Kit-Ligand—Stem Cell Factor

2020 ◽  
pp. 369-404 ◽  
Author(s):  
Peter Besmer
Keyword(s):  
Stem Cell ◽  
Stem Cell Factor ◽  
Kit Ligand

Downregulation of c-kit (Stem Cell Factor Receptor) in Transformed Hematopoietic Precursor Cells by Stroma Cells

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 554-563 ◽  
Author(s):  
Christoph Heberlein ◽  
Jutta Friel ◽  
Christine Laker ◽  
Dorothee von Laer ◽  
Ulla Bergholz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Line ◽  
Stem Cell Factor ◽  
Progenitor Cell ◽  
Receptor Expression ◽  
General Mechanism ◽  
Ligand Interaction ◽  
Kit Ligand ◽  
Kit Receptor ◽  
Progenitor Cell Line

Abstract We show a dramatic downregulation of the stem cell factor (SCF) receptor in different hematopoietic cell lines by murine stroma. Growth of the human erythroid/macrophage progenitor cell line TF-1 is dependent on granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3). However, TF-1 cells clone and proliferate equally well on stroma. Independent stroma-dependent TF-1 clones (TF-1S) were generated on MS-5 stroma. Growth of TF-1S and TF-1 cells on stroma still requires interaction between c-kit (SCF receptor) and its ligand SCF, because antibodies against c-kit inhibit growth to less than 2%. Surprisingly, c-kit receptor expression (RNA and protein) was downregulated by 2 to 3 orders of magnitude in TF-1S and TF-1 cells grown on stroma. This stroma-dependent regulation of the kit receptor in TF-1 was also observed on exposure to kit ligand-negative stroma, thus indicating the need for heterologous receptor ligand interaction. Removal of stroma induced upregulation by 2 to 4 orders of magnitude. Downregulation and upregulation of c-kit expression could also be shown for the megakaryocytic progenitor cell line M-07e and was comparable to that of TF-1, indicating that stroma-dependent regulation of c-kit is a general mechanism. Downregulation may be an economic way to compensate for the increased sensitivity of the c-kit/ligand interaction on stroma. The stroma-dependent c-kit regulation most likely occurs at the transcriptional level, because mechanisms, such as splicing, attenuation, differential promoter usage, or mRNA stability, could be excluded.

scholarly journals The rat c-kit ligand, stem cell factor, induces c-kit receptor-dependent mouse mast cell activation in vivo. Evidence that signaling through the c-kit receptor can induce expression of cellular function.

1992 ◽  
Vol 175 (1) ◽  
pp. 245-255 ◽  
Author(s):  
B K Wershil ◽  
M Tsai ◽  
E N Geissler ◽  
K M Zsebo ◽  
S J Galli
Keyword(s):  
Mast Cell ◽  
Stem Cell ◽  
Mast Cells ◽  
Stem Cell Factor ◽  
Cell Activation ◽  
Mast Cell Activation ◽  
Tyrosine Kinase Receptor ◽  
Kit Ligand ◽  
Kit Receptor

Interactions between products of the mouse W locus, which encodes the c-kit tyrosine kinase receptor, and the Sl locus, which encodes a ligand for c-kit receptor, which we have designated stem cell factor (SCF), have a critical role in the development of mast cells. Mice homozygous for mutations at either locus exhibit several phenotypic abnormalities including a virtual absence of mast cells. Moreover, the c-kit ligand SCF can induce the proliferation and maturation of normal mast cells in vitro or in vivo, and also can result in repair of the mast cell deficiency of Sl/Sld mice in vivo. We now report that administration of SCF intradermally in vivo results in dermal mast cell activation and a mast cell-dependent acute inflammatory response. This effect is c-kit receptor dependent, in that it is not observed when SCF is administered to mice containing dermal mast cells expressing functionally inactive c-kit receptors, is observed with both glycosylated and nonglycosylated forms of SCF, and occurs at doses of SCF at least 10-fold lower on a molar basis than the minimally effective dose of the classical dermal mast cell-activating agent substance P. These findings represent the first demonstration in vivo that a c-kit ligand can result in the functional activation of any cellular lineage expressing the c-kit receptor, and suggest that interactions between the c-kit receptor and its ligand may influence mast cell biology through complex effects on proliferation, maturation, and function.

