ELR+ CXC chemokine expression in benign and malignant colorectal conditions

BackgroundCXCR2 chemokine ligands CXCL1, CXCL5 and CXCL6 were shown to be involved in chemoattraction, inflammatory responses, tumor growth and angiogenesis. Here, we comparatively analyzed their expression profile in resection specimens from patients with colorectal adenoma (CRA) (n = 30) as well as colorectal carcinoma (CRC) (n = 48) and corresponding colorectal liver metastases (CRLM) (n = 16).MethodsChemokine expression was assessed by microdissection, quantitative real-time PCR (Q-RT-PCR), the enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC).ResultsIn contrast to CXCL6, we demonstrated CXCL1 and CXCL5 mRNA and protein expression to be significantly up-regulated in CRC and CRLM tissue specimens in relation to their matched tumor neighbor tissues. Moreover, both chemokine ligands were demonstrated to be significantly higher expressed in CRC tissues than in CRA tissues thus indicating a progressive increase in the transition from the premalignant condition to the development of the malignant status. Although a comparative analysis of the CXCL1/CXCL5 protein expression profiles in CRC patients revealed that the absolute expression level of CXCL1 was significantly higher in comparison to CXCL5, mRNA- and protein overexpression of CXCL5 in CRC and CRLM tissues was much more pronounced (80- and 60- fold in CRC tissues, respectively) in comparison to CXCL1 (5- and 3.5- fold in CRC tissues, respectively).ConclusionOur results demonstrate a significant association between CXCL1 and CXCL5 expression with CRC and CRLM suggesting for both chemokine ligands a potential role in the progression from CRA to CRC and thus, in the initiation of CRC.

[1]  M. Baggiolini Chemokines in pathology and medicine , 2001, Journal of internal medicine.

[2]  W. Gong,et al.  Chemokines and their role in tumor growth and metastasis. , 1998, Journal of immunological methods.

[3]  G. Dong,et al.  Growth Regulated Oncogene-α expression by murine squamous cell carcinoma promotes tumor growth, metastasis, leukocyte infiltration and angiogenesis by a host CXC Receptor-2 dependent mechanism , 2000, Oncogene.

[4]  C. Wolf‐Peeters,et al.  Tumor angiogenesis induced by granulocyte chemotactic protein-2 as a countercurrent principle. , 2001, The American journal of pathology.

[5]  G. Nicolson,et al.  Molecular mechanisms of cancer metastasis: tumor and host properties and the role of oncogenes and suppressor genes , 1991, Current opinion in oncology.

[6]  M. Burdick,et al.  Mechanism and biological significance of constitutive expression of MGSA/GRO chemokines in malignant melanoma tumor progression , 1997, Journal of leukocyte biology.

[7]  H. Herschman,et al.  Cloning and characterization of the human granulocyte chemotactic protein-2 gene. , 1997, Journal of immunology.

[8]  M. Sata,et al.  Increased Circulating Concentrations of Growth-Related Oncogene (GRO)-α in Patients with Inflammatory Bowel Disease , 2006, Digestive Diseases and Sciences.

[9]  F Schoonjans,et al.  MedCalc: a new computer program for medical statistics. , 1995, Computer methods and programs in biomedicine.

[10]  L. Sobin,et al.  TNM classification of malignant tumors, fifth edition (1997) , 1997, Cancer.

[11]  H. Friess,et al.  Blockade of the chemokine receptor CXCR2 inhibits pancreatic cancer cell-induced angiogenesis. , 2006, Cancer letters.

[12]  D. Markovitz,et al.  Human Immunodeficiency Virus Type 1 (HIV-1)-Induced GRO-α Production Stimulates HIV-1 Replication in Macrophages and T Lymphocytes , 2001, Journal of Virology.

[13]  M. Burdick,et al.  Depletion of CXCR2 Inhibits Tumor Growth and Angiogenesis in a Murine Model of Lung Cancer1 , 2004, The Journal of Immunology.

[14]  D. Notterman,et al.  GROα Is Highly Expressed in Adenocarcinoma of the Colon and Down-Regulates Fibulin-1 , 2006, Clinical Cancer Research.

[15]  G. Opdenakker,et al.  GCP-2/CXCL6 synergizes with other endothelial cell-derived chemokines in neutrophil mobilization and is associated with angiogenesis in gastrointestinal tumors. , 2005, Experimental cell research.

[16]  M. Iannettoni,et al.  Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer. , 1998, The Journal of clinical investigation.

