| 1. |
- Seidel, Sascha, et al.
(författare)
-
A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha
- 2010
-
Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 133, s. 983-995
-
Tidskriftsartikel (refereegranskat)abstract
- Glioma growth and progression depend on a specialized subpopulation of tumour cells, termed tumour stem cells. Thus, tumour stem cells represent a critical therapeutic target, but the molecular mechanisms that regulate them are poorly understood. Hypoxia plays a key role in tumour progression and in this study we provide evidence that the hypoxic tumour microenvironment also controls tumour stem cells. We define a detailed molecular signature of tumour stem cell genes, which are overexpressed by tumour cells in vascular and perinecrotic/hypoxic niches. Mechanistically, we show that hypoxia plays a key role in the regulation of the tumour stem cell phenotype through hypoxia-inducible factor 2 alpha and subsequent induction of specific tumour stem cell signature genes, including mastermind-like protein 3 (Notch pathway), nuclear factor of activated T cells 2 (calcineurin pathway) and aspartate beta-hydroxylase domain-containing protein 2. Notably, a number of these genes belong to pathways regulating the stem cell phenotype. Consistently, tumour stem cell signature genes are overexpressed in newly formed gliomas and are associated with worse clinical prognosis. We propose that tumour stem cells are maintained within a hypoxic niche, providing a functional link between the well-established role of hypoxia in stem cell and tumour biology. The identification of molecular regulators of tumour stem cells in the hypoxic niche points to specific signalling mechanisms that may be used to target the glioblastoma stem cell population.
|
|
| 2. |
- Fischer, Silvia, et al.
(författare)
-
Extracellular RNA Liberates Tumor Necrosis Factor-alpha to Promote Tumor Cell Trafficking and Progression
- 2013
-
Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 73:16, s. 5080-5089
-
Tidskriftsartikel (refereegranskat)abstract
- Extracellular RNA (eRNA) released from injured cells promotes tissue permeability, thrombosis, and inflammation in vitro and in vivo, and RNase1 pretreatment can reduce all these effects. In this study, we investigated the role of the eRNA/RNase1 system in tumor progression and metastasis. Under quiescent and stimulatory conditions, tumor cells released much higher levels of endogenous extracellular RNA (eRNA) than nontumor cells. In glioblastomas, eRNA was detected at higher levels in tumors than nontumor tissue. eRNA induced tumor cells to adhere to and migrate through human cerebral microvascular endothelial cells (HCMEC/D3), in a manner requiring activation of VEGF signaling. In addition, eRNA liberated TNF-alpha from macrophages in a manner requiring activation of the TNF-alpha-converting enzyme TACE. Accordingly, supernatants derived from eRNA-treated macrophages enhanced tumor cell adhesion to HCMEC/D3. TNF-alpha release evoked by eRNA relied upon signaling activation of mitogen-activated protein kinases and the NF-kappa B pathway. In subcutaneous xenograft models of human cancer, administration of RNase1 but not DNase decreased tumor volume and weight. Taken together, these results suggest that eRNA released from tumor cells has the capacity to promote tumor cell invasion through endothelial barriers by both direct and indirect mechanisms, including through a mechanism involving TNF-alpha release from tumor-infiltrating monocytes/macrophages. Our findings establish a crucial role for eRNA in driving tumor progression, and they suggest applications for extracellular RNase1 as an antiinvasive regimen for cancer treatment.
|
|
| 3. |
- Habig, Kathrin, et al.
(författare)
-
Low threshold unmyelinated mechanoafferents can modulate pain
- 2017
-
Ingår i: BMC Neurology. - : BIOMED CENTRAL LTD. - 1471-2377. ; 17
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Human, hairy skin contains a subgroup of C-fibers, the C-low threshold mechanoreceptive afferents ((C-LTMR) C-tactile or C-touch (CT) fibers) that are linked with the signaling of affective aspects of human touch. Recent studies suggest an involvement of these afferents in the modulation of pain in healthy volunteers. Small fiber neuropathy (SFN) is associated with a damage of C-fibers. Therefore, an impairment of C-LTMRs can be assumed. We aimed to elaborate a possible role of CT-afferents in pain modulation by investigating healthy volunteers and SFN-patients. Methods: Experiment I: 20 SFN-patients (12 women, median age 52.0 years) and 20 healthy controls (14 women, median age 43.0 years) participated in this prospective fMRI and psychophysical study. Heat-pain (HP), CT-targeted touch (slow brushing) and HP combined with CT-targeted touch were applied in randomized order to the left shank in a block design. The participants rated pain intensity on a visual analogue scale. Experiment II: We investigated a possible impact of pain intensity on CT induced pain modulation (10 healthy participants). The intensity of HP stimulation was chosen to induce pain intensity 50/100 (NRS). HP stimulation was applied with and without CT-targeted touch. Results: Experiment I: CT-stimulation was sufficient to reduce heat pain in healthy participants (p = 0.016), but not in SFN-patients. HP induced pain intensity was significantly higher (32,2 vs 52,6) in SFN-patients. During HP, bold responses in pain associated areas were observed in both groups. Additional CT-stimulation elicited no significant difference of bold responses compared to HP. Experiment II: In healthy volunteers, we reproduced a significant reduction of HP intensity by CT-stimulation (p = 0.038). Conclusions: CT input seems to be sufficient to modulate pain, independent of intensity of the pain stimulus. As a prerequisite, the CT fibers have to be intact as in healthy volunteers. If CT fibers are impaired -as in SFN-, CT-targeted touch does not modulate pain intensity. The location of CT-induced pain modulation might be attributed to the level of the dorsal horn since the cortical activation pattern of heat pain with and without CT-targeted touch did not differ in healthy subjects and in SFN-patients.
|
|
