title: Sustained endothelial expression of HoxA5 in vivo impairs pathological angiogenesis and tumor progression.
abstract: HoxA5 is expressed in quiescent endothelial cells (EC), but absent in activated angiogenic EC. To examine the efficacy of targeting HoxA5 therapeutically to quell pathologic or tumor angiogenesis, we generated an inducible, transgenic mouse model of sustained HoxA5 expression in ECs. During pathologic angiogenesis, sustained HoxA5 regulates expression several angiogenic effector molecules, notably increased expression of TSP-2 and reduced expression of VEGF, thus leading to inhibition of pathological angiogenesis in tissues. To evaluate if this impressive reduction of vascularization could also impact tumor angiogenesis, HoxA5 mice were bred with a mouse model of de novo squamous carcinogenesis, e.g., K14-HPV16 mice. Activation of EC-HoxA5 significantly reduced infiltration by mast cells into neoplastic skin, an early hallmark of progression to dysplasia, reduced angiogenic vasculature, and blunted characteristics of tumor progression. To evaluate HoxA5 as a therapeutic, topical application of a HoxA5 transgene onto early neoplastic skin of K14-HPV16 mice similarly resulted in a significant impairment of angiogenic vasculature and progression to dysplasia to a similar extent as observed with genetic delivery of HoxA5. Together these data indicate that HoxA5 represents a novel molecule for restricting pathological and tumorigenic angiogenesis.
authors.affiliation: Department of Surgery, Surgical Research Laboratory, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Ileana
authors.initials: I
authors.lastname: Cuevas
authors.affiliation: Department of Surgery, Surgical Research Laboratory, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Hans
authors.initials: H
authors.lastname: Layman
authors.affiliation: Department of Cell & Developmental Biology and Knight Cancer Institute, Oregon Health & Sciences University, Portland, Oregon, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Coussens
authors.affiliation: Department of Surgery, Surgical Research Laboratory, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Nancy
authors.initials: N
authors.lastname: Boudreau
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D018398:Homeodomain Proteins / Q000235:genetics*; D052162:Human papillomavirus 16; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009385:Neoplastic Processes; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D030361:Papillomavirus Infections / Q000235:genetics / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics*; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology / Q000821:virology; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000821:virology; D019699:Thrombospondins / Q000235:genetics; D014157:Transcription Factors; D019076:Transgenes / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D000099262:Thrombospondin 2
chemical_list: D018398:Homeodomain Proteins; D010750:Phosphoproteins; D019699:Thrombospondins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000099262:Thrombospondin 2; C059637:Hoxa5 protein, mouse; C467480:vascular endothelial growth factor A, mouse
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