[17]  P. Woll,et al.  Production and upregulation of granulocyte chemotactic protein-2/CXCL6 by IL-1β and hypoxia in small cell lung cancer , 2006, British Journal of Cancer.

[18]  R. Strieter,et al.  Structure and neutrophil-activating properties of a novel inflammatory peptide (ENA-78) with homology to interleukin 8 , 1991, The Journal of experimental medicine.

[19]  M. Shimada,et al.  Coordinate upregulation of interleukin-8 and growth-related gene product-α is present in the colonic mucosa of inflammatory bowel disease , 2001 .

[20]  U. Hopt,et al.  Chemokines in human colorectal carcinoma. , 2005, Anticancer research.

[21]  R. Booth Minimally invasive biomarkers for detection and staging of colorectal cancer. , 2007, Cancer letters.

[22]  V. O. Frick,et al.  Correlation of IL-8 with induction, progression and metastatic potential of colorectal cancer. , 2007, World journal of gastroenterology.

[23]  T. Giordano,et al.  Overexpression of CXC chemokines by an adrenocortical carcinoma: a novel clinical syndrome. , 2001, The Journal of clinical endocrinology and metabolism.

[24]  M. Burdick,et al.  Cancer CXC chemokine networks and tumour angiogenesis. , 2006, European journal of cancer.

[25]  Claudia Rubie,et al.  Involvement of Chemokine Receptor CCR6 in Colorectal Cancer Metastasis , 2006, Tumor Biology.

[26]  M. Burdick,et al.  The CXC Chemokine Receptor 2, CXCR2, Is the Putative Receptor for ELR+ CXC Chemokine-Induced Angiogenic Activity1 , 2000, The Journal of Immunology.

[27]  R. Kyle,et al.  Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. , 1992, Cytokine.

[28]  Aihua Li,et al.  Expression of interleukin 8 and its receptors in human colon carcinoma cells with different metastatic potentials. , 2001, Clinical Cancer Research.

[29]  R. Strieter,et al.  CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer , 2006, The Journal of experimental medicine.

[30]  A. Luster,et al.  Chemokines--chemotactic cytokines that mediate inflammation. , 1998, The New England journal of medicine.

[31]  K. Xie,et al.  Interleukin-8 and human cancer biology. , 2001, Cytokine & growth factor reviews.

[32]  M. Burdick,et al.  The tumorigenic and angiogenic effects of MGSA/GRO proteins in melanoma , 2000, Journal of leukocyte biology.

[33]  P. Dhawan,et al.  Role of CXCL1 in tumorigenesis of melanoma , 2002, Journal of leukocyte biology.

[34]  R. Strieter,et al.  CXC chemokines mechanism of action in regulating tumor angiogenesis , 2004, Angiogenesis.

[35]  A. Zlotnik,et al.  Chemokines: a new classification system and their role in immunity. , 2000, Immunity.

[36]  M. Burdick,et al.  Cyclooxygenase-2-Dependent Expression of Angiogenic CXC Chemokines ENA-78/CXC Ligand (CXCL) 5 and Interleukin-8/CXCL8 in Human Non-Small Cell Lung Cancer , 2004, Cancer Research.

[37]  Armen B. Shanafelt,et al.  The Functional Role of the ELR Motif in CXC Chemokine-mediated Angiogenesis (*) , 1995, The Journal of Biological Chemistry.

[38]  Aihua Li,et al.  Constitutive expression of growth regulated oncogene (gro) in human colon carcinoma cells with different metastatic potential and its role in regulating their metastatic phenotype , 2005, Clinical & Experimental Metastasis.

[39]  S. Christmas,et al.  Interleukin-8 as an autocrine growth factor for human colon carcinoma cells in vitro. , 2000, Cytokine.

[40]  B. Tilton,et al.  Enhanced Expression and Clinical Significance of CC‐Chemokine MIP‐3α in Hepatocellular Carcinoma , 2006, Scandinavian journal of immunology.

[41]  B. Tilton,et al.  Housekeeping gene variability in normal and cancerous colorectal, pancreatic, esophageal, gastric and hepatic tissues. , 2005, Molecular and cellular probes.

[42]  M. Burdick,et al.  Distinct CXC chemokines mediate tumorigenicity of prostate cancer cells. , 1999, The American journal of pathology.

[43]  H. McLeod,et al.  Therapeutic opportunities from tumour biology in metastatic colon cancer. , 2000, European journal of cancer.

[44]  A. Anisowicz,et al.  Structural, regulatory, and functional studies of the GRO gene and protein. , 1992, Cytokines.

[45]  S. Bustin Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays. , 2000, Journal of molecular endocrinology.