title: Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480.
abstract: STAT3 has important functions in both tumor cells and the tumor microenvironment to facilitate cancer progression. The STAT regulatory kinase Janus-activated kinase (JAK) has been strongly implicated in promoting oncogenesis of various solid tumors, including the use of JAK kinase inhibitors such as AZD1480. However, direct evidence that JAK drives STAT3 function and cancer pathogenesis at the level of the tumor microenvironment is yet to be established clearly. In this study, we show that AZD1480 inhibits STAT3 in tumor-associated myeloid cells, reducing their number and inhibiting tumor metastasis. Myeloid cell-mediated angiogenesis was also diminished by AZD1480, with additional direct inhibition of endothelial cell function in vitro and in vivo. AZD1480 blocked lung infiltration of myeloid cells and formation of pulmonary metastases in both mouse syngeneic experimental and spontaneous metastatic models. Furthermore, AZD1480 reduced angiogenesis and metastasis in a human xenograft tumor model. Although the effects of AZD1480 on the tumor microenvironment were important for the observed antiangiogenic activity, constitutive activation of STAT3 in tumor cells themselves could block these antiangiogenic effects, showing the complexity of the JAK/STAT signaling network in tumor progression. Together, our results indicated that AZD1480 can effectively inhibit tumor angiogenesis and metastasis mediated by STAT3 in stromal cells as well as tumor cells.
authors.affiliation: Department of Cancer Immunotherapeutics, Medical Oncology, Molecular Medicine, and Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrmann
authors.forename: Karen
authors.initials: K
authors.lastname: Reckamp
authors.forename: Wang
authors.initials: W
authors.lastname: Zhang
authors.forename: Sumanta
authors.initials: S
authors.lastname: Pal
authors.forename: Michael
authors.initials: M
authors.lastname: Hedvat
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Liang
authors.forename: Anna
authors.initials: A
authors.lastname: Scuto
authors.forename: Shaobu
authors.initials: S
authors.lastname: Weng
authors.forename: Deborah
authors.initials: D
authors.lastname: Morosini
authors.forename: Zhu A
authors.initials: ZA
authors.lastname: Cao
authors.forename: Michael
authors.initials: M
authors.lastname: Zinda
authors.forename: Robert
authors.initials: R
authors.lastname: Figlin
authors.forename: Dennis
authors.initials: D
authors.lastname: Huszar
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000473:pathology / Q000556:secondary; D005260:Female; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D007680:Kidney Neoplasms / Q000473:pathology; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D017154:Stromal Cells / Q000187:drug effects / Q000201:enzymology; D059016:Tumor Microenvironment / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: C545606:AZD 1480; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D053612:Janus Kinases