PDGFRB promotes liver metastasis formation of mesenchymal-like colorectal tumor cells.

In epithelial tumors, the platelet-derived growth factor receptor B (PDGFRB) is mainly expressed by stromal cells of mesenchymal origin. Tumor cells may also acquire PDGFRB expression following epithelial-to-mesenchymal transition (EMT), which occurs during metastasis formation. Little is known about PDGFRB signaling in colorectal tumor cells. We studied the relationship between PDGFRB expression, EMT, and metastasis in human colorectal cancer (CRC) cohorts by analysis of gene expression profiles. PDGFRB expression in primary CRC was correlated with short disease-free and overall survival. PDGFRB was co-expressed with genes involved in platelet activation, transforming growth factor beta (TGFB) signaling, and EMT in three CRC cohorts. PDGFRB was expressed in mesenchymal-like tumor cell lines in vitro and stimulated invasion and liver metastasis formation in mice. Platelets, a major source of PDGF, preferentially bound to tumor cells in a non-activated state. Platelet activation caused robust PDGFRB tyrosine phosphorylation on tumor cells in vitro and in liver sinusoids in vivo. Platelets also release TGFB, which is a potent inducer of EMT. Inhibition of TGFB signaling in tumor cells caused partial reversion of the mesenchymal phenotype and strongly reduced PDGFRB expression and PDGF-stimulated tumor cell invasion. These results suggest that PDGFRB may contribute to the aggressive phenotype of colorectal tumors with mesenchymal properties, most likely downstream of platelet activation and TGFB signaling.

[1]  Mariël Brok,et al.  Exploring Gene Expression Signatures for Predicting Disease Free Survival after Resection of Colorectal Cancer Liver Metastases , 2012, PloS one.

[2]  J. Foidart,et al.  A dynamic in vivo model of epithelial-to-mesenchymal transitions in circulating tumor cells and metastases of breast cancer , 2012, Oncogene.

[3]  J. Sleeman.  The metastatic niche and stromal progression , 2012, Cancer and Metastasis Reviews.

[4]  Junxing Huang,et al.  Elevation of platelet count in patients with colorectal cancer predicts tendency to metastases and poor prognosis. , 2012, Hepato-gastroenterology.

[5]  Y. Toiyama,et al.  Intravital dual‐colored visualization of colorectal liver metastasis in living mice using two photon laser scanning microscopy , 2012, Microscopy research and technique.

[6]  Caroline Dive,et al.  Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  Maximilian Reichert,et al.  EMT and Dissemination Precede Pancreatic Tumor Formation , 2012, Cell.

[8]  R. Moorehead,et al.  Mammary tumors that become independent of the type I insulin-like growth factor receptor express elevated levels of platelet-derived growth factor receptors , 2011, BMC Cancer.

[9]  Richard O Hynes,et al.  Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. , 2011, Cancer cell.

[10]  I. B. Borel Rinkes,et al.  The death receptor CD95 activates the cofilin pathway to stimulate tumour cell invasion , 2011, EMBO reports.

[11]  Edi Brogi,et al.  Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs , 2011, Nature Medicine.

[12]  S. Baek,et al.  Epicardial-Derived Cell Epithelial-to-Mesenchymal Transition and Fate Specification Require PDGF Receptor Signaling , 2011, Circulation research.

[13]  S. Thomson,et al.  Inducible expression of TGFβ, Snail and Zeb1 recapitulates EMT in vitro and in vivo in a NSCLC model , 2011, Clinical & Experimental Metastasis.

[14]  S. Agelaki,et al.  Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients , 2011, Breast Cancer Research.

[15]  B. Vincenzi,et al.  Circulating tumour cells lacking cytokeratin in breast cancer: the importance of being mesenchymal , 2011, Journal of cellular and molecular medicine.

[16]  Thorsten Maass,et al.  Liver specific overexpression of platelet‐derived growth factor‐B accelerates liver cancer development in chemically induced liver carcinogenesis , 2011, International journal of cancer.

