Beta 2-Microglobulin signaling and targeting in bone metastasis

Summary

Principal Investigator: Leland W K Chung
Abstract: In this revised application, we have taken the recommendations from the reviewers by focusing specifically on the development of anti-b2-Microglobulin (b2-M) antibody as a therapeutic agent for the treatment of human prostate cancer bone metastasis. In addition, we also provided new information on a putative b2-M receptor, a novel strategy exploiting b2-M-receptor mediated cell signaling mechanisms and combinatorial approach achieving synergism between anti-b2-M monoclonal antibody (mAb) plus radiation as a promising therapeutic regimen for prostate cancer bone metastases. The hypothesis of this proposal is that anti-b2-M mAb interferes with HFE (a hereditary hemochromatosis associated gene)-TFRC (Transferrin Receptor)-TF (Transferrin) complex and iron transport, thus provokes downstream redox signaling changes with microRNAs (miRNAs) serving as regulators for a series of cell stress response proteins and DNA repair enzymes that ultimately trigger cell death in cancer but not normal cells. Two Specific Aims are proposed in this revised application. Specific Aim 1: to develop anti-b2-M mAb as a therapeutic antibody for prostate cancer bone metastasis therapy using experimental human prostate cancer xenograft and transgenic mouse models, evaluate antibody toxicity in mice, and determine the synergistic interaction between anti-b2-M mAb plus ionizing radiation on the growth of prostate cancer cells and tumors. This Aim is based on our discovery that b2-M is a major growth factor and pleiotropic signaling molecule that confers the growth, survival, and epithelial to mesenchymal transition (EMT) of human prostate cancer cells. Successful accomplishment of this Aim will allow accelerated translation of targeting b2-M as a novel therapeutic approach for human prostate cancer bone metastasis. Specific Aim 2: to evaluate and validate a putative b2-M receptor, a non-classical major histocompatibility complex (MHC)-like molecule, the hereditary hemochromatosis associated gene, HFE. The functional role of HFE and its relationship to TFRC-TF complex, iron uptake, reactive oxygen species (ROS) production, DNA damages, and cell death will be assessed. In this aim, we will investigate the function of anti-b2-M mAb on TFRC-TF complex that could promote iron uptake via endosomal iron recycling, production of ROS and highly reactive hydroxy radicals that could cause DNA damages in cancer but not normal cells. Regulation of miRNAs, potential downstream targets of redox signaling, on cell stress response proteins and DNA repair enzymes will be specially emphasized. In summary, this revised application carefully follows the recommendations of the reviewers to develop novel approaches for targeting b2-M-mediated downstream growth and signaling pathways in human prostate cancer, which has exciting potential for clinical translation to manage prostate cancer bone metastasis. PUBLIC HEALTH RELEVANCE: Prostate cancer bone metastasis contributes to mortality and morbidity of prostate cancer patients. We have developed a new therapeutic approach by using a novel anti-b2-Microglobulin antibody plus radiation, which has been shown to completely abolish the growth of human tumors in mice. This project focuses on defining the molecular mechanism of this synergism and the appropriate preclinical studies to move these discoveries from bench to the bedside.
Funding Period: 2009-09-29 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. pmc Beta2-microglobulin signaling blockade inhibited androgen receptor axis and caused apoptosis in human prostate cancer cells
    Wen Chin Huang
    Molecular Urology and Therapeutics Program, Department of Urology and Winship Cancer Institute, Emory University School of Medicine, GA 30322, USA
    Clin Cancer Res 14:5341-7. 2008
  2. pmc Multiplexed quantum dot labeling of activated c-Met signaling in castration-resistant human prostate cancer
    Peizhen Hu
    Uro Oncology Research Program, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California, United States of America
    PLoS ONE 6:e28670. 2011
  3. pmc LIV-1 promotes prostate cancer epithelial-to-mesenchymal transition and metastasis through HB-EGF shedding and EGFR-mediated ERK signaling
    Hui Wen Lue
    Department of Biology, Georgia State University, Atlanta, Georgia, United States of America
    PLoS ONE 6:e27720. 2011
  4. pmc Activation of androgen receptor, lipogenesis, and oxidative stress converged by SREBP-1 is responsible for regulating growth and progression of prostate cancer cells
    Wen Chin Huang
    Uro Oncology Research Program, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
    Mol Cancer Res 10:133-42. 2012
  5. ncbi Characterization of the phosphoproteome in androgen-repressed human prostate cancer cells by Fourier transform ion cyclotron resonance mass spectrometry
    Xu Wang
    Department of Chemistry and Biochemistry, 95 Chieftain Way, Florida State University, Tallahassee, Florida 32306, United States
    J Proteome Res 10:3920-8. 2011
  6. pmc Serum prosaposin levels are increased in patients with advanced prostate cancer
    Shahriar Koochekpour
    Department of Urology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
    Prostate 72:253-69. 2012
  7. pmc EPLIN downregulation promotes epithelial-mesenchymal transition in prostate cancer cells and correlates with clinical lymph node metastasis
    S Zhang
    Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
    Oncogene 30:4941-52. 2011
  8. pmc Active sonic hedgehog signaling between androgen independent human prostate cancer cells and normal/benign but not cancer-associated prostate stromal cells
    Katsumi Shigemura
    Department of Urology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA
    Prostate 71:1711-22. 2011
  9. ncbi Immunohistochemical characterization of sonic hedgehog and its downstream signaling molecules during human penile development
    Bahig M Shehata
    Department of Pathology and Pediatrics, Emory University School of Medicine, Children s Healthcare of Atlanta, Atlanta, Georgia 30322 1101, USA
    Fetal Pediatr Pathol 30:244-51. 2011
  10. pmc PDGF upregulates Mcl-1 through activation of β-catenin and HIF-1α-dependent signaling in human prostate cancer cells
    Shareen Iqbal
    Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America
    PLoS ONE 7:e30764. 2012

