Choking Hypoxia-Inducible Factor 1α: A Novel Mechanism for Connective Tissue Growth Factor Inhibition of Angiogenesis

Abstract

Journal of the National Cancer Institute, Vol. 98, No. 14, July 19, 2006 Among the driving forces that orchestrate oncogenic transformation, aberrant tumor angiogenesis has evolved as a process assured by the conscription of various signaling pathways with redundant functions. These pathways converge on the same task: to produce more vessels, without ensuring correct structural constraints and proper function. Different cellular components in tissues are equipped with proangiogenic molecular machinery, as demonstrated by studies on the role of infl ammatory cells in tumor promotion that have driven the development of new therapies for cancer prevention and treatment ( 1 , 2 ) . Transcriptional reprogramming controlled by dysregulated signaling pathways is one of the mechanisms that are the basis for the cellular adaptations necessary for cancer establishment. In particular, one master regulator, the hypoxia-inducible transcription factor 1 (HIF-1) complex, which controls tissue homeostasis, seems to take center stage as a pervasive instigator of transformation for almost all cellular compartments in tissues. HIF-1, primarily recognized as a mediator of adaptive responses to tissue oxygenation, integrates diverse information related to energy status, glucose, and iron metabolism, as well as growth factor signaling in normoxia and hypoxia ( 3 , 4 ) . Furthermore, recent evidence indicates that HIF-1 – activated metabolic responses are essential for the recruitment and infi ltration of myeloid cells at early stages of infl ammation ( 5 ) . The decision to constitutively activate HIF-1 α as a means for coping with stressful or threatening local conditions in the microenvironment carries the high cost of increased risk of neoplastic transformation. HIF-1 also contributes to defi ne an invasive, lethal cancer phenotype by elevating the metabolic resources of cells through increased glucose uptake, glycolysis, and angiogenesis ( 6 ) . The HIF-1 α subunit of the heterodimeric transcriptional complex HIF-1 is the labile regulatory element destined to ubiquitination and default destruction in the absence of alerting signals from the microenvironment. Proteins of the von Hippel-Lindau (pVHL) – ubiquitin – proteasome pathway, isoforms of prolyl hydroxylases (PHDs), and the acetyltransferase ARD1 eliminate necessary HIF-1 α under normoxia in normal cells. Hydroxylation of HIF-1 α at proline residues 402 and 564 in the oxygendependent degradation (ODD) domain by PHDs targets HIF-1 α Affi liations of authors: Molecular Oncology Laboratory, National Cancer Research Institute, Genoa, Italy (FT, AA); University of Insubria, Varese, Italy (DMN). Correspondence to: Adriana Albini, PhD, Ist. Nazionale per la Ricerca sul Cancro, Molecular Oncology, Largo Rosanna Benzi, 10, Genova 16132, Italy (e-mail: adriana.albini@istge.it ).