title: Secretome analysis of an osteogenic prostate tumor identifies complex signaling networks mediating cross-talk of cancer and stromal cells within the tumor microenvironment.
abstract: A distinct feature of human prostate cancer (PCa) is the development of osteoblastic (bone-forming) bone metastases. Metastatic growth in the bone is supported by factors secreted by PCa cells that activate signaling networks in the tumor microenvironment that augment tumor growth. To better understand these signaling networks and identify potential targets for therapy of bone metastases, we characterized the secretome of a patient-derived xenograft, MDA-PCa-118b (PCa-118b), generated from osteoblastic bone lesion. PCa-118b induces osteoblastic tumors when implanted either in mouse femurs or subcutaneously. To study signaling molecules critical to these unique tumor/microenvironment-mediated events, we performed mass spectrometry on conditioned media of isolated PCa-118b tumor cells, and identified 26 secretory proteins, such as TGF-β2, GDF15, FGF3, FGF19, CXCL1, galectins, and β2-microglobulin, which represent both novel and previously published secreted proteins. RT-PCR using human versus mouse-specific primers showed that TGFβ2, GDF15, FGF3, FGF19, and CXCL1 were secreted from PCa-118b cells. TGFβ2, GDF15, FGF3, and FGF19 function as both autocrine and paracrine factors on tumor cells and stromal cells, that is, endothelial cells and osteoblasts. In contrast, CXCL1 functions as a paracrine factor through the CXCR2 receptor expressed on endothelial cells and osteoblasts. Thus, our study reveals a complex PCa bone metastasis secretome with paracrine and autocrine signaling functions that mediate cross-talk among multiple cell types within the tumor microenvironment.
authors.affiliation: From the Departments of ‡Translational Molecular Pathology.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Lee
authors.affiliation: ‖Department of Chemistry, Josip Juraj Strossmayer University, 31000 Osijek, Croatia;
authors.forename: Martina Srajer
authors.initials: MS
authors.lastname: Gajdosik
authors.affiliation: ****Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia;
authors.forename: Djuro
authors.initials: D
authors.lastname: Josic
authors.affiliation: ‡‡Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, RI 02903.
authors.forename: James G
authors.initials: JG
authors.lastname: Clifton
authors.affiliation: §Genitourinary Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX;
authors.forename: Christopher
authors.initials: C
authors.lastname: Logothetis
authors.affiliation: ¶Department of Medicine, Baylor College of Medicine, Houston, Texas 77030;
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Yu-Lee
authors.affiliation: §Genitourinary Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX;
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
authors.affiliation: §Genitourinary Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX;
authors.forename: Sankar N
authors.initials: SN
authors.lastname: Maity
authors.affiliation: From the Departments of ‡Translational Molecular Pathology, slin@mdanderson.org.
authors.forename: Sue-Hwa
authors.initials: SH
authors.lastname: Lin
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D002450:Cell Communication; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction; D017154:Stromal Cells / Q000502:physiology; D059016:Tumor Microenvironment
chemical_list: D017077:Culture Media, Conditioned; D009363:Neoplasm Proteins