[17]  Thinzar M. Lwin,et al.  Twist1-induced invadopodia formation promotes tumor metastasis. , 2011, Cancer cell.

[18]  Giuseppe Naso,et al.  Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients , 2011, Breast Cancer Research and Treatment.

[19]  Laurie J. Gay,et al.  Contribution of platelets to tumour metastasis , 2011, Nature Reviews Cancer.

[20]  C. Denis,et al.  Novel Function of Tenascin-C, a Matrix Protein Relevant to Atherosclerosis, in Platelet Recruitment and Activation Under Flow , 2011, Arteriosclerosis, thrombosis, and vascular biology.

[21]  Stuart Thomson,et al.  A systems view of epithelial–mesenchymal transition signaling states , 2010, Clinical & Experimental Metastasis.

[22]  T. Yeatman,et al.  Experimentally derived metastasis gene expression profile predicts recurrence and death in patients with colon cancer. , 2010, Gastroenterology.

[23]  T. Ørntoft,et al.  Metastasis-Associated Gene Expression Changes Predict Poor Outcomes in Patients with Dukes Stage B and C Colorectal Cancer , 2009, Clinical Cancer Research.

[24]  R. Huang,et al.  Epithelial-Mesenchymal Transitions in Development and Disease , 2009, Cell.

[25]  Tanja Fehm,et al.  Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients , 2009, Breast Cancer Research.

[26]  Raghu Kalluri,et al.  The basics of epithelial-mesenchymal transition. , 2009, The Journal of clinical investigation.

[27]  M. Petz,et al.  ILEI requires oncogenic Ras for the epithelial to mesenchymal transition of hepatocytes and liver carcinoma progression , 2009, Oncogene.

[28]  Christian von Mering,et al.  STRING 8—a global view on proteins and their functional interactions in 630 organisms , 2008, Nucleic Acids Res..

[29]  Stuart Thomson,et al.  Kinase switching in mesenchymal-like non-small cell lung cancer lines contributes to EGFR inhibitor resistance through pathway redundancy , 2008, Clinical & Experimental Metastasis.

[30]  Ines Gockel,et al.  PDGFRα/β expression correlates with the metastatic behavior of human colorectal cancer: A possible rationale for a molecular targeting strategy , 2008 .

[31]  P. V. van Diest,et al.  Differential Notch and TGFβ Signaling in Primary Colorectal Tumors and Their Corresponding Metastases , 2008, Cellular oncology : the official journal of the International Society for Cellular Oncology.

[32]  P. Lenting,et al.  Platelet Activation by Oxidized Low Density Lipoprotein Is Mediated by Cd36 and Scavenger Receptor-A , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[33]  R. Kalluri,et al.  Fibroblasts Derive from Hepatocytes in Liver Fibrosis via Epithelial to Mesenchymal Transition* , 2007, Journal of Biological Chemistry.

[34]  Héctor Peinado,et al.  Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? , 2007, Nature Reviews Cancer.

[35]  H. Huber,et al.  PDGF essentially links TGF-β signaling to nuclear β-catenin accumulation in hepatocellular carcinoma progression , 2007, Oncogene.

[36]  Youping Deng,et al.  GeneVenn - A web application for comparing gene lists using Venn diagrams , 2007, Bioinformation.

[37]  C. Bucana,et al.  Expression of activated platelet‐derived growth factor receptor in stromal cells of human colon carcinomas is associated with metastatic potential , 2006, International journal of cancer.

[38]  C. Cordon-Cardo,et al.  Autocrine PDGFR signaling promotes mammary cancer metastasis. , 2006, The Journal of clinical investigation.

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

[40]  J Han JM van Krieken,et al.  Macrodissection versus microdissection of rectal carcinoma: minor influence of stroma cells to tumor cell gene expression profiles , 2005, BMC Genomics.

