| 1. |
- Pietras, Kristian
(författare)
-
Inhibition of PDGF receptor signaling in tumor stroma : Effects on interstitial hypertension, drug uptake and therapeutic response
- 2002
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The role of platelet-derived growth factor (PDGF) in malignancies involves both autocrine and paracrine stimulation of cells within the tumor. The interstitial fluid pressure (IFP) is one of the forces that govern the transvascular flow of fluids. In both experimental and clinical cancers, the IFP is elevated and is thought to act as a barrier for delivery of drugs. Increasing evidence points to PDGF as a positive regulator of the interstitial fluid pressure in loose connective tissue. In this thesis, the effect of PDGF receptor inhibition on the tumor IFP, transvascular transport and efficacy of anti-cancer drugs is investigated.All studies were performed using tumor models that display extensive tumor stroma and PDGF receptor expression restricted to stroma cells. Blocking of PDGF receptor signaling significantly reduced the tumor IFP in various tumor models. In parallel, pre-treatment with PDGF antagonists increased the tumor content of cytotoxic agents without affecting the uptake in other organs. Moreover, combination treatment with PDGF receptor inhibitors and chemotherapeutic agents dramatically enhanced the anti-tumor effects of the cytotoxic drugs, whereas treatment with only PDGF receptor inhibitors did not affect the growth of the tumors. Beneficial effects on the tumor reponse to radioimmunotherapy were also produced after concomitant administration of PDGF antagonists. Importantly, anti-angiogenic effects, changes in cell composition and increased tumor cell sensitivity to cytotoxic agents were ruled out as the cause for the synergistic effects. Studies with different temporal scheduling of PDGF receptor inhibitors demonstrated a perfect correlation between a reduced IFP, an increased transvascular transport and an enhanced therapeutic effect of cytotoxic drugs, strongly suggesting that the phenomena are causally linked.The studies presented herein illustrate for the first time the potential of cells in the stroma compartment as a target for efforts to treat cancer. In conclusion, a novel, possibly general, strategy to enhance the effects of conventional anti-cancer drugs has been identified.
|
|
| 2. |
- Jögi, Annika, et al.
(författare)
-
Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype.
- 2002
-
Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 99:10, s. 7021-7026
-
Tidskriftsartikel (refereegranskat)abstract
- Insufficient oxygen and nutrient supply often restrain solid tumor growth, and the hypoxia-inducible factors (HIF) 1 alpha and HIF-2 alpha are key transcription regulators of phenotypic adaptation to low oxygen levels. Moreover, mouse gene disruption studies have implicated HIF-2 alpha in embryonic regulation of tyrosine hydroxylase, a hallmark gene of the sympathetic nervous system. Neuroblastoma tumors originate from immature sympathetic cells, and therefore we investigated the effect of hypoxia on the differentiation status of human neuroblastoma cells. Hypoxia stabilized HIF-1 alpha and HIF-2 alpha proteins and activated the expression of known hypoxia-induced genes, such as vascular endothelial growth factor and tyrosine hydroxylase. These changes in gene expression also occurred in hypoxic regions of experimental neuroblastoma xenografts grown in mice. In contrast, hypoxia decreased the expression of several neuronal/neuroendocrine marker genes but induced genes expressed in neural crest sympathetic progenitors, for instance c-kit and Notch-1. Thus, hypoxia apparently causes dedifferentiation both in vitro and in vivo. These findings suggest a novel mechanism for selection of highly malignant tumor cells with stem-cell characteristics.
|
|
| 3. |
- Edsjö, Anders, et al.
(författare)
-
Differences in early and late responses between neurotrophin-stimulated trkA- and trkC-transfected SH-SY5Y neuroblastoma cells
- 2001
-
Ingår i: Cell Growth & Differentiation. - 1044-9523. ; 12:1, s. 39-50
-
Tidskriftsartikel (refereegranskat)abstract
- Despite their sympathetic neuroblast origin, highly malignant neuroblastoma tumors and derived cell lines have no or low expression of the neurotrophin receptor genes, trkA and trkC. Expression of exogenous trkA in neuroblastoma cells restores their ability to differentiate in response to nerve growth factor (NGF). Here we show that stable expression of trkC in SH-SY5Y neuroblastoma cells resulted in morphological and biochemical differentiation upon treatment with neurotrophin-3 (NT-3). To some extent, trkA- and trkC-transfected SH-SY5Y (SH-SY5Y/trkA and SH-SY5Y/trkC) cells resembled one another in terms of early signaling events and neuronal marker gene expression, but important differences were observed. Although induced Erk 1/2 and Akt/PKB phosphorylation was stronger in NT-3-stimulated SH-Y5Y/trkC cells, activation of the immediate-early genes tested was more prominent in NGF-treated SH-SY5Y/ trkA cells. In particular, c-fos was not induced in the SH-SY5Y/trkC cells. There were also phenotypic differences. The concentrations of norepinephrine, the major sympathetic neurotransmitter, and growth cone-located synaptophysin, a neurosecretory granule protein, were increased in NGF-treated SH-SY5Y/trkA but not in NT-3-treated SH-SY5Y/trkC cells. Our data suggest that NT-3/p145trkC and NGF/p140trkA signaling differ in some aspects in neuroblasoma cells, and that this may explain the phenotypic differences seen in the long-term neurotrophin-treated cells.
|
|
| 4. |
- Edsjö, Anders, et al.
