ASK1-dependent endothelial cell activation is critical in ovarian cancer growth and metastasis.

We have recently reported that tumor-associated macrophages (TAMs) promote early transcoelomic metastasis of ovarian cancer by facilitating TAM-ovarian cancer cell spheroid formation. ASK1 is known to be important for macrophage activation and inflammation-mediated tumorigenesis. In the present study, we show that ASK1 deficiency attenuates TAM-spheroid formation and ovarian cancer progression in an orthotopic ovarian cancer model. Interestingly, ASK1 in stroma, but not in TAMs, is critical for peritoneal tumor growth of ovarian cancer. Moreover, overexpression of an ASK1 inhibitory protein (suppressor of cytokine signaling-1; SOCS1) in vascular endothelium attenuates vascular permeability, TAM infiltration, and ovarian cancer growth. Mechanistically, we show that ASK1 mediates degradation of endothelial junction protein VE-cadherin via a lysosomal pathway to promote macrophage transmigration. Importantly, a pharmacological ASK1 inhibitor prevents tumor-induced vascular leakage, macrophage infiltration, and tumor growth in two mouse models. Since transcoelomic metastasis is also associated with many other cancers, such as pancreatic and colon cancers, our study provides ASK1 as a therapeutic target for the treatment of ovarian cancer and other transcoelomic metastasis cancers.

[1]  Wang Min,et al.  Tumor-associated macrophages drive spheroid formation during early transcoelomic metastasis of ovarian cancer. , 2016, The Journal of clinical investigation.

[2]  J. McGee,et al.  TGFβ signaling regulates epithelial-mesenchymal plasticity in ovarian cancer ascites-derived spheroids. , 2016, Endocrine-related cancer.

[3]  A. Sugimoto,et al.  Intact LKB1 activity is required for survival of dormant ovarian cancer spheroids , 2015, Oncotarget.

[4]  R. Drapkin,et al.  Combined therapy with thrombospondin‐1 type I repeats (3TSR) and chemotherapy induces regression and significandy improves survival in a preclinical model of advanced stage epithelial ovarian cancer , 2015, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[5]  W. Min,et al.  Thioredoxin-2 Inhibits Mitochondrial Reactive Oxygen Species Generation and Apoptosis Stress Kinase-1 Activity to Maintain Cardiac Function , 2015, Circulation.

[6]  Wang Min,et al.  Carbamoylating Activity Associated with the Activation of the Antitumor Agent Laromustine Inhibits Angiogenesis by Inducing ASK1-Dependent Endothelial Cell Death , 2014, PloS one.

[7]  Will Liao,et al.  The cellular and molecular origin of tumor-associated macrophages , 2014, Science.

[8]  W. Min,et al.  SOCS1 prevents graft arteriosclerosis by preserving endothelial cell function. , 2014, Journal of the American College of Cardiology.

[9]  G. Freeman,et al.  Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. , 2013, Cancer research.

[10]  Christina S. Leslie,et al.  CSF-1R inhibition alters macrophage polarization and blocks glioma progression , 2013, Nature Medicine.

[11]  G. Coukos,et al.  Deciphering and reversing tumor immune suppression. , 2013, Immunity.

[12]  C. Lewis,et al.  Macrophage regulation of tumor responses to anticancer therapies. , 2013, Cancer cell.

[13]  S. Kutschera,et al.  VEGFR2 induces c-Src signaling and vascular permeability in vivo via the adaptor protein TSAd , 2012, The Journal of experimental medicine.

[14]  Karin Jirström,et al.  Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. , 2011, Cancer discovery.

[15]  P. Carmeliet,et al.  HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. , 2011, Cancer cell.

[16]  R. Jain,et al.  Polarization of tumor-associated macrophages: a novel strategy for vascular normalization and antitumor immunity. , 2011, Cancer cell.

[17]  J. Au,et al.  Intraperitoneal therapy for peritoneal cancer. , 2010, Future oncology.

[18]  Jeffrey W. Pollard,et al.  Macrophage Diversity Enhances Tumor Progression and Metastasis , 2010, Cell.

[19]  Steven J. M. Jones,et al.  Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. , 2010, The New England journal of medicine.

[20]  A. Jemal,et al.  Cancer Statistics, 2009 , 2009, CA: a cancer journal for clinicians.

[21]  W. Min,et al.  JAK2 and SHP2 Reciprocally Regulate Tyrosine Phosphorylation and Stability of Proapoptotic Protein ASK1* , 2009, Journal of Biological Chemistry.

[22]  Hiromi Nakamura,et al.  ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis , 2009, The EMBO journal.

[23]  Elisabetta Dejana,et al.  The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. , 2009, Developmental cell.

