Osteopontin promotes vascular endothelial growth factor-dependent breast tumor growth and angiogenesis via autocrine and paracrine mechanisms.
Angiogenesis is the hallmark of cancer, and development of aggressiveness of primary tumor depends on de novo angiogenesis. Here, using multiple in vitro and in vivo models, we report that osteopontin (OPN) triggers vascular endothelial growth factor (VEGF)-dependent tumor progression and angiogenesis by activating breast tumor kinase (Brk)/nuclear factor-inducing kinase/nuclear factor-kappaB (NF-kappaB)/activating transcription factor-4 (ATF-4) signaling cascades through autocrine and paracrine mechanisms in breast cancer system. Our results revealed that both exogenous and tumor-derived OPN play significant roles in VEGF-dependent tumor angiogenesis. Clinical specimen analysis showed that OPN and VEGF expressions correlate with levels of neuropilin-1, Brk, NF-kappaB, and ATF-4 in different grades of breast cancer. Consequently, OPN plays essential role in two key aspects of tumor progression: VEGF expression by tumor cells and VEGF-stimulated neovascularization. Thus, targeting OPN and its regulated signaling network could be a novel strategy to block tumor angiogenesis and may develop an effective therapeutic approach for the management of breast cancer.
Chakraborty
Goutam
G
National Center for Cell Science, Pune, India.
Jain
Shalini
S
Kundu
Gopal C
GC
D051701:Activating Transcription Factor 4 / Q000032:analysis / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication; D001943:Breast Neoplasms / Q000098:blood supply* / Q000473:pathology*; D002465:Cell Movement; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D039942:Neuropilin-1 / Q000032:analysis / Q000378:metabolism; D053495:Osteopontin / Q000494:pharmacology / Q000502:physiology*; D019899:Paracrine Communication; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D051701:Activating Transcription Factor 4; D016328:NF-kappa B; D009363:Neoplasm Proteins; D039942:Neuropilin-1; D053495:Osteopontin; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000097782:NF-kappaB-Inducing Kinase; C497109:ATF4 protein, human; C088375:PTK6 protein, human