Research, 8Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9Bioinformatics and Molecular Analysis Section, Computational Bioscience and Engineering Laboratory, Center for Information Technology, 10Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland; and 11Hebrew University-Hadassah Medical School, Jerusalem, Israel Abstract microenvironment. A variety of signals orchestrate the response to Cancers have been described as wounds that do not heal, injury that results in regeneration and repair of a wound. Both suggesting that the two share common features. By comparing tissue regeneration and carcinogenesis involve cell proliferation, microarray data from a model of renal regeneration and survival, and migration that are controlled by growth factors and repair (RRR) with reported gene expression in renal cell cytokines as well as inflammatory and angiogenic signals. Signals carcinoma (RCC), we asked whether those two processes do, in that promote cell proliferation, survival, and invasiveness derive fact, share molecular features and regulatory mechanisms. from multiple cellular and extracellular sources in the microenvi- The majority (77%) of the genes expressed in RRR and RCC ronment of wounds and cancer. Therefore, wounds and cancers were concordantly regulated, whereas only 23% were discor- share a number of phenotypic similarities in cellular behavior, dant (i.e., changed in opposite directions). The orchestrated signaling molecules, and gene expression. Haddow first recognized processes of regeneration, involving cell proliferation and the similarities between wound healing and carcinogenesis, immune response, were reflected in the concordant genes. The whereas Dvorak described cancer as wounds that do not heal discordant gene signature revealed processes (e.g., morpho- (1, 2). Understanding the similarities between wounds and cancers genesis and glycolysis) and pathways (e.g., hypoxia-inducible may yield new insights into the malignant phenotype. Under- factor and insulin-like growth factor-I) that reflect the standing the differences which relate to the ‘‘failure to heal’’ may intrinsic pathologic nature of RCC. This is the first study that provide insights into the loss of control in cancer, thereby compares gene expression patterns in RCC and RRR. It does providing the basis for novel diagnostic and therapeutic targets. so, in particular, with relation to the hypothesis that RCC Microarray technology has allowed the characterization and resembles the wound healing processes seen in RRR. However, comparison of global gene expression signatures of regenerating careful attention to the genes that are regulated in the and malignant tissues. A microarray study comparing skin wounds discordant direction provides new insights into the critical and tumors provided molecular evidence that keratinocytes at differences between renal carcinogenesis and wound healing. wound margins have gene expression profiles similar to these of The observations reported here provide a conceptual frame- squamous cell carcinoma (3). Chang et al. studied changes in the work for further efforts to understand the biology and to global gene expression profiles of fibroblasts exposed to serum in vitro develop more effective diagnostic biomarkers and therapeutic and compared those profiles with the publicly available strategies for renal tumors and renal ischemia. (Cancer Res gene expression data for numerous tumors (4, 5). That analysis 2006; 66(14): 7216-24) suggested a similarity between the gene expression profile of fibroblasts, a cell type associated with the wound healing process, Introduction and that of the cancer. Furthermore, the serum response signature was predictive for survival of breast cancer patients. Our present Tissue regeneration and tumorigenesis are complex, adaptive study extends those observations to renal regeneration and renal processes controlled by cues from the host and from the tissue carcinoma, and also for the first time examines comprehensively the differences between the two gene expression profiles as well as the similarities. Note: Supplementary data for this article are available at the authors’ web site: The kidney is a member of a restricted class of organs capable of http://home.ccr.cancer.gov/who/rissj/cdc/ and http://discover.nci.nih.gov/host/ 2006_cancers_abstract.jsp. regeneration and repair following damage events such as ischemic Current address for J.C. Barrett: Novartis Institutes for BioMedical Research, injury, a major cause of acute renal failure in both native (6) and Cambridge, MA 02139. transplanted organs (7). Clinically and biologically, ischemic acute Requests for reprints: Joseph Riss, Wound Healing and Oncogenesis, Laboratory of Biosystems and Cancer, Center for Cancer Research, National Cancer Institute, NIH, renal failure is a complex but orderly continuum that, for Building 37/Room 5032, 37 Convent MSC 4264, Bethesda, MD 20892. Phone: 301-402- simplification, can be separated into a series of four overlapping 7203; Fax: 301-480-2772; E-mail: [email protected]. I2006 American Association for Cancer Research. phases referred to as ‘‘initiation’’ (renal blood flow and cellular ATP doi:10.1158/0008-5472.CAN-06-0040 decrease), ‘‘extension’’ (a prolonged hypoxia and continued Cancer Res 2006; 66: (14). July 15, 2006 7216 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2006 American Association for Cancer Research. Cancers as Wounds that Do Not Heal production and release of inflammatory chemokines and cytokines processed, and frozen in an identical manner. For histologic studies, the after acute ischemia ceases), ‘‘maintenance,’’ (some cells undergo kidneys were bivalved in the coronal plane and fixed in formalin (10%). apoptosis whereas others proliferate, acquire the ability to migrate, Immunohistochemistry. Fixed and paraffin-embedded tissue speci- and synthesize extracellular matrix proteins, which help reestablish mens were deparaffinized, rehydrated, subjected to antigen unmasking (16), and treated to block nonspecific staining. For the latter procedure, sections and maintain the structural integrity of cells and tubules), and were incubated for 20 minutes at 24jCwith1%HO in methanol, followed ‘‘recovery’’ (cellular function improves slowly, blood flow returns to 2 2 by blocking for 30 minutes with 5% normal horse serum in PBS. Polyclonal normal or near normal, and epithelial cells establish intracellular antibody against Ki67 (NCL-Ki67p; Novocastra Labs, New Castle upon Tyne, and intercellular homeostasis; ref 8). United Kingdom) or mouse glucose transporter (Glut-1; Alpha Diagnostic Renal cell carcinoma (RCC), which accounts for 3% of all adult Int., San Antonio, TX) was added (1:1,000 dilution) for 16 hours at 4jC, male malignancies in the U.S. (9), is a clinicopathologically followed by incubation for 30 minutes at room temperature with heterogeneous disease that includes several histologically distinct biotinylated secondary goat anti-rabbit IgG and incubation for 30 minutes cellular subtypes (10). RCC is thought to originate in proximal renal with avidin-biotin peroxidase conjugate (1:50 dilution; Vectastain Elite tubules most of the time and in distal tubules occasionally (11). Universal Kit; Vector Laboratories, Burlingame, CA). Color was developed Five human genes are associated with predisposition to RCC: von using Vector Laboratories 3,3-diaminobenzidine kit for 10 minutes, followed Hippel-Lindau (VHL), met proto-oncogene (MET), fumarate by counterstaining with Mayer’s hematoxylin. Negative controls were done with nonimmune serum or PBS. Three investigators evaluated the hydratase (FH), Birt-Hogg-Dube (BHD/FLCN), and hyperparathy- HRPT2 immunohistochemistry independently. roidism 2 ( ; ref. 12). RCC could develop following chronic Microarray procedures. Mouse cDNA microarrays (NIH/NCI GEM2) renal regeneration and repair (RRR) in individuals with polycystic containing 9,596 cDNA spots from the Integrated Molecular Analysis of kidney disease or in renal allografts (13, 14). Genomes and their Expression consortium were used to quantitate mRNA Our study tests the hypothesis that there are patterns of gene expression in the kidney samples. A reference sample consisting of an equal expression common to RRR and RCC. We used a mouse model of mixture of six normal mouse tissues (brain, heart, kidney, liver, lung, and ischemia/reperfusion (in which the left renal artery was ligated spleen) was used in the competitive hybridization experiments. For the transiently) to characterize
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