Research Grants

  1. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
  2. Mechanisms of GVHD
    Joseph H Antin; Fiscal Year: 2013
  3. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
  4. Characterization of Pathways Controlling Cancer at the Level of Gene Regulation
    Phillip A Sharp; Fiscal Year: 2013
  5. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013

Detail Information

Publications40

  1. pmc Beta2-microglobulin signaling blockade inhibited androgen receptor axis and caused apoptosis in human prostate cancer cells
    Wen Chin Huang
    Molecular Urology and Therapeutics Program, Department of Urology and Winship Cancer Institute, Emory University School of Medicine, GA 30322, USA
    Clin Cancer Res 14:5341-7. 2008
    ..The objective of this study is to determine the mechanism by which targeting beta2M using anti-beta2M antibody inhibited growth and induced apoptosis in prostate cancer cells...
  2. pmc Multiplexed quantum dot labeling of activated c-Met signaling in castration-resistant human prostate cancer
    Peizhen Hu
    Uro Oncology Research Program, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California, United States of America
    PLoS ONE 6:e28670. 2011
    ..MQDL is a powerful tool for assessing biomarker expression and it offers molecular insights into cancer progression at both the cell and tissue level with high degree of sensitivity...
  3. pmc LIV-1 promotes prostate cancer epithelial-to-mesenchymal transition and metastasis through HB-EGF shedding and EGFR-mediated ERK signaling
    Hui Wen Lue
    Department of Biology, Georgia State University, Atlanta, Georgia, United States of America
    PLoS ONE 6:e27720. 2011
    ..LIV-1 could be an attractive therapeutic target for the eradication of pre-existing human prostate cancer and bone and soft tissue metastases...
  4. pmc Activation of androgen receptor, lipogenesis, and oxidative stress converged by SREBP-1 is responsible for regulating growth and progression of prostate cancer cells
    Wen Chin Huang
    Uro Oncology Research Program, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
    Mol Cancer Res 10:133-42. 2012
    ....
  5. ncbi Characterization of the phosphoproteome in androgen-repressed human prostate cancer cells by Fourier transform ion cyclotron resonance mass spectrometry
    Xu Wang
    Department of Chemistry and Biochemistry, 95 Chieftain Way, Florida State University, Tallahassee, Florida 32306, United States
    J Proteome Res 10:3920-8. 2011
    ..Androgen-induced proliferation inhibitor (APRIN) was detected in its phosphorylated form, implicating a molecular mechanism underlying the ARCaP phenotype...
  6. pmc Serum prosaposin levels are increased in patients with advanced prostate cancer
    Shahriar Koochekpour
    Department of Urology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
    Prostate 72:253-69. 2012
    ..The clinicohistopathological significance of serum PSAP levels and its tissue expression and association with predictive or prognostic variable in primary or advanced PCa are not known...
  7. pmc EPLIN downregulation promotes epithelial-mesenchymal transition in prostate cancer cells and correlates with clinical lymph node metastasis
    S Zhang
    Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
    Oncogene 30:4941-52. 2011
    ..This study reveals a novel molecular mechanism for converting cancer cells into a highly invasive and malignant form, and has important implications in prognosis and treating metastasis at early stages...
  8. pmc Active sonic hedgehog signaling between androgen independent human prostate cancer cells and normal/benign but not cancer-associated prostate stromal cells
    Katsumi Shigemura
    Department of Urology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA
    Prostate 71:1711-22. 2011
    ..Since hormone refractory prostate cancer with bone metastasis is difficult to treat, it is crucial to investigate how androgen independent (AI) human prostate cancer cells communicate with their associated stroma...
  9. ncbi Immunohistochemical characterization of sonic hedgehog and its downstream signaling molecules during human penile development
    Bahig M Shehata
    Department of Pathology and Pediatrics, Emory University School of Medicine, Children s Healthcare of Atlanta, Atlanta, Georgia 30322 1101, USA
