title: Perk-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress.
abstract: It has been well established that the tumor microenvironment can promote tumor cell adaptation and survival. However, the mechanisms that influence malignant progression have not been clearly elucidated. We have previously demonstrated that cells cultured under hypoxic/anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR). Here, we show that tumors derived from K-Ras-transformed Perk(-/-) mouse embryonic fibroblasts (MEFs) are smaller and exhibit less angiogenesis than tumors with an intact ISR. Furthermore, Perk promotes a tumor microenvironment that favors the formation of functional microvessels. These observations were corroborated by a microarray analysis of polysome-bound RNA in aerobic and hypoxic Perk(+/+) and Perk(-/-) MEFs. This analysis revealed that a subset of proangiogenic transcripts is preferentially translated in a Perk-dependent manner; these transcripts include VCIP, an adhesion molecule that promotes cellular adhesion, integrin binding, and capillary morphogenesis. Taken with the concomitant Perk-dependent translational induction of additional proangiogenic genes identified by our microarray analysis, this study suggests that Perk plays a role in tumor cell adaptation to hypoxic stress by regulating the translation of angiogenic factors necessary for the development of functional microvessels and further supports the contention that the Perk pathway could be an attractive target for novel antitumor modalities.
authors.affiliation: Ottawa Health Research Institute, Ottawa, ON K1H 1C4, Canada.
authors.forename: Jaime D
authors.initials: JD
authors.lastname: Blais
authors.forename: Christina L
authors.initials: CL
authors.lastname: Addison
authors.forename: Robert
authors.initials: R
authors.lastname: Edge
authors.forename: Theresa
authors.initials: T
authors.lastname: Falls
authors.forename: Huijun
authors.initials: H
authors.lastname: Zhao
authors.forename: Kishore
authors.initials: K
authors.lastname: Wary
authors.forename: Costas
authors.initials: C
authors.lastname: Koumenis
authors.forename: Heather P
authors.initials: HP
authors.lastname: Harding
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: Martin
authors.initials: M
authors.lastname: Holcik
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D005347:Fibroblasts / Q000201:enzymology; D020869:Gene Expression Profiling; D019073:HT29 Cells; D006801:Humans; D000860:Hypoxia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D014176:Protein Biosynthesis; D013312:Stress, Physiological / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D019892:eIF-2 Kinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D019892:eIF-2 Kinase