title: Mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma.
abstract: We hypothesized that signaling through multiple mitogen-activated protein kinase (MAPK) kinase (MKK) pathways is essential for the growth and vascularization of soft-tissue sarcomas, which are malignant tumors derived from mesenchymal tissues. We tested this using HT-1080, NCI, and Shac fibrosarcoma-derived cell lines and anthrax lethal toxin (LeTx), a bacterial toxin that inactivates MKKs. Western blots confirmed that LeTx treatment reduced the levels of phosphorylated extracellular signal-regulated kinase and p38 MAPK in vitro. Although short treatments with LeTx only modestly affected cell proliferation, sustained treatment markedly reduced cell numbers. LeTx also substantially inhibited the extracellular release of angioproliferative factors including vascular endothelial growth factor, interleukin-8, and basic fibroblast growth factor. Similar results were obtained with cell lines derived from malignant fibrous histiocytomas, leiomyosarcomas, and liposarcomas. In vivo, LeTx decreased MAPK activity and blocked fibrosarcoma growth. Growth inhibition correlated with decreased cellular proliferation and extensive necrosis, and it was accompanied by a decrease in tumor mean vessel density as well as a reduction in serum expression of angioproliferative cytokines. Vital imaging using high-resolution ultrasound enhanced with contrast microbubbles revealed that the effects of LeTx on tumor perfusion were remarkably rapid (<24 h) and resulted in a marked reduction of perfusion within the tumor but not in nontumor tissues. These results are consistent with our initial hypothesis and lead us to propose that MKK inhibition by LeTx is a broadly effective strategy for targeting neovascularization in fibrosarcomas and other similar proliferative lesions.
authors.affiliation: Laboratory of Cancer and Developmental Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Elissa A
authors.initials: EA
authors.lastname: Boguslawski
authors.forename: Bree D
authors.initials: BD
authors.lastname: Berghuis
authors.forename: John J
authors.initials: JJ
authors.lastname: Young
authors.forename: Zhongfa
authors.initials: Z
authors.lastname: Zhang
authors.forename: Kim
authors.initials: K
authors.lastname: Hardy
authors.forename: Kyle
authors.initials: K
authors.lastname: Furge
authors.forename: Eric
authors.initials: E
authors.lastname: Kort
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Frankel
authors.forename: Rick V
authors.initials: RV
authors.lastname: Hay
authors.forename: James H
authors.initials: JH
authors.lastname: Resau
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Duesbery
mesh_terms: D000942:Antigens, Bacterial / Q000494:pharmacology; D001427:Bacterial Toxins / Q000494:pharmacology; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005354:Fibrosarcoma / Q000098:blood supply* / Q000473:pathology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D015398:Signal Transduction
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin; D020928:Mitogen-Activated Protein Kinases