[41]  P. V. van Diest,et al.  Ischemia/reperfusion accelerates the outgrowth of hepatic micrometastases in a highly standardized murine model , 2005, Hepatology.

[42]  Alison Stopeck,et al.  Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  Ruth J. Muschel,et al.  Coagulation Facilitates Tumor Cell Spreading in the Pulmonary Vasculature during Early Metastatic Colony Formation , 2004, Cancer Research.

[44]  I. B. Borel Rinkes,et al.  Validation of bioluminescence imaging of colorectal liver metastases in the mouse. , 2004, The Journal of surgical research.

[45]  J. Ball,et al.  Statistics review 12: Survival analysis , 2004, Critical care.

[46]  C. Bucana,et al.  Inhibition of platelet-derived growth factor receptor phosphorylation by STI571 (Gleevec) reduces growth and metastasis of human pancreatic carcinoma in an orthotopic nude mouse model. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[47]  J. Massagué,et al.  Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer , 2003, Nature Reviews Cancer.

[48]  Thomas Waerner,et al.  Expression profiling of epithelial plasticity in tumor progression , 2003, Oncogene.

[49]  I. B. Borel Rinkes,et al.  Enhanced antitumour efficacy by combining conventional chemotherapy with angiostatin or endostatin in a liver metastasis model , 2002, The British journal of surgery.

[50]  I. Verlaan,et al.  Regulating c-Ras function cholesterol depletion affects caveolin association, GTP loading, and signaling , 2001, Current Biology.

[51]  I. B. Borel Rinkes,et al.  Continuous administration of angiostatin inhibits accelerated growth of colorectal liver metastases after partial hepatectomy. , 2000, Cancer research.

[52]  A. Varki,et al.  Distinct selectin ligands on colon carcinoma mucins can mediate pathological interactions among platelets, leukocytes, and endothelium. , 1999, The American journal of pathology.

[53]  R. Farndale,et al.  Collagen-platelet interaction: Gly-Pro-Hyp is uniquely specific for platelet Gp VI and mediates platelet activation by collagen. , 1999, Cardiovascular research.

[54]  C. Heldin,et al.  Mechanism of action and in vivo role of platelet-derived growth factor. , 1999, Physiological reviews.

[55]  H. Beug,et al.  TGFβ signaling is necessary for carcinoma cell invasiveness and metastasis , 1998, Current Biology.

[56]  A. Varki,et al.  P-selectin deficiency attenuates tumor growth and metastasis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[57]  L. Påhlman,et al.  Stromal expression of platelet-derived growth factor beta-receptor and platelet-derived growth factor B-chain in colorectal cancer. , 1993, Laboratory investigation; a journal of technical methods and pathology.

[58]  K. Rubin,et al.  Microvascular pericytes express platelet-derived growth factor-beta receptors in human healing wounds and colorectal adenocarcinoma. , 1993, The American journal of pathology.

[59]  S. Karpatkin,et al.  Role of adhesive proteins in platelet tumor interaction in vitro and metastasis formation in vivo. , 1988, The Journal of clinical investigation.

[60]  S. Karpatkin,et al.  Effect of antiplatelet antibody on the development of pulmonary metastases following injection of CT26 colon adenocarcinoma, Lewis lung carcinoma, and B16 amelanotic melanoma tumor cells into mice. , 1984, Cancer research.

[61]  E. Sunami,et al.  Impact of Preoperative Thrombocytosis on the Survival of Patients with Primary Colorectal Cancer , 2011, World Journal of Surgery.

[62]  C. Heldin,et al.  PDGF receptors as targets in tumor treatment. , 2007, Advances in cancer research.

[63]  L. Seymour,et al.  Positive immunostaining for platelet derived growth factor (PDGF) is an adverse prognostic factor in patients with advanced breast cancer , 2004, Breast Cancer Research and Treatment.

[64]  T. Kawaguchi,et al.  Analysis of the lodgement and extravasation of tumor cells in experimental models of hematogenous metastasis , 2004, Cancer and Metastasis Reviews.