Secretome of Bone Marrow Mesenchymal Stem Cells: an Emerging Player in Lung Cancer Progression and Mechanisms of Translation Initiation

Introduction: Non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related death. Patients with advanced stage have poor prognosis while metastatic spread accounts for>70% of patients deaths. The major advances in treatment of NSCLC have brought only minor improvements in survival; therefore novel strategic treatment approaches are 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 (BM)-MSCs on NSCLC cell lines with special emphasis on the role of translation initiation.

Methods: NSCLC cell lines were treated with normal BM-MSCs` conditioned medium(secretome) and assesed for changes in the cells` viability/ proliferation/death/migration and immunoblotted for translation initiation factors (eIF4E,eIF4GI), and their targets/regulators.

Results: Our results demonstarted deleterious effects on the cells’ proliferation, viability, death and migration. We also demonstrated reduced levels of translation initiation factors implicated in cancer progression eIF4E and eIF4GI, their targets, and regulators. Finally, we outlined a mechanism by which BM-MSCs` secretome affected NSCLCs` MAPK signaling, downredulated the cells` migration and diminshed translation initiation factors` levles.

Conclusions: We showed a direct dialogue between BM-MSCs’ secretome and NSCLC cells that manipulates translation initiation and critically affects cell fate. We showed inhibitory effect on the lung cancer cells’ migration that is regulated both by MAPK signaling and by translation initiation mechanism.

We suggest that theraputic approach that will sabotage the dialoge, espacially in the BM microenviornment, may diminish metastatic spread and improve the patients life quality.