Association between host tissue vascularity and the prognostically relevant tumor vascularity in human cervical cancer

Höckel, Susanne; Schlenger, Karlheinz; Vaupel, Peter; Höckel, Michael

doi:10.3892/ijo.19.4.827

Cited by 37 publications

(41 citation statements)

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“…The presence of areas with low (,1%) O 2 tension is associated with increased metastasis and poor patient survival [5], giving rise to the notion that hypoxia is a hallmark of malignant cancer. The discovery that hypoxia alters cell biology [6] (e.g.…”

Section: Low Micro-environmental O 2 Tension and Ph As Hallmarks Of Cmentioning

confidence: 99%

The chemistry, physiology and pathology of pH in cancer

Swietach

Vaughan‐Jones

Harris

et al. 2014

Phil. Trans. R. Soc. B

466

352

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Cell survival is conditional on the maintenance of a favourable acid–base balance (pH). Owing to intensive respiratory CO 2 and lactic acid production, cancer cells are exposed continuously to large acid–base fluxes, which would disturb pH if uncorrected. The large cellular reservoir of H + -binding sites can buffer pH changes but, on its own, is inadequate to regulate intracellular pH. To stabilize intracellular pH at a favourable level, cells control trans-membrane traffic of H + -ions (or their chemical equivalents, e.g. ) using specialized transporter proteins sensitive to pH. In poorly perfused tumours, additional diffusion-reaction mechanisms, involving carbonic anhydrase (CA) enzymes, fine-tune control extracellular pH. The ability of H + -ions to change the ionization state of proteins underlies the exquisite pH sensitivity of cellular behaviour, including key processes in cancer formation and metastasis (proliferation, cell cycle, transformation, migration). Elevated metabolism, weakened cell-to-capillary diffusive coupling, and adaptations involving H + /H + -equivalent transporters and extracellular-facing CAs give cancer cells the means to manipulate micro-environmental acidity, a cancer hallmark. Through genetic instability, the cellular apparatus for regulating and sensing pH is able to adapt to extracellular acidity, driving disease progression. The therapeutic potential of disturbing this sequence by targeting H + /H + -equivalent transporters, buffering or CAs is being investigated, using monoclonal antibodies and small-molecule inhibitors.

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Section: Low Micro-environmental O 2 Tension and Ph As Hallmarks Of Cmentioning

confidence: 99%

The chemistry, physiology and pathology of pH in cancer

Swietach

Vaughan‐Jones

Harris

et al. 2014

Phil. Trans. R. Soc. B

466

352

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“…Although prolonged hypoxia is detrimental, cancer cells adapt to survive under hypoxic conditions and are thus selected to become more resistant to therapy (Harris, 2002). Accordingly, high levels of tumor hypoxia are associated with a poor prognosis in several cancers (Hockel and Vaupel, 2001). HIF-1 has a dual role in response to hypoxia, in that it mediates hypoxia-induced cell death (Carmeliet et al, 1998) as well as antiapoptotic responses including the expression of several survival genes and angiogenic factors (e.g.…”

Section: Introductionmentioning

confidence: 99%

REDD1 integrates hypoxia-mediated survival signaling downstream of phosphatidylinositol 3-kinase

Schwarzer¹,

Tondera²,

Arnold³

et al. 2004

Oncogene

120

108

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Cancer cells frequently evade apoptosis during tumorigenesis by acquiring mutations in apoptotic regulators. Chronic activation of the PI 3-kinase-Akt pathway through loss of the tumor suppressor PTEN is one mechanism by which these cells can gain increased protection against apoptosis. We report here that REDD1 (RTP801) can act as a transcriptional downstream target of PI 3-kinase signaling in human prostate cancer cells (PC-3). REDD1 expression is markedly reduced in PC-3 cells treated with LY294002 (LY) or Rapamycin and strongly induced under hypoxic conditions in a hypoxiainducible factor-1 (HIF-1)-dependent manner. Loss of function studies employing antisense molecules or RNA interference indicate that REDD1 is essential for invasive growth of prostate cancer cells in vitro and in vivo. Reduced REDD1 levels can sensitize cells towards apoptosis, whereas elevated levels of REDD1 induced by hypoxia or overexpression desensitize cells to apoptotic stimuli. Taken together our data designate REDD1 as a novel target for therapeutic intervention in prostate cancer.

