Transplanting normal vascular proangiogenic cells to tumor-bearing mice triggers vascular remodeling and reduces hypoxia in tumors.
Blood vessels deliver oxygen and nutrients to tissues, and vascular networks are spatially organized to meet the metabolic needs for maintaining homeostasis. In contrast, the vasculature of tumors is immature and leaky, resulting in insufficient delivery of nutrients and oxygen. Vasculogenic processes occur normally in adult tissues to repair "injured" blood vessels, leading us to hypothesize that bone marrow mononuclear cells (BMMNC) may be able to restore appropriate vessel function in the tumor vasculature. Culturing BMMNCs in endothelial growth medium resulted in the early outgrowth of spindle-shaped attached cells expressing CD11b/Flt1/Tie2/c-Kit/CXCR4 with proangiogenic activity. Intravenous administration of these cultured vascular proangiogenic cells (VPC) into nude mice bearing pancreatic cancer xenografts and Pdx1-Cre;LSL-Kras(G12D);p53(lox/+) genetically engineered mice that develop pancreatic ductal adenocarcinoma significantly reduced areas of hypoxia without enhancing tumor growth. The resulting vasculature structurally mimicked normal vessels with intensive pericyte coverage. Increases in vascularized areas within VPC-injected xenografts were visualized with an ultrasound diagnostic system during injection of a microbubble-based contrast agent (Sonazoid), indicating a functional "normalization" of the tumor vasculature. In addition, gene expression profiles in the VPC-transplanted xenografts revealed a marked reduction in major factors involved in drug resistance and "stemness" of cancer cells. Together, our findings identify a novel alternate approach to regulate abnormal tumor vessels, offering the potential to improve the delivery and efficacy of anticancer drugs to hypoxic tumors.
Sasajima
Junpei
J
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical College, Asahikawa, Hokkaido, Japan.
Mizukami
Yusuke
Y
Sugiyama
Yoshiaki
Y
Nakamura
Kazumasa
K
Kawamoto
Toru
T
Koizumi
Kazuya
K
Fujii
Rie
R
Motomura
Wataru
W
Sato
Kazuya
K
Suzuki
Yasuaki
Y
Tanno
Satoshi
S
Fujiya
Mikihiro
M
Sasaki
Katsunori
K
Shimizu
Norihiko
N
Karasaki
Hidenori
H
Kono
Toru
T
Kawabe
Jun-ichi
J
Ii
Masaaki
M
Yoshiara
Hiroki
H
Kamiyama
Naohisa
N
Ashida
Toshifumi
T
Bardeesy
Nabeel
N
Chung
Daniel C
DC
Kohgo
Yutaka
Y
D000230:Adenocarcinoma / Q000098:blood supply* / Q000378:metabolism / Q000601:surgery*; D042501:Angiogenic Proteins / Q000096:biosynthesis; D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D039481:CD11b Antigen / Q000096:biosynthesis; D048708:Cell Growth Processes / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000097:blood / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism / Q000601:surgery*; D010641:Phenotype; D023041:Xenograft Model Antitumor Assays
D042501:Angiogenic Proteins; D039481:CD11b Antigen; D016207:Cytokines; D010100:Oxygen