[24]  W. Min,et al.  Mechanisms of endothelial dysfunction, injury, and death. , 2009, Annual review of pathology.

[25]  W. Min,et al.  AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice. , 2008, The Journal of clinical investigation.

[26]  Xia Zhang,et al.  The Isolation and Characterization of Murine Macrophages , 2008, Current protocols in immunology.

[27]  W. Min,et al.  AIP1 Is Critical in Transducing IRE1-mediated Endoplasmic Reticulum Stress Response* , 2008, Journal of Biological Chemistry.

[28]  N. Van Rooijen,et al.  Macrophages mediate inflammation-enhanced metastasis of ovarian tumors in mice. , 2007, Cancer research.

[29]  H. Aburatani,et al.  ASK1-dependent recruitment and activation of macrophages induce hair growth in skin wounds , 2007, The Journal of cell biology.

[30]  R. Agarwal,et al.  Mechanisms of transcoelomic metastasis in ovarian cancer. , 2006, The Lancet. Oncology.

[31]  M. David,et al.  Cutting Edge: Apoptosis-Regulating Signal Kinase 1 Is Required for Reactive Oxygen Species-Mediated Activation of IFN Regulatory Factor 3 by Lipopolysaccharide1 , 2006, The Journal of Immunology.

[32]  S. Gordon,et al.  Ovarian Cancer Cells Polarize Macrophages Toward A Tumor-Associated Phenotype1 , 2006, The Journal of Immunology.

[33]  W. Min,et al.  SOCS1 Inhibits Tumor Necrosis Factor-induced Activation of ASK1-JNK Inflammatory Signaling by Mediating ASK1 Degradation* , 2006, Journal of Biological Chemistry.

[34]  R. Freedman,et al.  Defective Antitumor Function of Monocyte-Derived Macrophages from Epithelial Ovarian Cancer Patients , 2006, Clinical Cancer Research.

[35]  John Condeelis,et al.  Macrophages: Obligate Partners for Tumor Cell Migration, Invasion, and Metastasis , 2006, Cell.

[36]  W. Min,et al.  Hsp90–Akt phosphorylates ASK1 and inhibits ASK1-mediated apoptosis , 2005, Oncogene.

[37]  Kunihiro Matsumoto,et al.  ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity , 2005, Nature Immunology.

[38]  G. Trinchieri,et al.  Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. , 2005, Cancer research.

[39]  W. Min,et al.  Thioredoxin Promotes ASK1 Ubiquitination and Degradation to Inhibit ASK1-Mediated Apoptosis in a Redox Activity-Independent Manner , 2002, Circulation research.

[40]  Jing Chen,et al.  Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK–ERK independent mechanism , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[41]  W. Min,et al.  Laminar flow inhibits TNF-induced ASK1 activation by preventing dissociation of ASK1 from its inhibitor 14-3-3. , 2001, The Journal of clinical investigation.

[42]  T Takahashi,et al.  ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis , 2001, EMBO reports.

[43]  Xuan Sun,et al.  Akt Phosphorylates and Negatively Regulates Apoptosis Signal-Regulating Kinase 1 , 2001, Molecular and Cellular Biology.

[44]  D. Hilton,et al.  SOCS: physiological suppressors of cytokine signaling. , 2000, Journal of cell science.

[45]  Thomas N. Sato,et al.  Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. , 1999, Science.

[46]  P. Schwartzberg,et al.  Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. , 1999, Molecular cell.

[47]  D. Henley,et al.  Microtubule Dysfunction Induced by Paclitaxel Initiates Apoptosis through Both c-Jun N-terminal Kinase (JNK)-dependent and -Independent Pathways in Ovarian Cancer Cells* , 1999, The Journal of Biological Chemistry.

[48]  Minoru Takagi,et al.  Induction of Apoptosis by ASK1, a Mammalian MAPKKK That Activates SAPK/JNK and p38 Signaling Pathways , 1997, Science.

[49]  A. A. Miles,et al.  Vascular reactions to histamine, histamine‐liberator and leukotaxine in the skin of guinea‐pigs , 1952, The Journal of physiology.

[50]  E. Lengyel,et al.  Expression of the homeobox gene HOXA9 in ovarian cancer induces peritoneal macrophages to acquire an M2 tumor-promoting phenotype. , 2014, The American journal of pathology.

[51]  A. Jemal,et al.  Cancer statistics, 2012 , 2012, CA: a cancer journal for clinicians.

[52]  L. Tanoue.  Cancer Statistics, 2009 , 2010 .

[53]  A. Bikfalvi,et al.  Tumor angiogenesis , 2020, Advances in cancer research.

[54]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.