MCP1 directs trafficking of hematopoietic stem cell-derived fibroblast precursors in solid tumor.
Our previous studies have demonstrated that hematopoietic stem cells (HSCs) are a novel source of carcinoma-associated fibroblasts. However, the mechanisms regulating recruitment and homing of HSC-derived carcinoma-associated fibroblasts or their precursors to the tumor microenvironment are unknown. Herein, we demonstrate using a single cell transplantation model that circulating fibroblast precursors (CFPs) are of HSC origin. This population increased with tumor burden in vivo and functional in vitro studies showed that CFPs preferentially migrated and differentiated into fibroblasts in response to tumor, suggesting that HSC-derived CFPs serve as an intermediate between the bone marrow and tumor. Based on this chemotactic ability and our demonstration of a monocyte lineage origin for CFPs, we investigated the role of monocyte chemoattractant protein (MCP1) in mediating CFP recruitment/homing. Blocking tumor-produced MCP1 inhibited in vitro migration of CFPs in response to multiple tumor types, indicating broad biological significance for this CFP/chemokine interaction. In vivo, CCR2-expressing CFPs increased in circulation during the period of active tumor growth and stromal development. Inhibition of MCP1 during tumor development resulted in decreased tumor volume in tumor-bearing mice. Together these findings confirm an HSC origin for CFPs, demonstrate a role for MCP1 in regulating their contribution to the tumor microenvironment, and suggest a potential therapeutic target for limiting tumor growth.
Abangan
Romeo S
RS
Ralph H. Johnson VA Medical Center, Charleston, SC 29401, USA.
Williams
Christopher R
CR
Mehrotra
Meenal
M
Duncan
James D
JD
Larue
Amanda C
AC
D000818:Animals; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009368:Neoplasm Transplantation
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D005353:Fibronectins