Myeloid cells contribute to tumor lymphangiogenesis.
The formation of new blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis) promotes tumor outgrowth and metastasis. Previously, it has been demonstrated that bone marrow-derived cells (BMDC) can contribute to tumor angiogenesis. However, the role of BMDC in lymphangiogenesis has largely remained elusive. Here, we demonstrate by bone marrow transplantation/reconstitution and genetic lineage-tracing experiments that BMDC integrate into tumor-associated lymphatic vessels in the Rip1Tag2 mouse model of insulinoma and in the TRAMP-C1 prostate cancer transplantation model, and that the integrated BMDC originate from the myelomonocytic lineage. Conversely, pharmacological depletion of tumor-associated macrophages reduces lymphangiogenesis. No cell fusion events are detected by genetic tracing experiments. Rather, the phenotypical conversion of myeloid cells into lymphatic endothelial cells and their integration into lymphatic structures is recapitulated in two in vitro tube formation assays and is dependent on fibroblast growth factor-mediated signaling. Together, the results reveal that myeloid cells can contribute to tumor-associated lymphatic vessels, thus extending the findings on the previously reported role of hematopoietic cells in lymphatic vessel formation.
Zumsteg
Adrian
A
Institute of Biochemistry and Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
Baeriswyl
Vanessa
V
Imaizumi
Natsuko
N
Schwendener
Reto
R
Rüegg
Curzio
C
Christofori
Gerhard
G
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D007340:Insulinoma / Q000473:pathology; D042583:Lymphangiogenesis / Q000187:drug effects; D042601:Lymphatic Vessels / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology; D022423:Myeloid Cells / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology*; D009389:Neovascularization, Pathologic; D011471:Prostatic Neoplasms / Q000473:pathology