TSU68 prevents liver metastasis of colon cancer xenografts by modulating the premetastatic niche.

The aim of this study was to investigate the inhibitory effect of TSU68 [(Z)-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid; SU6668], an inhibitor of vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor beta, and fibroblast growth factor receptor 1 (FGFR1), on colon cancer liver metastasis, and to test the hypothesis that TSU68 modulates the microenvironment in the liver before the formation of metastasis. First, we implanted the highly metastatic human colon cancer TK-4 orthotopically into the cecal walls of nude mice, followed by twice-daily administration of TSU68 (400 mg/kg/d) or vehicle. Five weeks of treatment with TSU68 significantly inhibited liver metastasis compared with the control group (P<0.001). Next, we analyzed the gene expression profile in premetastatic liver using microarrays. Microarray and quantitative reverse transcription-PCR analysis showed that mRNA levels for the chemokine CXCL1 were significantly increased in tumor-bearing mice compared with non-tumor-bearing mice. Moreover, CXCL1 expression was significantly decreased by TSU68 treatment. CXCR2 expression was detected predominantly on tumor cells in orthotopic tumors compared with ectopic tumors. The number of migrating neutrophils in premetastatic liver was significantly decreased in the TSU68-treated group (P<0.001). The amount of interleukin-12 (IL-12) p40 in the portal vein was significantly decreased by TSU68 (P=0.02). Blockade of both CXCR2 and IL-12 p40 with a neutralizing antibody significantly inhibited liver metastasis. These results suggest that the CXCL1/CXCR2 axis is important in cancer metastasis and that TSU68 may modulate the premetastatic niche in the target organ through suppression of the inflammatory response, which might be an alternative mechanism used by antiangiogenic agents.

[1]  Christian R Gomez,et al.  An Age-associated Increase in Pulmonary Inflammation after Burn Injury Is Abrogated by Cxcr2 Inhibition , 2022 .

[2]  D. Nolan,et al.  Endothelial Progenitor Cells Control the Angiogenic Switch in Mouse Lung Metastasis , 2008, Science.

[3]  細木 久裕.  Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes , 2008 .

[4]  M. Kitagawa,et al.  ARA54 is involved in transcriptional regulation of the cyclin D1 gene in human cancer cells. , 2007, Carcinogenesis.

[5]  Ricky T. Tong,et al.  Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. , 2007, Cancer research.

[6]  Hiroyuki Aburatani,et al.  Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis , 2006, Nature Cell Biology.

[7]  Judong Pan,et al.  Stromal Derived Factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis , 2006, Molecular Cancer.

[8]  Andrea Rosario Beccari,et al.  ELR+ CXC chemokines and their receptors (CXC chemokine receptor 1 and CXC chemokine receptor 2) as new therapeutic targets. , 2006, Pharmacology & therapeutics.

[9]  R. Kerbel.  Antiangiogenic Therapy: A Universal Chemosensitization Strategy for Cancer? , 2006, Science.

[10]  S. Hwang,et al.  Chemokines, chemokine receptors, and cancer metastasis , 2006, Journal of leukocyte biology.

[11]  Hiroshi Yamamoto,et al.  The secreted form of the p40 subunit of interleukin (IL)‐12 inhibits IL‐23 functions and abrogates IL‐23‐mediated antitumour effects , 2006, Immunology.

[12]  Ma Dong,et al.  Bevacizumab plus Irinotecan,Fluorouracil,and Leucovorin for Metastatic Colorectal Cancer , 2006 .

[13]  S. Rafii,et al.  VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche , 2005, Nature.

[14]  T. Kubota,et al.  TSU-68 (SU6668) inhibits local tumor growth and liver metastasis of human colon cancer xenografts via anti-angiogenesis. , 2005, Oncology reports.

[15]  R. Jain.  Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy , 2005, Science.

[16]  D. Hicklin,et al.  Monoclonal antibodies targeting the VEGF receptor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy , 1998, Cancer and Metastasis Reviews.

