title: Recombinant leukemia inhibitory factor suppresses human medullary thyroid carcinoma cell line xenografts in mice.
abstract: Medullary thyroid carcinoma (MTC) is a neoplasm of the endocrine system, which originates from parafollicular C-cells of the thyroid gland. For MTC therapy, the Food and Drug Administration recently approved vandetanib and cabozantinib, multi-kinase inhibitors targeting RET and other tyrosine kinase receptors of vascular endothelial growth factor, epidermal growth factor, or hepatocyte growth factor. Nevertheless, not all patients with the progressive MTC respond to these drugs, requiring the development of additional therapeutic modalities that have distinct activity. Previously, we reported that expression of activated Ras or Raf in the human MTC cell lines, TT and MZ-CRC-1, can induce growth arrest and RET downregulation via a leukemia inhibitory factor (LIF)-mediated autocrine/paracrine loop. In this study, we aimed to evaluate bacterially-produced recombinant human LIF for its efficacy to suppress human MTC xenografts in mice. Here, we report that, consistent with its effects in vitro, locally or systemically administered recombinant LIF effectively suppressed growth of TT and MZ-CRC-1 xenografts in mice. Further, as predicted from its effects in TT and MZ-CRC-1 cell cultures in vitro, recombinant LIF activated the JAK/STAT pathway and downregulated RET and E2F1 expression in tumors in mice. These results suggest that LIF is a potent cytostatic agent for MTC cells, which regulates unique mechanisms that are not targeted by currently available therapeutic agents.
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Starenki
authors.forename: Nishant K
authors.initials: NK
authors.lastname: Singh
authors.forename: Davin R
authors.initials: DR
authors.lastname: Jensen
authors.forename: Francis C
authors.initials: FC
authors.lastname: Peterson
authors.forename: Jong-In
authors.initials: JI
authors.lastname: Park
mesh_terms: D000818:Animals; D018278:Carcinoma, Neuroendocrine; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005260:Female; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D011994:Recombinant Proteins; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D050687:E2F1 Transcription Factor; D053605:Leukemia Inhibitory Factor; D011994:Recombinant Proteins; D050791:STAT Transcription Factors; D051096:Proto-Oncogene Proteins c-ret; D053612:Janus Kinases
keywords: LIF; Leukemia inhibitory factor; MALDI-TOF; MEN; MTC; Medullary thyroid carcinoma; PBS; RET; STAT3; leukemia inhibitory factor; matrix-assisted laser desorption/ionization-time-of-flight; medullary thyroid carcinoma; multiple endocrine neoplasia; phosphate-buffered saline; rearranged during transfection