    Fetal Pediatr Pathol 30:244-51. 2011
    ..The intensity of Shh staining was greatest in the urethral epithelium at 14 weeks gestation, correlating with the time of urethral tubularization. Results suggest a role for Shh in human male genital development...
  10. pmc PDGF upregulates Mcl-1 through activation of β-catenin and HIF-1α-dependent signaling in human prostate cancer cells
    Shareen Iqbal
    Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America
    PLoS ONE 7:e30764. 2012
    ..Aberrant platelet derived growth factor (PDGF) signaling has been associated with prostate cancer (PCa) progression. However, its role in the regulation of PCa cell growth and survival has not been well characterized...
  11. pmc RANK-mediated signaling network and cancer metastasis
    Gina Chia Yi Chu
    Departments of Medicine and Surgery, Samuel Orchin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA
    Cancer Metastasis Rev 33:497-509. 2014
    ....
  12. pmc Convergent RANK- and c-Met-mediated signaling components predict survival of patients with prostate cancer: an interracial comparative study
    Peizhen Hu
    Uro Oncology Research Program, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California, United States of America
    PLoS ONE 8:e73081. 2013
    ..Neuropilin-1, p-NF-κB p65 and VEGF are predictors for the overall survival of Chinese men with PC. These results collectively support interracial differences in cell signaling networks that can predict the survival of PC patients...
  13. pmc Can stroma reaction predict cancer lethality?
    Michael R Freeman
    Authors Affiliations Departments of Medicine, Surgery, Biomedical Sciences, and Biostatistics and Bioinformatics Center, Samuel Oschin Comprehensive Cancer Center, Cedars Sinai Medical Center, Los Angeles, California
    Clin Cancer Res 19:4905-7. 2013
    ....
  14. pmc Inhibition of β2-microglobulin/hemochromatosis enhances radiation sensitivity by induction of iron overload in prostate cancer cells
    Sajni Josson
    Uro Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, California, United States of America
    PLoS ONE 8:e68366. 2013
    ..Therefore, we hypothesized that β2-M is a rational target to treat prostate cancer bone metastasis...
  15. pmc β2-Microglobulin-mediated signaling as a target for cancer therapy
    Takeo Nomura
    Department of Urology, Oita University Faculty of Medicine, 1 1 Idaigaoka, Hasama machi, Yufu, Oita 879 5593, Japan
    Anticancer Agents Med Chem 14:343-52. 2014
    ....
  16. pmc Heptamethine cyanine based (64)Cu-PET probe PC-1001 for cancer imaging: synthesis and in vivo evaluation
    Li Xiao
    Department of Radiology, University of Virginia, Charlottesville, VA 22908, USA
    Nucl Med Biol 40:351-60. 2013
    ..Development of a heptamethine cyanine based tumor-targeting PET imaging probe for noninvasive detection and diagnosis of breast cancer...
  17. pmc Epidermal growth factor promotes protein degradation of epithelial protein lost in neoplasm (EPLIN), a putative metastasis suppressor, during epithelial-mesenchymal transition
    Shumin Zhang
    Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    J Biol Chem 288:1469-79. 2013
    ..This study elucidated a novel molecular mechanism for EGF regulation of EMT and invasiveness in PCa cells, indicating that blockade of EGF signaling could be beneficial in preventing and retarding PCa metastasis at early stages...
  18. pmc β2-microglobulin induces epithelial to mesenchymal transition and confers cancer lethality and bone metastasis in human cancer cells
    Sajni Josson
    Uro Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, California, USA
    Cancer Res 71:2600-10. 2011
    ..These results demonstrate the role of β2-M in cancer metastasis and lethality. Thus, β2-M and its downstream signaling pathways are promising prognostic markers of cancer metastases and novel therapeutic targets for cancer therapy...
  19. pmc PrLZ protects prostate cancer cells from apoptosis induced by androgen deprivation via the activation of Stat3/Bcl-2 pathway
    Dong Zhang
    Department of Urology, The First Affiliated Hospital of Medical School, Xi an Jiaotong University, Xi an, Shaanxi, PR China
    Cancer Res 71:2193-202. 2011
    ....
