The role of hypoxia-inducible factors in cancer

Maynard, Mindy A.; Ohh, Michael

doi:10.1007/s00018-007-7082-2

Cited by 125 publications

(133 citation statements)

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“…Hypoxia-inducible factor has been shown to play a major role in the angiogenesis and growth of various tumours, including breast (Leek et al, 2002), bladder (Palit et al, 2005), renal (Klatte et al, 2007), pancreatic (Shibaji et al, 2003) and cervical (Birner et al, 2000) cancers. Indeed, overexpression of, in particular, HIF-1a, has been correlated with unfavourable prognosis in a number of malignancies (Theodoropoulos et al, 2005;Maynard and Ohh, 2007;Trastour et al, 2007).…”

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confidence: 99%

Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis

et al. 2009

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The hypoxia-mediated response of tumours is a major determining factor in growth and metastasis. Understanding tumour biology under hypoxic conditions is crucial for the development of antiangiogenic therapy. Using one of the largest cohorts of rectal adenocarcinomas to date, this study investigated hypoxia-inducible factor-1a (HIF-1a) and HIF-2a protein expression in relation to rectal cancer recurrence and cancer-specific survival. Patients (n ¼ 90) who had undergone surgery for rectal adenocarcinoma, with no prior neoadjuvant therapy or metastatic disease, and for whom adequate follow-up data were available were selected. Microvessel density (MVD), HIF-1a and HIF-2a expressions were assessed immunohistologically with the CD34 antibody for vessel identification and the NB100-131B and NB100-132D3 antibodies for HIF-1a and HIF-2a, respectively. In a multifactorial analysis, results were correlated with tumour stage, recurrence rate and long-term survival. Microvessel density was higher across T and N stages (Po0.001) and associated with poor survival (hazard ratio (HR) ¼ 8.7, Po0.005) and decreased disease-free survival (HR ¼ 4.7, Po0.005). hypoxia-inducible factor-1a and -2a were expressed in 450% of rectal cancers (HIF-1a, 54%, 48/90; HIF-2a, 64%, 58/90). HIF-1a positivity was associated with both TNM stage (Po0.05) and vascular invasion (Po0.005). In contrast, no associations were shown between HIF-2a expression and any pathological features, and HIF-1a positivity had no effect on outcome. The study showed an independent association between HIF-1a expression and advanced TNM stage with poor outcome. Our results indicate that HIF-1a, but not HIF-2a, might be used as a marker of prognosis, in addition to methods currently used, to enhance patient management.

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confidence: 99%

Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis

et al. 2009

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“…There are three VHL gene products: a full-length 213 amino acid protein and two shorter isoforms, resulting from an alternative splicing excluding the second exon and an alternative translation initiated from an in-frame ATG codon respectively (Richards et al 1996, Kaelin 2008. VHL is involved in oxygendependent regulation of hypoxia-inducible factor (HIF) by constituting a part of the E3 ubiquitin ligase complex that ubiquitinates HIF-1a, thereby targeting it for proteasomal degradation (Maynard & Ohh 2007, Kaelin 2008. VHL is considered a classical tumor suppressor gene in the sense that, in accordance with Knudsons two-hit model, biallelic inactivation is usually required for tumorigenesis (Knudson 1971(Knudson , 1996.…”

Section: Ret-associated Pccs and Pglsmentioning

confidence: 99%

“…EGLN1 is a member of the EGLN prolyl hydroxylase family, consisting of EGLN1, EGLN2, and EGLN3 (also termed PHD2, PHD1, and PHD3). In the presence of oxygen, the EGLN proteins catalyze a proline hydroxylation of HIF-a, allowing it to be recognized and targeted for degradation by the VHL containing E3 ubiquitin ligase complex (Maynard & Ohh 2007). EGLN1 appears to be the main HIF prolyl hydroxylase under conditions of normal oxygen levels (Berra et al 2003).…”

Section: Egl Nine Homologmentioning

confidence: 99%

“…2). HIFs are sequence-specific DNA-binding transcription factors that activate several genes promoting adaptation and survival under conditions of reduced oxygen Endocrine-Related Cancer (2011) 18 R253-R276 www.endocrinology-journals.org levels (hypoxia; reviewed by Maynard & Ohh (2007), Tennant et al (2009), andGimenez-Roqueplo (2010)). Active HIF is a heterodimer consisting of one a and one b subunit.…”

Section: Hif-a Regulation and Pseudohypoxiamentioning

confidence: 99%

“…The VHL protein, pVHL, is part of an E3 ubiquitin ligase complex that ubiquitinates HIF-a and thereby targets it for degradation by the 26S proteasome (Maynard & Ohh 2007). The interaction requires proline hydroxylation of HIF-a in order for it to be recognized by the E3 complex.…”

Section: Hif-a Regulation and Pseudohypoxiamentioning

confidence: 99%

See 2 more Smart Citations

Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas

Welander¹,

Söderkvist²,

Gimm³

2011

Endocrine-Related Cancer

308

318

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Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors of the adrenal glands and the sympathetic and parasympathetic paraganglia. They can occur sporadically or as a part of different hereditary tumor syndromes. About 30% of PCCs and PGLs are currently believed to be caused by germline mutations and several novel susceptibility genes have recently been discovered. The clinical presentation, including localization, malignant potential, and age of onset, varies depending on the genetic background of the tumors. By reviewing more than 1700 reported cases of hereditary PCC and PGL, a thorough summary of the genetics and clinical features of these tumors is given, both as part of the classical syndromes such as multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease, neurofibromatosis type 1, and succinate dehydrogenase-related PCC-PGL and within syndromes associated with a smaller fraction of PCCs/PGLs, such as Carney triad, Carney-Stratakis syndrome, and MEN1. The review also covers the most recently discovered susceptibility genes including KIF1Bb, EGLN1/PHD2, SDHAF2, TMEM127, SDHA, and MAX, as well as a comparison with the sporadic form. Further, the latest advances in elucidating the cellular pathways involved in PCC and PGL development are discussed in detail. Finally, an algorithm for genetic testing in patients with PCC and PGL is proposed.

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