Hypoxia‐inducible factor‐1α is associated with angiogenesis, and expression of bFGF, PDGF‐BB, and EGFR in invasive breast cancer

Bos, Reinhard; Diest, Paul J. van; Jong, Johannes S. de; Groep, Petra van der; Valk, Paul van der; Wall, Elsken van der

doi:10.1111/j.1365-2559.2005.02045.x

Cited by 169 publications

(129 citation statements)

References 48 publications

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“…In addition to its role in up-regulating glycolysis in response to hypoxia, HIF-1α is also the main transcription factor for vascular endothelial growth factor (VEGF), which stimulates angiogenesis [168,[180][181][182]. HIF-1α is part of the IGF-1/ PI3K/Akt signaling pathway that also indirectly influences expression of β FGF, another key angiogenesis growth factor [168,183]. Hence the sustained vascularity of tumors can be linked mechanistically to the metabolic requirements of substrate level phosphorylation necessary for tumor cell survival.…”

Section: Sustained Vascularity (Angiogenesis)mentioning

confidence: 99%

Cancer as a Metabolic Disease

Seyfried¹

2012

194

291

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Emerging evidence indicates that impaired cellular energy metabolism is the defining characteristic of nearly all cancers regardless of cellular or tissue origin. In contrast to normal cells, which derive most of their usable energy from oxidative phosphorylation, most cancer cells become heavily dependent on substrate level phosphorylation to meet energy demands. Evidence is reviewed supporting a general hypothesis that genomic instability and essentially all hallmarks of cancer, including aerobic glycolysis (Warburg effect), can be linked to impaired mitochondrial function and energy metabolism. A view of cancer as primarily a metabolic disease will impact approaches to cancer management and prevention.

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Section: Sustained Vascularity (Angiogenesis)mentioning

confidence: 99%

Cancer as a Metabolic Disease

Seyfried¹

2012

194

291

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“…HIF-1a induces transcription of genes that are involved in angiogenesis, cell survival, proliferation and promotes an aggressive tumor phenotype. 31,32 Several studies demonstrated high microvessel count and high microvessel density in tumors with fibrotic focus, especially in case a fibrotic focus is relatively large and harbors necrosis. 13,14 The fibroblasts occupying a fibrotic focus are reported to be highly proliferative and have the ability to express proteinase, which is crucial for developing metastases.…”

Section: Featurementioning

confidence: 99%

Fibrotic focus and hypoxia in male breast cancer

et al. 2012

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Fibrotic focus is a scar-like lesion near the center of a carcinoma and has been associated with high-grade, lymph node metastases and poor survival in female breast cancers. Hypoxia is suggested to be the crucial link between fibrotic focus and aggressive tumor phenotype and is also itself a poor prognostic marker. We here set out to study fibrotic focus and hypoxia in male breast cancer for the first time. In a group of 134 male breast cancer patients, the presence and size of a fibrotic focus and the expression of three hypoxia-related immunohistochemical stainings, hypoxia-inducible factor-1a, carbonic anhydrase IX and Glut-1 were studied in correlation with clinicopathological features and prognosis. Fibrotic focus was seen in 25% of the male breast cancer cases and was correlated with hypoxia-inducible factor-1a overexpression (P ¼ 0.023), high grade (P ¼ 0.005), high mitotic activity (P ¼ 0.005) and lymph node metastases (P ¼ 0.037). Hypoxia-inducible factor-1a-positive tumors were more often high grade (P ¼ 0.003) and HER2 amplified (P ¼ 0.005). Glut-1 expression was also more common in grade 3 tumors (P ¼ 0.038), but no association between carbonic anhydrase IX and any clinicopathological feature was found. Fibrotic focus 48 mm and hypoxia-inducible factor-1a overexpression were correlated with decreased patients' outcome (P ¼ 0.035 and 0.008, respectively). Hypoxia-inducible factor1a overexpression was an independent and the most powerful predictor of survival in multivariate analysis (P ¼ 0.029; hazard ratio 2.5). In conclusion, the presence of a fibrotic focus is associated with hypoxia-inducible factor-1a overexpression, and both are associated with aggressive tumor phenotype and poor survival in male breast cancer. These markers seem to have similar clinical importance as previously reported in female breast cancer. Modern Pathology (2012) 25, 1397-1404; doi:10.1038/modpathol.2012.101; published online 8 June 2012Keywords: fibrotic focus; hypoxia; male breast cancer; prognosis Male breast cancer is uncommon and represents o1% of all breast cancers. 1 Large series in male breast cancer are lacking and much of the knowledge is generalized from breast cancer in female subjects. The limited data published on male breast cancer indicate that there are genetic and phenotypic differences between male and female breast cancer. [2][3][4][5][6] Initially, prognosis in men was claimed to be poor with higher incidence of lymph node metastases at the time of discovery, but more recent studies showed that prognosis of male and female breast cancers corrected for stage and age is similar. [7][8][9] Although tumor size and lymph node status are independent prognosticators in male breast cancer, 9,10 there still is a need for more accurate outcome predictors of male breast cancer.A fibrotic focus is a scar-like lesion consisting of an area of mainly collagen and fibroblasts, often located near the center of a carcinoma. Fibrotic focus is associated with poor survival in female breast cancer and with high grade, hig...

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“…38,39 In tumors, various growth factors aberrantly secreted as part of paracrine or autocrine loops, have been implicated in stabilizing or up-regulating at transcriptional level the HIF1a. [40][41][42] To test whether in EOC cells HIF1a is inducible by PDGF, immortalized epithelial ovarian cancer cells were treated with PDGF BB in the presence or absence of imatinib, PD98059 and rapamycin. Cells were maintained in low oxygen atmosphere (2% O2) and HIF1a was measured in nuclear protein fractions by immunoblotting.…”

Section: Vegf Is Expressed In Ovarian Tumors and Is Secreted By Primamentioning

confidence: 99%