  20. pmc Androgen receptor survival signaling is blocked by anti-beta2-microglobulin monoclonal antibody via a MAPK/lipogenic pathway in human prostate cancer cells
    Wen Chin Huang
    Uro Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, USA
    J Biol Chem 285:7947-56. 2010
    ....
  21. pmc Tumor-stroma co-evolution in prostate cancer progression and metastasis
    Sajni Josson
    Uro Oncology Research, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA, USA
    Semin Cell Dev Biol 21:26-32. 2010
    ....
  22. pmc Progressive epithelial to mesenchymal transitions in ARCaP E prostate cancer cells during xenograft tumor formation and metastasis
    Hui He
    Department of Urology, The First Affiliated Hospital, Xi an Jiaotong University, Xi an, China
    Prostate 70:518-28. 2010
    ..We have reported that ARCaP(E) human prostate cancer cells undergo EMT-like changes during xenograft growth in athymic mice...
  23. pmc Human prostate fibroblasts induce growth and confer castration resistance and metastatic potential in LNCaP Cells
    George N Thalmann
    Department of Urology, University of Bern, Inselspital, 3010 Bern, Switzerland
    Eur Urol 58:162-71. 2010
    ..The tumor microenvironment is important for progressive and metastatic disease...
  24. pmc Transcription variants of the prostate-specific PrLZ gene and their interaction with 14-3-3 proteins
    Ruoxiang Wang
    Department of Urology, Emory University School of Medicine, Atlanta, GA 30322, USA
    Biochem Biophys Res Commun 389:455-60. 2009
    ..This information is a valuable addition to the investigation of the oncogenic properties of the PrLZ gene...
  25. pmc Beta2-microglobulin as a potential factor for the expansion of mesenchymal stem cells
    Ying Zhu
    State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, Third Military Medical University, Chongqing, China
    Biotechnol Lett 31:1361-5. 2009
    ..The use of beta2M might have promising implications for future clinical application of MSCs...
  26. pmc Visualizing human prostate cancer cells in mouse skeleton using bioconjugated near-infrared fluorescent quantum dots
    Chunmeng Shi
    Department of Urology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Urology 74:446-51. 2009
    ..To visualize human prostate cancer cells in mouse bone with bioconjugated near-infrared quantum dot (QD) probes. Near-infrared fluorescent probes using QDs can visualize tumors in deep tissues in vivo...
  27. pmc Soluble factors derived from stroma activated androgen receptor phosphorylation in human prostate LNCaP cells: roles of ERK/MAP kinase
    Katsumi Shigemura
    Molecular Urology and Therapeutics Program, Department of Urology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Prostate 69:949-55. 2009
    ..In this study, we characterized AR phosphorylation in LNCaP cells co-cultured with the conditioned medium (CM) from human prostate stromal fibroblasts...
  28. pmc Vascular endothelial growth factor regulates myeloid cell leukemia-1 expression through neuropilin-1-dependent activation of c-MET signaling in human prostate cancer cells
    Shumin Zhang
    Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
    Mol Cancer 9:9. 2010
    ..Mcl-1 overexpression has been associated with progression in leukemia and some solid tumors including prostate cancer (PCa). However, the regulatory mechanism for Mcl-1 expression in PCa cells remains elusive...
  29. pmc Differential expression of the alpha2 chain of the interleukin-13 receptor in metastatic human prostate cancer ARCaPM cells
    Hui He
    Department of Urology, The First Affiliated Hospital, Xi an Jiaotong University, Xi an, China
    Prostate 70:993-1001. 2010
    ..Availability of a human prostate cancer cell line with high level of IL13Ralpha2 expression will facilitate the development of therapeutic modalities...
  30. pmc Human prostate cancer harbors the stem cell properties of bone marrow mesenchymal stem cells
    Haiyen E Zhau
    Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA
    Clin Cancer Res 17:2159-69. 2011
    ..We examined human prostate cancer cell lines and clinical prostate cancer specimens for additional bone marrow mesenchymal stem cell properties...
  31. pmc Snail-mediated regulation of reactive oxygen species in ARCaP human prostate cancer cells
