survey results:
a)
Tyrosine protein kinases (PDGFR family: - PDGF( Platelet-derived growth factor) and associated proteins:
a)
Tyrosine protein kinases (PDGFR family: - PDGF( Platelet-derived growth factor) and associated proteins:
->Seems like PDGF and families kinases are well studied in this stroma-cancer- microenvironment while comparing to the other kinase proteins<-:
Local production of Platelet-derived growth factor (PDGF) in the marrow microenvironment stimulates tumor growth and progression by affecting tumor and stromal cells as well as may play an important role in regulating hematopoietic and stromal cell proliferation(1,5)
The potential mechanisms underlying this tumorigenic conversion is that, in in-vivo, persistent PDGF-B expression induced enhanced tumor cell proliferation by paracrine (1) stimulation and autocrine growth(2) of the stroma, (and increased expression of the hepatocyte growth factor ) but only transiently stimulated stromal cell proliferation and angiogenesis. In vitro and in vivo studies identified fibroblasts as PDGF target cells essential for mediating transient angiogenesis and persistent epithelial hyperproliferation and benign tumor formation phenotype(1).
In fibroblast cultures, long-term PDGF-BB treatment caused an initial up-regulation of vascular endothelial growth factor (VEGF)-A, followed by a drastic VEGF down-regulation and myofibroblast differentiation.
This PDGF has also been shown to physically interact with glycosaminoglycans which are abundant in the fibrosarcoma cell microenvironment. In this study, the authors found that chondroitin sulfate A enhance the mitogenic activity of platelet-derived growth factor in fibrosarcoma cells utilizing a pathway which involves tyrosine kinases. This result introduces a new modulating role for chondroitin sulfate in signalling pathways critical for cancer growth(2).
Platelet-derived growth factor (PDGF) also plays role in stimulating multipotent and erythroid progenitors as well as stromal fibroblasts. Any of the three dimeric forms of PDGF (AA, AB, or BB) could potentially interact with these cells (5). Endothelial cells and fibroblasts are important constituents of the haemopoietic microenvironment. Growth and function of these cells are controlled by a variety of cytokines, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).
Immunofluorescence studies and time course analyses suggested that the primary effect of the inhibitors was interference with the proliferation and function of fibroblasts and endothelial cells which in turn resulted in decreased haemopoiesis and increased adipogenesis. This was associated with decreased levels in conditioned media of granulocyte-macrophage colony-stimulating factor, interleukin-6 and leptin. VEGF and PDGF may play a hitherto underestimated role in the control of blood cell formation. VEGF/PDGF receptor inhibitors may have therapeutic potential in stroma diseases such as myelofibrosis. Since they weaken the stimulatory signals provided by the microenvironment, they may also be of value in the treatment of leukaemia and other neoplastic bone marrow diseases(3).
In an another study(4), stimulation of Swiss 3T3 fibroblasts with platelet-derived growth factor (PDGF) results in a transient increase in intracellular free Ca2+ concentration ([Ca2+]i) and a phospholipase A2 (PLA2)-dependent release of arachidonic acid (AA). This PDGF-induced PLA2 dependent AA release in Swiss 3T3 fibroblast is regulated by both PKC-dependent and -independent mechanisms, and is activated by high concentrations of free Ca2+ in the microenvironment beneath the plasma membrane during Ca2+ influx via plasma-membrane Ca2+ channels, despite buffering by EGTA of [Ca2+]i in the bulk cytoplasm of the cell( 4).
[One curiosity question is: does PDGF play any role in the osteoblastic niche???]
Further more, studies in medium conditioned by MBA-2, murine bone marrow-derived endothelial cells, contains PDGF activity that competes for PDGF binding to human foreskin fibroblasts and is mitogenic for these fibroblasts(5). In addition to this, further studies were also found that cytokines such as transforming growth factor-beta (TGF-beta) regulate hematopoiesis and stimulate PDGF in certain mesenchymal cells (5).
Platelet-derived growth factor (PDGF) also plays role in stimulating multipotent and erythroid progenitors as well as stromal fibroblasts. Any of the three dimeric forms of PDGF (AA, AB, or BB) could potentially interact with these cells (5). Endothelial cells and fibroblasts are important constituents of the haemopoietic microenvironment. Growth and function of these cells are controlled by a variety of cytokines, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).
Immunofluorescence studies and time course analyses suggested that the primary effect of the inhibitors was interference with the proliferation and function of fibroblasts and endothelial cells which in turn resulted in decreased haemopoiesis and increased adipogenesis. This was associated with decreased levels in conditioned media of granulocyte-macrophage colony-stimulating factor, interleukin-6 and leptin. VEGF and PDGF may play a hitherto underestimated role in the control of blood cell formation. VEGF/PDGF receptor inhibitors may have therapeutic potential in stroma diseases such as myelofibrosis. Since they weaken the stimulatory signals provided by the microenvironment, they may also be of value in the treatment of leukaemia and other neoplastic bone marrow diseases(3).
In an another study(4), stimulation of Swiss 3T3 fibroblasts with platelet-derived growth factor (PDGF) results in a transient increase in intracellular free Ca2+ concentration ([Ca2+]i) and a phospholipase A2 (PLA2)-dependent release of arachidonic acid (AA). This PDGF-induced PLA2 dependent AA release in Swiss 3T3 fibroblast is regulated by both PKC-dependent and -independent mechanisms, and is activated by high concentrations of free Ca2+ in the microenvironment beneath the plasma membrane during Ca2+ influx via plasma-membrane Ca2+ channels, despite buffering by EGTA of [Ca2+]i in the bulk cytoplasm of the cell( 4).
[One curiosity question is: does PDGF play any role in the osteoblastic niche???]
Further more, studies in medium conditioned by MBA-2, murine bone marrow-derived endothelial cells, contains PDGF activity that competes for PDGF binding to human foreskin fibroblasts and is mitogenic for these fibroblasts(5). In addition to this, further studies were also found that cytokines such as transforming growth factor-beta (TGF-beta) regulate hematopoiesis and stimulate PDGF in certain mesenchymal cells (5).
Referencess:
1 Lederle W etal in Am J Pathol 2006 Nov;169(5):1767-83 Platelet-derived growth factor-BB controls epithelial tumor phenotype by differential growth factor regulation in stromal cells
2Fthenou E etal in Int J Biochem Cell Biol. 2006;38(12):2141-50 Chondroitin sulfate A chains enhance platelet derived growth factor-mediated signalling in fibrosarcoma cells.
3 Dührsen U etal in Growth Factors 2001;19(1):1-17. Effects of vascular endothelial and platelet-derived growth factor receptor inhibitors on long-term cultures from normal human bone marrow.
4. Chow SC etal in Biochim Biophys Acta. 1993 Oct 7;1179(1):81-8Mechanisms of platelet-derived growth factor-induced arachidonic acid release in Swiss 3T3 fibroblasts: the role of a localized increase in free Ca2+ concentration beneath the plasma membrane and the activation of protein kinase C.
5. Abboud SL. Blood. 1993 May 15;81(10):2547-53 A bone marrow stromal cell line is a source and target for platelet-derived growth factor
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