[17]  Megumi Baba,et al.  Orthotopic implantation of a colon cancer xenograft induces high expression of cyclooxygenase-2. , 2003, Cancer letters.

[18]  M. Burdick,et al.  The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases. , 2003, American journal of respiratory and critical care medicine.

[19]  I. Fidler,et al.  The organ microenvironment and cancer metastasis. , 2002, Differentiation; research in biological diversity.

[20]  M. Shibuya,et al.  MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. , 2002, Cancer cell.

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

[22]  A. Ullrich,et al.  Smart drugs: tyrosine kinase inhibitors in cancer therapy. , 2002, Cancer cell.

[23]  Megumi Baba,et al.  Prevention of liver metastasis of human colon cancer by selective matrix metalloproteinase inhibitor MMI-166. , 2002, Cancer letters.

[24]  Rakesh K. Jain,et al.  Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy , 2001, Nature Medicine.

[25]  K. Pahan,et al.  Induction of Nitric-oxide Synthase and Activation of NF-κB by Interleukin-12 p40 in Microglial Cells* , 2001, The Journal of Biological Chemistry.

[26]  T. Mcclanahan,et al.  Involvement of chemokine receptors in breast cancer metastasis , 2001, Nature.

[27]  L. Ellis,et al.  Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms. , 2001, Cancer research.

[28]  M. Ohta,et al.  Prevention of Hepatic and Peritoneal Metastases by the Angiogenesis Inhibitor FR‐118487 after Removal of Growing Tumor in Mice , 2001, Japanese journal of cancer research : Gann.

[29]  Cherrington,et al.  SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. , 2000, Cancer research.

[30]  J. Mestan,et al.  PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. , 2000, Cancer research.

[31]  L. Ellis,et al.  Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis. , 1999, Cancer research.

[32]  Megumi Baba,et al.  Antitumor Effect on Human Gastric Cancer and Induction of Apoptosis by Vascular Endothelial Growth Factor Neutralizing Antibody , 1999, Japanese journal of cancer research : Gann.

[33]  A. Ullrich,et al.  SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. , 1999, Cancer research.

[34]  Leonard,et al.  Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. , 1997, Cancer research.

[35]  C. Bucana,et al.  Correlation of metastasis-related gene expression with metastatic potential in human prostate carcinoma cells implanted in nude mice using an in situ messenger RNA hybridization technique. , 1997, The American journal of pathology.

[36]  Tatsuo Tanaka,et al.  Efficacy of an angiogenesis inhibitor, TNP‐470, in xenotransplanted human colorectal cancer with high metastatic potential , 1996, Cancer.

[37]  Ann Richmond,et al.  HMGI(Y) and Sp1 in addition to NF-κB regulate transcription of the MGSA/GROα gene , 1995 .

[38]  Tatsuo Tanaka,et al.  Comparison of the inhibitory effect of the angiogenesis inhibitor, TNP‐470, and mitomycin c on the growth and liver metastasis of human colon cancer , 1995, International journal of cancer.

[39]  H. Konno,et al.  Prevention of hepatic metastasis of human colon cancer by angiogenesis inhibitor TNP-470. , 1995, Cancer research.

[40]  C. Geczy,et al.  Acute inflammatory activity of the S100 protein CP-10. Activation of neutrophils in vivo and in vitro. , 1994, Journal of immunology.

[41]  R. Kendall,et al.  Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[42]  W. Wood,et al.  Characterization of two high affinity human interleukin-8 receptors. , 1992, The Journal of biological chemistry.

[43]  S Paget,et al.  THE DISTRIBUTION OF SECONDARY GROWTHS IN CANCER OF THE BREAST. , 1889 .

[44]  J. Folkman,et al.  Angiogenic factors. , 1987, Science.

[45]  J. Folkman.  Tumor angiogenesis: therapeutic implications. , 1971, The New England journal of medicine.