(författare)
-
Expression of trkB in Human Neuroblastoma in Relation to MYCN Expression and Retinoic Acid Treatment.
- 2003
-
Ingår i: Laboratory Investigation. - 1530-0307. ; 83:6, s. 813-823
-
Tidskriftsartikel (refereegranskat)abstract
- Expression of full-length trkB can be found in some highly malignant neuroblastoma tumors with an amplified MYCN gene. This contrasts sympathetic neuroblasts, from which neuroblastomas are thought to arise, which neither express trkB nor are dependent on the p145trkB ligands, brain-derived neurotrophic factor (BDNF) or neurotrophin-4/5, for their normal development. In this study we show that trkB was expressed in two out of five neuroblastoma tumors with amplified MYCN, while no trkB expression was observed when the MYCN gene was overexpressed in a non–MYCN-amplified neuroblastoma cell line. This shows that MYCN overexpression per se is not sufficient to induce trkB expression. trkB expression and BDNF responsiveness in neuroblastoma cells can be induced by all-trans-retinoic acid (RA). When SH-SY5Y cells were stimulated with a combination of RA and BDNF, norepinephrine and tyrosine hydroxylase levels were unaltered, showing that the cells did not change toward a more catecholaminergic sympathetic phenotype. However, expression of growth-associated protein 43, indicative of a neuronal phenotype, was elevated. Vesicular acetylcholine transporter, choline acetyl transferase, and neuropeptide tyrosine mRNA levels also increased in RA-BDNF–treated cells, which could suggest that these cells develop into a sympathetic cholinergic phenotype. In addition, treatment with RA-induced expression of the platelet-derived growth factor receptor-alpha. As previously shown for BDNF, platelet-derived growth factor stimulated growth of the RA-treated cells, findings that could have clinical relevance. If these receptors mediate a mitogenic signal in vivo also, this might limit the effect of RA treatment on neuroblastoma patients.
|
|
| 5. |
|
|
| 6. |
- Guzhova, Irina, et al.
(författare)
-
Interferon-gamma cooperates with retinoic acid and phorbol ester to induce differentiation and growth inhibition of human neuroblastoma cells
- 2001
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 94:1, s. 97-108
-
Tidskriftsartikel (refereegranskat)abstract
- The prognosis of patients with advanced stages of neuroblastoma with N-myc amplification remains poor despite escalated therapy, a situation that has called for alternative therapeutic approaches. Neuroblastoma cells, which represent immature peripheral neuronal cells, treated with certain physiologic and nonphysiologic agents such as retinoic acid (RA), phorbol esters and interferons (IFN) in vitro undergo cellular differentiation and stop to divide, a process that mimics normal neuronal development. Such "differentiation therapy" using RA after autologous bone marrow transplantation has recently given encouraging results in neuroblastoma patients with advanced disease. Considering approaches for improved differentiation therapy, we investigated possible synergistic effects of combining agents known to influence neuroblastoma growth and differentiation in vitro. Our results show that combined treatment with IFN-gamma and RA or the phorbol ester 12-O-tetradecanoyl-phorbol acetate (TPA) had synergistic or enhancing effects on morphologic differentiation and neurite outgrowth in 5 of 5 neuroblastoma cell lines, 3 of which expressed very high levels of N-myc mRNA due to N-myc amplification. The combinations RA+IFN-gamma or TPA+IFN-gamma also enhanced induced growth inhibition in all 5 cell lines, in several cases resulting in complete growth arrest under conditions where cells stimulated with either agent alone continued to grow. The phenotypic effects of the combined RA+IFN-gamma or TPA+IFN-gamma treatments were in most, but not all, investigated cases accompanied by moderate reductions in N-myc expression, suggesting that the cooperative signals may counteract N-Myc activity at several levels. The cooperativity between IFN-gamma and other differentiation signals may be relevant for approaches to improve the therapy for high-risk neuroblastoma with N-myc-amplification.
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Jögi, Annika, et al.
(författare)
-
Modulation of Basic Helix-Loop-Helix Transcription Complex Formation by Id Proteins during Neuronal Differentiation.
- 2002
-
Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 277:11, s. 9118-9126
-
Tidskriftsartikel (refereegranskat)abstract
- It is assumed that the Id helix-loop-helix (HLH) proteins act by associating with ubiquitously expressed basic HLH (bHLH) transcription factors, such as E47 and E2-2, which prevents these factors from forming functional hetero- or homodimeric DNA binding complexes. Several tissue-specific bHLH proteins, including HASH-1, dHAND, and HES-1, are important for development of the nervous system. Neuroblastoma tumors are derived from the sympathetic nervous system and exhibit neural crest features. In differentiating neuroblastoma cells, HASH-1 is down-regulated, and there is coincident up-regulation of the transcriptional repressor HES-1, which is known to bind the HASH-1 promoter. We found that the three Id proteins expressed in neuroblastoma cells (Id1, Id2, and Id3) were down-regulated during induced differentiation, indicating that Id proteins help keep the tumor cells in an undifferentiated state. Studying interactions, we noted that all four Id proteins could dimerize with E47 or E2-2, but not with HASH-1 or dHAND. However, the Id proteins did complex with HES-1, and increased levels of Id2 reduced the DNA binding activity of HES-1. Furthermore, HES-1 interfered with Id2/E2-2 complex formation. The ability of Id proteins to affect HES-1 activity is of particular interest in neuronal cells, where regulation of HES-1 is essential for the timing of neuronal differentiation.
|
|
