title: A critical role for GRP78/BiP in the tumor microenvironment for neovascularization during tumor growth and metastasis.
abstract: Glucose-regulated protein 78 (GRP78)/BiP is a multifunctional protein which plays a major role in endoplasmic reticulum (ER) protein processing, protein quality control, maintaining ER homeostasis, and controlling cell signaling and viability. Previously, using a transgene-induced mammary tumor model, we showed that Grp78 heterozygosity impeded cancer growth through suppression of tumor cell proliferation and promotion of apoptosis and the Grp78(+/-) mice exhibited dramatic reduction (70%) in the microvessel density (MVD) of the endogenous mammary tumors, while having no effect on the MVD of normal organs. This observation suggests that GRP78 may critically regulate the function of the host vasculature within the tumor microenvironment. In this article, we interrogated the role of GRP78 in the tumor microenvironment. In mouse tumor models in which wild-type (WT), syngeneic mammary tumor cells were injected into the host, we showed that Grp78(+/-) mice suppressed tumor growth and angiogenesis during the early phase but not during the late phase of tumor growth. Growth of metastatic lesions of WT, syngeneic melanoma cells in the Grp78(+/-) mice was potently suppressed. We created conditional heterozygous knockout of GRP78 in the host endothelial cells and showed severe reduction of tumor angiogenesis and metastatic growth, with minimal effect on normal tissue MVD. Furthermore, knockdown of GRP78 expression in immortalized human endothelial cells showed that GRP78 is a critical mediator of angiogenesis by regulating cell proliferation, survival, and migration. Our findings suggest that concomitant use of current chemotherapeutic agents and novel therapies against GRP78 may offer a powerful dual approach to arrest cancer initiation, progression, and metastasis.
authors.affiliation: Department of Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California 90089, USA.
authors.forename: Dezheng
authors.initials: D
authors.lastname: Dong
authors.forename: Christopher
authors.initials: C
authors.lastname: Stapleton
authors.forename: Biquan
authors.initials: B
authors.lastname: Luo
authors.forename: Shigang
authors.initials: S
authors.lastname: Xiong
authors.forename: Wei
authors.initials: W
authors.lastname: Ye
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Niyati
authors.initials: N
authors.lastname: Jhaveri
authors.forename: Genyuan
authors.initials: G
authors.lastname: Zhu
authors.forename: Risheng
authors.initials: R
authors.lastname: Ye
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Bruhn
authors.forename: Noah
authors.initials: N
authors.lastname: Craft
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.forename: Florence M
authors.initials: FM
authors.lastname: Hofman
authors.forename: Amy S
authors.initials: AS
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics; D059016:Tumor Microenvironment
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse