Inhibition of CXCR4 by CTCE-9908 inhibits breast cancer metastasis to lung and bone.

Metastasis occurs, in part, due to tumor cell responses to chemokine secretion by ectopic organs or tissues. SDF-1 is constitutively expressed in tissues where metastases frequently develop while breast carcinoma cells express the receptor for SDF-1, CXCR4, which is correlated with increased bone metastasis and poor overall survival. We hypothesized that treatment with a CXCR4 antagonist, CTCE-9908, would decrease incidence of bone and lung metastasis. Treatment with CTCE-9908 (25 mg/kg) began the day prior to or the day of intravenous or intracardiac tumor cell inoculation of MDA-MB-231 human breast carcinoma cells expressing enhanced green fluorescent protein (GFP) into athymic mice. After 5 or 8 weeks (i.c. and i.v. injections, respectively), the presence of fluorescent foci at metastatic sites was assessed. Somewhat surprisingly, CTCE-9908 treatment did not decrease incidence of metastasis as hypothesized. However, CTCE-9908 did decrease metastatic burden (i.e., size of metastases) in all organs examined (lungs, bone, heart, liver, kidneys, pancreas and spleen). Based upon this and other studies, the use of CTCE-9908 is promising as an adjuvant therapy for metastatic disease.

[1]  S. Eccles,et al.  Metastasis: recent discoveries and novel treatment strategies , 2007, The Lancet.

[2]  T. Kipps,et al.  Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1alpha. , 2005, Blood.

[3]  Jianhua Wang,et al.  The pivotal role of CXCL12 (SDF-1)/CXCR4 axis in bone metastasis , 2007, Cancer and Metastasis Reviews.

[4]  Hirokazu Tamamura,et al.  Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells. , 2005, Blood.

[5]  P. Allavena,et al.  Increased Survival, Proliferation, and Migration in Metastatic Human Pancreatic Tumor Cells Expressing Functional CXCR4 , 2004, Cancer Research.

[6]  Craig Murdoch,et al.  CXCR4: chemokine receptor extraordinaire , 2000, Immunological reviews.

[7]  Kedar S Vaidya,et al.  BRMS1 suppresses breast cancer experimental metastasis to multiple organs by inhibiting several steps of the metastatic process. , 2008, The American journal of pathology.

[8]  David Zurakowski,et al.  A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. , 2006, Journal of the National Cancer Institute.

[9]  V. Wee Yong,et al.  CXCR4 Is a Major Chemokine Receptor on Glioma Cells and Mediates Their Survival* , 2002, The Journal of Biological Chemistry.

[10]  F. Balkwill,et al.  The chemokine network in cancer--much more than directing cell movement. , 2004, The International journal of developmental biology.

[11]  Takuya Akashi,et al.  Chemokine receptors in cancer metastasis and cancer cell‐derived chemokines in host immune response , 2007, Cancer science.

[12]  Evan T Keller,et al.  Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. , 2002, Cancer research.

[13]  M. Ratajczak,et al.  Tissue-specific muscle, neural and liver stem/progenitor cells reside in the bone marrow, respond to an SDF-1 gradient and are mobilized into peripheral blood during stress and tissue injury. , 2004, Blood cells, molecules & diseases.

[14]  D. Piwnica-Worms,et al.  CXCR 4 Regulates Growth of Both Primary and Metastatic Breast Cancer , 2004 .

[15]  T. Dittmar,et al.  Adhesion molecules and chemokines: the navigation system for circulating tumor (stem) cells to metastasize in an organ-specific manner , 2007, Clinical & Experimental Metastasis.

[16]  C. Cordon-Cardo,et al.  A multigenic program mediating breast cancer metastasis to bone. , 2003, Cancer cell.

[17]  C. Bordignon,et al.  Expression of CXCR4, the receptor for stromal cell‐derived factor‐1 on fetal and adult human lymphohematopoietic progenitors , 1999, European journal of immunology.

[18]  A. Sahin,et al.  Chemokine receptor CXCR4 expression in breast cancer as a potential predictive marker of isolated tumor cells in bone marrow , 2005, Clinical & Experimental Metastasis.

[19]  S. Nishikawa,et al.  Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1 , 1996, Nature.

[20]  L. Akslen,et al.  Role of Angiogenesis in Human Tumor Dormancy: Animal Models of the Angiogenic Switch , 2006, Cell cycle.

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

[22]  Geoffrey C Gurtner,et al.  Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1 , 2004, Nature Medicine.

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

[24]  A. Ho,et al.  The Many Facets of SDF-1α, CXCR4 Agonists and Antagonists on Hematopoietic Progenitor Cells , 2007, Journal of biomedicine & biotechnology.

[25]  M. Hung,et al.  Breast cancer brain metastases , 2007, Cancer and Metastasis Reviews.

[26]  J. Kappes,et al.  Kinetics of Metastatic Breast Cancer Cell Trafficking in Bone , 2006, Clinical Cancer Research.

[27]  L. Helman,et al.  Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases , 2007, Clinical & Experimental Metastasis.

[28]  Xiaoqi Liu,et al.  Breast cancer metastasis suppressor 1 inhibits SDF-1alpha-induced migration of non-small cell lung cancer by decreasing CXCR4 expression. , 2008, Cancer letters.

[29]  A. Ben-Baruch,et al.  Host microenvironment in breast cancer development: Inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor–microenvironment interactions , 2002, Breast Cancer Research.

[30]  T. Springer,et al.  The Chemokine SDF-1 Is a Chemoattractant for Human CD34+ Hematopoietic Progenitor Cells and Provides a New Mechanism to Explain the Mobilization of CD34+ Progenitors to Peripheral Blood , 1997, The Journal of experimental medicine.

[31]  D. Welch.  Do we need to redefine a cancer metastasis and staging definitions? , 2006, Breast disease.

[32]  N. Fujii,et al.  Kisspeptin-10-induced signaling of GPR54 negatively regulates chemotactic responses mediated by CXCR4: a potential mechanism for the metastasis suppressor activity of kisspeptins. , 2005, Cancer research.

[33]  R. Bronson,et al.  Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[34]  R. Shah,et al.  CXCL12 overexpression and secretion by aging fibroblasts enhance human prostate epithelial proliferation in vitro , 2005, Aging cell.