PF4 Promotes Platelet Production and Lung Cancer Growth.
Co-option of host components by solid tumors facilitates cancer progression and can occur in both local tumor microenvironments and remote locations. At present, the signals involved in long-distance communication remain insufficiently understood. Here, we identify platelet factor 4 (PF4, CXCL4) as an endocrine factor whose overexpression in tumors correlates with decreased overall patient survival. Furthermore, engineered PF4 over-production in a Kras-driven lung adenocarcinoma genetic mouse model expanded megakaryopoiesis in bone marrow, augmented platelet accumulation in lungs, and accelerated de novo adenocarcinogenesis. Additionally, anti-platelet treatment controlled mouse lung cancer progression, further suggesting that platelets can modulate the tumor microenvironment to accelerate tumor outgrowth. These findings support PF4 as a cancer-enhancing endocrine signal that controls discrete aspects of bone marrow hematopoiesis and tumor microenvironment and that should be considered as a molecular target in anticancer therapy.
Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA.
Ferdinando
F
Pucci
Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Steffen
S
Rickelt
Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA.
Andita P
AP
Newton
Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA; Graduate Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
Christopher
C
Garris
Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
Ernesto
E
Nunes
Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA; Graduate Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
Charles
C
Evavold
Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA.
Christina
C
Pfirschke
Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA; Graduate Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
Camilla
C
Engblom
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
Mari
M
Mino-Kenudson
Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Richard O
RO
Hynes
Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA; Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, MA 02115, USA.
Ralph
R
Weissleder
Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA; Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: mpittet@mgh.harvard.edu.
Mikael J
MJ
Pittet
D000230:Adenocarcinoma / Q000097:blood / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D019070:Cell Lineage; D049109:Cell Proliferation; D018450:Disease Progression; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000473:pathology*; D008533:Megakaryocytes / Q000378:metabolism; D051379:Mice; D010978:Platelet Factor 4 / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D016019:Survival Analysis
C117307:KRAS protein, human; D010978:Platelet Factor 4; D016283:Proto-Oncogene Proteins p21(ras)