Overexpression of Hypoxia Inducible Factor-1 Alpha is an Independent Risk Factor for Recurrence After Curative Resection of Colorectal Liver Metastases

Shimomura, Manabu; Hinoi, Takao; Kuroda, Satoshi; Adachi, Tomohiko; Kawaguchi, Yasuo; Sasada, Tatsunari; Takakura, Yuji; Egi, Hiroyuki; Okajima, Masazumi; Tashiro, Hirotaka; Nishizaki, Takashi; Ohdan, Hideki

doi:10.1245/s10434-013-2945-2

Cited by 31 publications

(33 citation statements)

References 28 publications

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“…Patients with positive HIF-1a and VEGF tumors tended to have a poorer prognosis and shorter survival time (Cao et al, 2009). HIF-1a overexpression was also positively correlated with colorectal liver metastasis and phosphoinositide-3-kinase catalytic subunit alpha mutation status and served as an independent risk factor for malignancy recurrence after curative resection of colorectal liver metastasis (Shimomura et al, 2013). Elevated expression of HIF-1a was associated with vascular invasion and a poor prognosis for patients with hepatocellular carcinoma (Zheng et al, 2013).…”

Section: Hif-1a and Cancer Prognosismentioning

confidence: 92%

Molecular Responses to Hypoxia-Inducible Factor 1α and Beyond

2014

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Cellular response to changes in oxygen tension during normal development or pathologic processes is, in part, regulated by hypoxia-inducible factor (HIF), an oxygen-sensitive transcription factor. HIF activity is primarily controlled through post-translational modifications and stabilization of HIF-1a and HIF-2a proteins and is regulated by a number of cellular pathways involving both oxygen-dependent and -independent mechanisms. Stabilization of HIF-1a activates transcription of genes that participate in key pathways in carcinogenesis, such as angiogenesis, dedifferentiation, and invasion. Since its discovery more than two decades ago, HIF-1a has become a hot topic in molecular research and has been implicated not only in disease pathology but also in prognosis. In this review, we will focus on recent insights into HIF-1a regulation, function, and gene expression. We will also discuss emerging data on the involvement of HIF in cancer prognosis and therapeutic interventions.

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Section: Hif-1a and Cancer Prognosismentioning

confidence: 92%

Molecular Responses to Hypoxia-Inducible Factor 1α and Beyond

2014

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“…Tumor hypoxia activates the hypoxia-inducible factors (Hifs), which induce an adaptive response associated with an array of processes that foster tumor progression (1)(2)(3)(4). Most famous is the angiogenic switch, leading to the formation of immature, leaky vessels that however cannot re-install normoxia but instead enhance the spread of disease (5).…”

Section: Introductionmentioning

confidence: 99%

Antihypoxic Potentiation of Standard Therapy for Experimental Colorectal Liver Metastasis through Myo-Inositol Trispyrophosphate

Limani¹,

Linecker²,

Kachaylo³

et al. 2016

Clinical Cancer Research

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PURPOSE: Tumor hypoxia activates hypoxia-inducible factors (Hifs), which induce a range of malignant changes including vascular abnormalities. Here, we determine whether inhibition of the hypoxic tumor response through myo-inositol trispyrophosphate (ITPP), a compound with antihypoxic properties, is able to cause prolonged vascular normalization that can be exploited to improve standardof-care treatment. EXPERIMENTAL DESIGN: We tested ITPP on two syngeneic orthotopic mouse models of lethal colorectal cancer liver metastasis. Tumors were monitored by MRI and analyzed for the hypoxic response and their malignant potential. A Hif activator and in vitro assays were used to define the working mode of ITPP. Hypoxic response and vasculature were re-evaluated 4 weeks after treatment. Finally, we determined survival following ITPP monotherapy, FOLFOX monotherapy, FOLFOX plus Vegf antibody, and FOLFOX plus ITPP, both overlapping and sequential. RESULTS: ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least 4 weeks after treatment cessation. Compared with FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure. CONCLUSIONS: Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing anticancer treatment in a way amenable to clinical translation. Clin Cancer Res; 22(23); 5887-97. DOI: https://doi.org/10.1158/1078-0432. Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-125980 Accepted Version Originally published at: Limani, P; Linecker, M; Kachaylo, E; Tschuor, C; Kron, P; Schlegel, A; Ungethuem, U; Jang, J H; Georgiopoulou, S; Claude Nicolau, C; Lehn, J-M; Graf, R; Humar, B; Clavien, P-A (2016). Antihypoxic potentiation of standard therapy for experimental colorectal liver metastasis through myo-inositol trispyrophosphate. Clinical Cancer Research, 22 (23) Results. ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least four weeks after treatment cessation. Compared to FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure. Conclusions.Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing antic...

