Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis.
Tissue factor (TF) is the primary cellular initiator of blood coagulation and a modulator of angiogenesis and metastasis in cancer. Indeed, systemic hypercoagulability in patients with cancer and TF overexpression by cancer cells are both closely associated with tumor progression, but their causes have been elusive. We now report that in human colorectal cancer cells, TF expression is under control of 2 major transforming events driving disease progression (activation of K-ras oncogene and inactivation of the p53 tumor suppressor), in a manner dependent on MEK/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3'-kinase (PI3K). Furthermore, the levels of cell-associated as well as circulating (microvesicle-associated) TF activity are linked to the genetic status of cancer cells. Finally, RNA interference experiments suggest that TF expression is an important effector of the K-ras-dependent tumorigenic and angiogenic phenotype in vivo. Thus, this study establishes a causal link between cancer coagulopathy, angiogenesis, and genetic tumor progression.
Yu
Joanne L
JL
Henderson Research Centre, Experimental Thrombosis Research, McMaster University, Hamilton, ON, Canada L8V 1C3.
May
Linda
L
Lhotak
Vladimir
V
Shahrzad
Siranoush
S
Shirasawa
Senji
S
Weitz
Jeffrey I
JI
Coomber
Brenda L
BL
Mackman
Nigel
N
Rak
Janusz W
JW
D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016158:Genes, p53 / Q000502:physiology; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013925:Thromboplastin / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology
D013925:Thromboplastin