Hypoxia-Inducible Factor-1α Is a Key Regulator of Metastasis in a Transgenic Model of Cancer Initiation and Progression

Liao, Daiqing; Corle, Courtney; Seagroves, Tiffany N.; Johnson, Randall S.

doi:10.1158/0008-5472.can-06-2701

Cited by 319 publications

(263 citation statements)

References 32 publications

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“…HIF-2a antibody specificity has been validated in both studies and hence is unlikely to explain the discrepancy. In agreement with our data showing significant correlation of HIF-1a expression with disseminated disease stages, conditional deletion of HIF-1a in the mammary epithelium of mice expressing the PyMT oncoprotein resulted in retarded tumor growth and decreased pulmonary metastasis (Liao et al, 2007).…”

Section: Discussionsupporting

confidence: 93%

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

et al. 2011

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Tumor progression is intrinsically tied to the clonal selection of tumor cells with acquired phenotypes allowing to cope with a hostile microenvironment. Hypoxiainducible factors (HIFs) master the transcriptional response to local tissue hypoxia, a hallmark of solid tumors. Here, we report significantly longer patient survival in breast cancer with high levels of HIF-2a. Amphiregulin (AREG) and WNT1-inducible signaling pathway protein-2 (WISP2) expression was strongly HIF2a-dependent and their promoters were particularly responsive to HIF-2a. The endogenous AREG promoter recruited HIF-2a in the absence of a classical HIF-DNA interaction motif, revealing a novel mechanism of gene regulation. Loss of AREG expression in HIF-2a-depleted cells was accompanied by reduced activation of epidermal growth factor (EGF) receptor family members. Apparently opposing results from patient and in vitro data point to an HIF-2a-dependent auto-stimulatory tumor phenotype that, while promoting EGF signaling in cellular models, increased the survival of diagnosed and treated human patients. Our findings suggest a model where HIF2a-mediated autocrine growth signaling in breast cancer sustains a state of cellular self-sufficiency, thereby masking unfavorable microenvironmental growth conditions, limiting adverse selection and improving therapy efficacy. Importantly, HIF-2a/AREG/WISP2-expressing tumors were associated with luminal tumor differentiation, indicative of a better response to classical treatments. Shifting the HIF-1/2a balance toward an HIF-2-dominated phenotype could thus offer a novel approach in breast cancer therapy.

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Section: Discussionsupporting

confidence: 93%

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

et al. 2011

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“…These results stand in contrast to the analysis of immortalised murine embryonic fibroblasts, where a genetic inactivation of HIF-1a resulted in a substantial growth defect under hypoxia (Seagroves et al, 2001). Furthermore, murine mammary tumour cells from mice with Cre-loxP-mediated inactivation of HIF-1a failed to reach the logarithmic growth phase under low oxygen conditions (Liao et al, 2007). In line with these observations, human colon cancer cell lines HCT116 and RKO showed a growth defect under both normoxic and hypoxic conditions when HIF-1a was inactivated (Dang et al, 2006).…”

Section: Discussioncontrasting

confidence: 78%

HIF-1α determines the metastatic potential of gastric cancer cells

et al. 2009

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Gastric adenocarcinoma is characterised by rapid emergence of systemic metastases, resulting in poor prognosis due to vanished curative treatment options. Better understanding of the molecular basis of gastric cancer spread is needed to design innovative treatments. The transcription factor HIF-1a (hypoxia-inducible factor 1a) is frequently overexpressed in human gastric cancer, and inhibition of HIF-1a has proven antitumour efficacy in rodent models, whereas the relevance of HIF-1a for the metastatic phenotype of gastric adenocarcinoma remains elusive. Therefore, we have conducted a comprehensive analysis of the role of HIF-1a for pivotal metastasis-associated processes of human gastric cancer. Immunhistochemistry for HIF-1a showed specific staining at the invading tumour edge in 90% of human gastric cancer samples, whereas normal gastric tissue was negative and only a minority of early gastric cancers (T1 tumours) showed specific staining. Hypoxia-inducible factor 1a-deficient cells showed a significant reduction of migratory, invasive and adhesive properties in vitro. Furthermore, the HIF-1a-inhibitor 2-methoxy-estradiol significantly reduced metastatic properties of gastric cancer cells. The accentuated expression at the invading edge together with the in vitro requirement of HIF-1a for migration, invasion and adherence argues for a pivotal role of HIF-1a in local invasion and, ultimately, systemic tumour spread. These results warrant the exploration of HIF-1a-inhibiting substances in clinical treatment studies of advanced gastric cancer.

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“…Possibly, HIF-2a controls gene expression in (hypoxia-induced) metastatic disease, whereas HIF1a plays a more prominent role during normal oxygen homeostasis. This is supported by the finding that HIF-1a does not induce metastasis formation in a transgenic mouse model, but does facilitate this process (Liao et al, 2007). The regulation of TWIST1 by the HIF pathway in mammalian cells provides an attractive explanation for the poor survival seen in patients with HIF overexpression (Bos et al, 2003).…”

Section: Twist1 Is a Target Of Hif-2a Eh Gort Et Almentioning

confidence: 92%

The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2α

et al. 2007

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Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that play a crucial role in oxygen homeostasis. Intratumoral hypoxia and genetic alterations lead to HIF activity, which is a hallmark of solid cancer and is associated with poor clinical outcome. HIF activity is regulated by an evolutionary conserved mechanism involving oxygen-dependent HIFa protein degradation. To identify novel components of the HIF pathway, we performed a genome-wide RNA interference screen in Caenorhabditis elegans, to suppress HIF-dependent phenotypes, like egg-laying defects and hypoxia survival. In addition to hif-1 (HIFa) and aha-1 (HIFb), we identified hlh-8, gska-3 and spe-8. The hlh-8 gene is homologous to the human oncogene TWIST1. We show that TWIST1 expression in human cancer cells is enhanced by hypoxia in a HIF-2a-dependent manner. Furthermore, intronic hypoxia response elements of TWIST1 are regulated by HIF-2a, but not HIF-1a. These results identify TWIST1 as a direct target gene of HIF-2a, which may provide insight into the acquired metastatic capacity of hypoxic tumors.

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Hypoxia-Inducible Factor-1α Is a Key Regulator of Metastasis in a Transgenic Model of Cancer Initiation and Progression

Cited by 319 publications

References 32 publications

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

HIF-1α determines the metastatic potential of gastric cancer cells

The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2α

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