    Petrina Barnett
    Center for Cancer Research and Therapeutic Development, Department of Biological Sciences, Clark Atlanta University, Atlanta, GA 30314, USA
    Biochem Biophys Res Commun 404:34-9. 2011
    ..Therefore, Snail may be an attractive molecule for therapeutic targeting to prevent tumor progression in human prostate cancer...
  32. pmc Inhibition of ADAM9 expression induces epithelial phenotypic alterations and sensitizes human prostate cancer cells to radiation and chemotherapy
    Sajni Josson
    Uro Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, California 90048, USA
    Prostate 71:232-40. 2011
    ..Recent studies demonstrated the importance of ADAM9 in prostate cancer relapse upon therapy. In this study, we determined the role of ADAM9 in the therapeutic resistance to radiation and chemotherapy...
  33. ncbi Osteoblasts can stimulate prostate cancer growth and transcriptionally down-regulate PSA expression in cell line models
    Yingming Li
    Department of Urology, University of Minnesota, Minneapolis, MN 55455, USA
    Urol Oncol 29:802-8. 2011
    ..To investigate the effect of bone environment on cellular proliferation, mature prostate-specific antigen (PSA) production and secretion, and PSA transcriptional regulation of prostate cancer cells...
  34. pmc Near IR heptamethine cyanine dye-mediated cancer imaging
    Xiaojian Yang
    Molecular Urology and Therapeutics, Department of Urology, Winship Cancer Institute, Atlanta, GA, USA
    Clin Cancer Res 16:2833-44. 2010
    ..Near-IR fluorescence imaging has great potential for noninvasive in vivo imaging of tumors. In this study, we show the preferential uptake and retention of two hepatamethine cyanine dyes, IR-783 and MHI-148, in tumor cells and tissues...
  35. pmc Matched pairs of human prostate stromal cells display differential tropic effects on LNCaP prostate cancer cells
    Xiaojuan Sun
    Molecular Urology and Therapeutics, Department of Urology and Winship Cancer Institute, Emory University School of Medicine, 1365B Clifton Road, NE, Suite B5103, Atlanta, GA 30322, USA
    In Vitro Cell Dev Biol Anim 46:538-46. 2010
    ..This work thus established a panel of valuable human prostate stromal cell lines, which could be used in co-culture to study the interaction between prostate cancer and prostate stromal cells...
  36. pmc Phorbol ester phorbol-12-myristate-13-acetate induces epithelial to mesenchymal transition in human prostate cancer ARCaPE cells
    Hui He
    Department of Urology, The First Affiliated Hospital, Xi an Jiaotong University, Xi an, China
    Prostate 70:1119-26. 2010
    ..It is known that phorbol ester phorbol-12-myristate-13-acetate (PMA), a potent antagonist to both conventional and novel protein kinase C (PKC) isoenzymes, induces cancer cell scattering...
  37. pmc Detection of live circulating tumor cells by a class of near-infrared heptamethine carbocyanine dyes in patients with localized and metastatic prostate cancer
    Chen Shao
    Uro Oncolgy Research Laboratories, Samuel Oschin Comprehensive Cancer Institute at Cedars Sinai Medical Center, Los Angles, California, United States of America Urologic Oncology Program, Samuel Oschin Comprehensive Cancer Institute at Cedars Sinai Medical Center, Los Angles, California, United States of America Department of Urology Xijing Hospital, The Fourth Military Medical University, Xi an, Shaanxi, China
    PLoS ONE 9:e88967. 2014
    ..Our study demonstrates the feasibility of applying of this staining technique to identify live CTCs, creating an opportunity for further molecular interrogation of a more biologically relevant CTC population. ..

Research Grants30

  1. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  2. Mechanisms of GVHD
    Joseph H Antin; Fiscal Year: 2013
    ..Ultimately we envision an integrated genomic profile that will determine the type of GVHD prophylaxis that will be most effective. ..
  3. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
  4. Characterization of Pathways Controlling Cancer at the Level of Gene Regulation
    Phillip A Sharp; Fiscal Year: 2013
    ..The interactions and involvement of Rb and miRNAs in induction of cell death following DNA damage will also be studied. ..
  5. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....