Interleukin 6 mediated recruitment of mesenchymal stem cells to the hypoxic tumor milieu.
Mesenchymal stem cells (MSCs) are a heterogeneous population of non-hematopoietic precursor cells predominantly found in the bone marrow. They have been recently reported to home towards the hypoxic tumor microenvironment in vivo. Interleukin-6 is a multifunctional cytokine normally involved in the regulation of the immune and inflammatory response. In addition to its normal function, IL-6 signaling has been implicated in tumorigenesis. Solid tumors develop hypoxia as a result of inadequate O(2) supply. Interestingly, tumor types with increased levels of hypoxia are known to have increased resistance to chemotherapy as well as increased metastatic potential. Here, we present evidence that under hypoxic conditions (1.5% O(2)) breast cancer cells secrete high levels of IL-6, which serve to activate and attract MSCs. We now report that secreted IL-6 acts in a paracrine fashion on MSCs stimulating the activation of both Stat3 and MAPK signaling pathways to enhance migratory potential and cell survival. Inhibition of IL-6 signaling utilizing neutralizing antibodies leads to attenuation of MSC migration. Specifically, increased migration is dependent on IL-6 signaling through the IL-6 receptor. Collectively, our data demonstrate that hypoxic tumor cells specifically recruit MSCs, which through activation of signaling and survival pathways facilitate tumor progression.
Rattigan
Yanique
Y
Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA.
Hsu
Jing-Mei
JM
Mishra
Pravin J
PJ
Glod
John
J
Banerjee
Debabrata
D
D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D054443:Cell Migration Assays; D002470:Cell Survival / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051020:bcl-X Protein / Q000378:metabolism
D000906:Antibodies; C494811:BCL2L1 protein, human; D017077:Culture Media, Conditioned; C508600:IL6 protein, human; D015850:Interleukin-6; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051020:bcl-X Protein; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3