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“…In some tumor cells, glycolysis is up-regulated (the Warburg effect (30)), and HIF-1␣ is stabilized; these observations have been linked to tumor propagation and metastasis (31)(32)(33).…”

mentioning

confidence: 99%

Structural and Mechanistic Studies on the Inhibition of the Hypoxia-inducible Transcription Factor Hydroxylases by Tricarboxylic Acid Cycle Intermediates

Hewitson

Liénard

McDonough

et al. 2007

Journal of Biological Chemistry

205

184

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In humans both the levels and activity of the ␣-subunit of the hypoxia-inducible transcription factor (HIF-␣) are regulated by its post-translation hydroxylation as catalyzed by iron-and 2-oxoglutarate (2OG)-dependent prolyl and asparaginyl hydroxylases (PHD1-3 and factor-inhibiting HIF (FIH), respectively). One consequence of hypoxia is the accumulation of tricarboxylic acid cycle intermediates (TCAIs). In vitro assays were used to assess non-2OG TCAIs as inhibitors of purified PHD2 and FIH. Under the assay conditions, no significant FIH inhibition was observed by the TCAIs or pyruvate, but fumarate, succinate, and isocitrate inhibited PHD2. Mass spectrometric analyses under nondenaturing conditions were used to investigate the binding of TCAIs to PHD2 and supported the solution studies. X-ray crystal structures of FIH in complex with Fe(II) and fumarate or succinate revealed similar binding modes for each in the 2OG co-substrate binding site. The in vitro results suggest that the cellular inhibition of PHD2, but probably not FIH, by fumarate and succinate may play a role in the Warburg effect providing that appropriate relative concentrations of the components are achieved under physiological conditions.In humans and other mammals, the ␣␤ heterodimeric hypoxia-inducible transcription factor (HIF) 4 (1) regulates the oxygen-dependent transcription of an array of genes, including those encoding for enzymes involved in glycolysis and those proteins involved in oxygen delivery. The HIF-␤ subunit (HIF-␤) is identical to aryl hydrocarbon nuclear translocator, and its levels are oxygen-independent. Both the levels and transcriptional activity of the ␣-subunit (HIF-␣) are oxygen-regulated, and hydroxylation of human HIF-␣ at one of two prolyl residues (Pro-402 or Pro-564 in human HIF-1␣) (2, 3) within the oxygen-dependent degradation domain enables binding of HIF-␣ to the von Hippel-Lindau protein, the targeting element of an ubiquitin-protein isopeptide ligase complex. Subsequent ubiquitylation leads to proteasomal degradation of HIF-␣ (for recent reviews see Refs. 4 -7). In humans this mechanism is augmented by hydroxylation of an asparaginyl residue in the C-terminal transcriptional activation domain of HIF-1␣ (8); this modification blocks the interaction of HIF-1␣ with the transcriptional co-activator CBP/p300 so disabling HIF-mediated transcription. During hypoxia, the reduction or ablation of HIF hydroxylase activity leads to accumulation of HIF-1␣, dimerization with HIF-1␤, and consequent transcription of genes involved in the hypoxic response. Hydroxylation of human HIF-1␣ is catalyzed by four Fe(II)-and 2-oxoglutarate (2OG)-dependent dioxygenases (9, 10), which use molecular oxygen and the tricarboxylic acid cycle intermediate (TCAI) 2OG as co-substrates to produce CO 2 and the TCAI succinate as co-products (Fig. 1). Of the HIF hydroxylases, i.e. three prolyl hydroxylases (PHD1, -2, and -3) (11-13) and one asparaginyl hydroxylase (factor-inhibiting HIF (FIH)) (8, 14), PHD2 is proposed to be the most important...

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Association between host tissue vascularity and the prognostically relevant tumor vascularity in human cervical cancer

Cited by 37 publications

References 0 publications

The chemistry, physiology and pathology of pH in cancer

The chemistry, physiology and pathology of pH in cancer

REDD1 integrates hypoxia-mediated survival signaling downstream of phosphatidylinositol 3-kinase

Structural and Mechanistic Studies on the Inhibition of the Hypoxia-inducible Transcription Factor Hydroxylases by Tricarboxylic Acid Cycle Intermediates

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