title: Secretome of human bone marrow mesenchymal stem cells: an emerging player in lung cancer progression and mechanisms of translation initiation.
abstract: Non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related death worldwide. Patients presenting with advanced-stage NSCLC have poor prognosis, while metastatic spread accounts for >70 % of patient's deaths. The major advances in the treatment of lung cancer have brought only minor improvements in survival; therefore, novel strategic treatment approaches are urgently needed. Accumulating data allocate a central role for the cancer microenvironment including mesenchymal stem cells (MSCs) in acquisition of drug resistance and disease relapse. Furthermore, studies indicate that translation initiation factors are over expressed in NSCLC and negatively impact its prognosis. Importantly, translation initiation is highly modulated by microenvironmental cues. Therefore, we decided to examine the effect of bone marrow MSCs (BM-MSCs) from normal donors on NSCLC cell lines with special emphasis on translation initiation mechanism in the crosstalk. We cultured NSCLC cell lines with BM-MSC conditioned media (i.e., secretome) and showed deleterious effects on the cells' proliferation, viability, death, and migration. We also demonstrated reduced levels of translation initiation factors implicated in cancer progression [eukaryotic translation initiation factor 4E (eIF4E) and eukaryotic translation initiation factor 4GI (eIF4GI)], their targets, and regulators. Finally, we outlined a mechanism by which BM-MSCs' secretome affected NSCLC's mitogen-activated protein kinase (MAPK) signaling pathway, downregulated the cell migration, and diminished translation initiation factors' levels. Taken together, our study demonstrates that there is direct dialogue between the BM-MSCs' secretome and NSCLC cells that manipulates translation initiation and critically affects cell fate. We suggest that therapeutic approach that will sabotage this dialogue, especially in the BM microenvironment, may diminish lung cancer metastatic spread and morbidity and improve the patient's life quality.
authors.affiliation: Lung Cancer Research, Meir Medical Center, Kfar Saba, 44281, Israel. oshrat.attar@clalit.org.il.|Oncogenetic Laboratories, Meir Medical Center, Kfar Saba, 44281, Israel. oshrat.attar@clalit.org.il.|Sackler Faculty of Medicine, Tel Aviv University Ramat Aviv, Tel Aviv, 69978, Israel. oshrat.attar@clalit.org.il.
authors.forename: Oshrat
authors.initials: O
authors.lastname: Attar-Schneider
authors.affiliation: Lung Cancer Research, Meir Medical Center, Kfar Saba, 44281, Israel.|Sackler Faculty of Medicine, Tel Aviv University Ramat Aviv, Tel Aviv, 69978, Israel.
authors.forename: Victoria
authors.initials: V
authors.lastname: Zismanov
authors.affiliation: Oncogenetic Laboratories, Meir Medical Center, Kfar Saba, 44281, Israel.|Sackler Faculty of Medicine, Tel Aviv University Ramat Aviv, Tel Aviv, 69978, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Drucker
authors.affiliation: Lung Cancer Research, Meir Medical Center, Kfar Saba, 44281, Israel.|Oncology Department, Lung Cancer Unit, Meir Medical Center, Kfar Saba, 44281, Israel.|Sackler Faculty of Medicine, Tel Aviv University Ramat Aviv, Tel Aviv, 69978, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Gottfried
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D018450:Disease Progression; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D010442:Peptide Chain Initiation, Translational; D020543:Proteome / Q000378:metabolism*
chemical_list: C411571:EIF4ENIF1 protein, human; C113920:EIF4G1 protein, human; D039603:Eukaryotic Initiation Factor-4G; D029543:Nucleocytoplasmic Transport Proteins; D020543:Proteome; D020928:Mitogen-Activated Protein Kinases
keywords: Human mesenchymal stem cells; Migration; NSCLC; Translation initiation; eIF4E/eIF4GI