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“…68,6 9 Bu tür büyüme faktörlerinin kendi akraba reseptörlerine bağlanması sinyal transdüksiyonu yolaklarını aktive ederek hücre proliferasyonunu/sağkalımını destekler ve HIF-1alfa'nın kendisinin de ekpresyonunu stimule eder. 70 Büyüme faktörleri hipoksiyle beraber bazı hücrelerde MAPK ve fosfatidilinositol 3 kinaz (P13K) sinyal yolaklarını aktive edebilir, hücre proliferasyonunu kolaylaştırabilirler. Bu ise IGF2 ve TGF-alfa kodlayıcıları da dahil olmak üzere bazı büyü-me faktörleri, HIF-1alfa hedef genlerinin transkripsiyonel aktivitelerini artırır ve böylece kanser oluşumunda kritik bir öneme sahip olan otokrin-sinyalleme yolaklarına yardımcı olur.…”

Section: Hif-1'in Hedef Genleriunclassified

“…Bu ise IGF2 ve TGF-alfa kodlayıcıları da dahil olmak üzere bazı büyü-me faktörleri, HIF-1alfa hedef genlerinin transkripsiyonel aktivitelerini artırır ve böylece kanser oluşumunda kritik bir öneme sahip olan otokrin-sinyalleme yolaklarına yardımcı olur. 6,69,70 Kanser gelişimi Bazı insan kanserlerinde, muhtemelen intratümöral hipoksi veya genetik alterasyonlar sonucu HIF-1alfa ve HIF-2alfa'nın aşırı ekspresyonu bulunmuştur. 5,71 Tümör büyüklüğü artarken, tümör kütlesinin içerisi yeterli kan damarı oluşturuluncaya kadar giderek hipoksikleşir.…”

Section: Hif-1'in Hedef Genleriunclassified

Hypoxia-inducible factor-1: Physiological and Pathological Response to Hypoxia of Cell

Demirel¹,

Çetinkaya²

2014

Sakarya Med J

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Oksijen homeostazında kritik bir rol oynayan hipoksiyle indüklenen faktör-1 (HIF-1); anjiyogenezis, eritropoezis, demir metabolizması ve glukoz metabolizması gibi metabolik süreçlerin transkripsiyonel regülatörüdür. Ayrıca fetal ve posnatal hayat sürecinde anahtar fizyolojik sistemlerin düzenlenmesi için gereklidir. HIF-1 heterodimerik bir protein olup oksijen regülasyonunda rol alan HIF-1α (homologları HIF-2α ve HIF-3α) ve nükleusta bulunan HIF-1α alt ünitelerinden oluşmaktadır. HIF-1'in α alt ünitesinin stabilitesi ve aktivitesi hidroksilasyon, ubikütinasyon, asetilasyon ve fosforilasyon gibi transkripsiyon sonrası modifikasyonlarla sağlanmaktadır. Normokside, HIF1-α'nın oksijen-bağımlı degradasyon (ODD) bölgesinde yer alan iki prolinin hidroksilasyonu ve bir lizinin asetilasyonuyla başlayan bu regülasyon bir tümör baskılayıcı gen olan von Hippel-Lindau proteini (pVHL) ile E3 ligaz kompleksi tarafından ubikütin-proteazom yolu ile gerçekleştirilmektedir. Hipoksik koşullarda, hidroksillenemeyen HIF-1α alt ünitesi stabil hale gelir ve cAMP, protein/p300 gibi koaktivatörler ile etkinleşerek nükleusa geçer. HIF-1α alt ünitesi ile birleşerek hipoksiye cevap genlerinin ekspresyonunu regüle eder. HIF-1'in aşırı ekspresyonu çeşitli kanser olgularında saptanmış ve HIF-1'in hedeflenmesinin kanser tedavisinde yeni bir yaklaşım olabileceği düşünülmüştür. Hypoxia-inducible factor 1 (HIF-1) which has a critical role in the homeostasis of oxygen, is a transcriptional regulator of metabolic processes such as angiogenesis, erythropoiesis, iron metabolism and glucose metabolism. It is also essential for the regulation of key physiological systems in the process of fetal and postnatal life. HIF-1 is a heterodimeric protein consists of HIF-1� (homologues HIF-2� and HIF-2�) that involved in the regulation of oxygen and HIF-1� subunits that situated in the nucleus. Stability and activity of HIF-1� subunit is provided with post-transcriptional modification such as hydroxylation Özet AbstractMakale / Article

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Overexpression of Hypoxia Inducible Factor-1 Alpha is an Independent Risk Factor for Recurrence After Curative Resection of Colorectal Liver Metastases

Cited by 31 publications

References 28 publications

Molecular Responses to Hypoxia-Inducible Factor 1α and Beyond

Molecular Responses to Hypoxia-Inducible Factor 1α and Beyond

Antihypoxic Potentiation of Standard Therapy for Experimental Colorectal Liver Metastasis through Myo-Inositol Trispyrophosphate

Hypoxia-inducible factor-1: Physiological and Pathological Response to Hypoxia of Cell

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