title: LIM-homeobox gene 2 promotes tumor growth and metastasis by inducing autocrine and paracrine PDGF-B signaling.
abstract: An epithelial-mesenchymal transition (EMT) is a critical process during embryonic development and the progression of epithelial tumors to metastatic cancers. Gene expression profiling has uncovered the transcription factor LIM homeobox gene 2 (Lhx2) with up-regulated expression during TGFβ-induced EMT in normal and cancerous breast epithelial cells. Loss and gain of function experiments in transgenic mouse models of breast cancer and of insulinoma in vivo and in breast cancer cells in vitro indicate that Lhx2 plays a critical role in primary tumor growth and metastasis. Notably, the transgenic expression of Lhx2 during breast carcinogenesis promotes vessel maturation, primary tumor growth, tumor cell intravasation and metastasis by directly inducing the expression of platelet-derived growth factor (PDGF)-B in tumor cells and by indirectly increasing the expression of PDGF receptor-β (PDGFRβ) on tumor cells and pericytes. Pharmacological inhibition of PDGF-B/PDGFRβ signaling reduces vessel functionality and tumor growth and Lhx2-induced cell migration and cell invasion. The data indicate a dual role of Lhx2 during EMT and tumor progression: by inducing the expression of PDGF-B, Lhx2 provokes an autocrine PDGF-B/PDGFRβ loop required for cell migration, invasion and metastatic dissemination and paracrine PDGF-B/PDGFRβ signaling to support blood vessel functionality and, thus, primary tumor growth.
authors.affiliation: Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Kuzmanov
authors.affiliation: Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland; Novartis, Basel, Switzerland.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hopfer
authors.affiliation: Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland; Novartis, Basel, Switzerland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Marti
authors.affiliation: Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Meyer-Schaller
authors.affiliation: Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland; Roche, Basel, Switzerland.
authors.forename: Mahmut
authors.initials: M
authors.lastname: Yilmaz
authors.affiliation: Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland. Electronic address: gerhard.christofori@unibas.ch.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Christofori
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D019899:Paracrine Communication; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis* / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C489783:LHX2 protein, human; D060850:LIM-Homeodomain Proteins; C499523:Lhx1 protein, mouse; D020574:Proto-Oncogene Proteins c-sis; D014157:Transcription Factors; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: EMT; Lhx2; Metastasis; PDGF-B; Tumor progression