Expression of stem cell factor (SCF), a KIT ligand, in gastrointestinal stromal tumors (GISTs): A potential marker for tumor proliferation

2008 ◽  
Vol 204 (11) ◽  
pp. 799-807 ◽  
Author(s):  
Kazuhiko Hirano ◽  
Yukiko Shishido-Hara ◽  
Akiko Kitazawa ◽  
Kaoruko Kojima ◽  
Ayumi Sumiishi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Factor ◽  
Gastrointestinal Stromal Tumors ◽  
Tumor Proliferation ◽  
Stromal Tumors ◽  
Kit Ligand ◽  
Potential Marker

Effect of stem cell factor (c-kit ligand) on clonogenic leukemic precursor cells: Synergy with other hematopoietic growth factors

1994 ◽  
Vol 47 (4) ◽  
pp. 328-330 ◽  
Author(s):  
Hua-Kang Wu ◽  
Shigeru Chiba ◽  
Hisamaru Hirai ◽  
Fumimaro Takaku ◽  
Yoshio Yazaki
Keyword(s):  
Stem Cell ◽  
Growth Factors ◽  
Stem Cell Factor ◽  
Precursor Cells ◽  
Hematopoietic Growth Factors ◽  
Kit Ligand ◽  
Factor C

scholarly journals Recombinant human stem cell factor (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo.

1996 ◽  
Vol 183 (6) ◽  
pp. 2681-2686 ◽  
Author(s):  
J J Costa ◽  
G D Demetri ◽  
T J Harrist ◽  
A M Dvorak ◽  
D F Hayes ◽  
...  
Keyword(s):  
Mast Cell ◽  
Stem Cell ◽  
Mast Cells ◽  
Stem Cell Factor ◽  
Serum Levels ◽  
Human Mast Cell ◽  
Tyrosine Kinase Receptor ◽  
Kit Ligand ◽  
Wheal And Flare

Stem cell factor (SCF), also known as mast cell growth factor, kit ligand, and steel factor, is the ligand for the tyrosine kinase receptor (SCFR) that is encoded by the c-kit proto-oncogene. We analyzed the effects of recombinant human SCF (r-hSCF, 5-50 micrograms/kg/day, injected subcutaneously) on mast cells and melanocytes in a phase I study of 10 patients with advanced breast carcinoma. A wheal and flare reaction developed at each r-hSCF injection site; by electron microscopy, most dermal mast cells at these sites exhibited extensive, anaphylactic-type degranulation. A 14-d course of r-hSCF significantly increased dermal mast cell density at sites distant to those injected with the cytokine and also increased both urinary levels of the major histamine metabolite, methyl-histamine, and serum levels of mast cell alpha-tryptase. Five subjects developed areas of persistent hyperpigmentation at r-hSCF injection sites; by light microscopy, these sites exhibited markedly increased epidermal melanization and increased numbers of melanocytes. The demonstration that r-hSCF can promote both the hyperplasia and the functional activation of human mast cells and melanocytes in vivo has implications for our understanding of the role of endogenous SCF in health and disease. These findings also indicate that the interaction between SCF and its receptor represents a potential therapeutic target for regulating the numbers and functional activity of both mast cells and cutaneous melanocytes.

scholarly journals Evidence that stem cell factor is involved in the rebound thrombocytosis that follows 5-fluorouracil treatment

Blood ◽  
1992 ◽  
Vol 80 (4) ◽  
pp. 904-911 ◽  
Author(s):  
P Hunt ◽  
KM Zsebo ◽  
MM Hokom ◽  
A Hornkohl ◽  
NC Birkett ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Factor ◽  
Genetic Approach ◽  
Wild Type ◽  
Platelet Production ◽  
Kit Ligand ◽  
Important Regulator ◽  
In Vivo Administration ◽  
Mast Cell Growth Factor

The mechanisms responsible for 5-fluorouracil (5FU)-induced rebound thrombocytosis are not completely understood. SI/SI(d) mice, which do not undergo rebound thrombocytosis in response to 5FU, provide a genetic approach to the study of this phenomenon. Recent reports by several groups that the SI locus encodes a protein known variably as stem cell factor (SCF), mast cell growth factor, or kit ligand, suggests the possibility that the lack of wild-type SCF in SI/SI(d) mice is responsible for their defective response to 5FU-induced thrombocytopenia. It is shown in this report that SCF-treated SI/SI(d) mice are as capable as their wild-type littermates in undergoing rebound thrombocytosis. W/Wv mice, mutated at the locus encoding the SCF receptor, also do not undergo rebound thrombocytosis, but are not responsive to SCF treatment. In normal mice, it is shown by RNA solution hybridization that SCF mRNA expression is increased during the 5FU-induced platelet nadir period. It is also shown by autoradiography that maturing megakaryocytes express SCF receptors, and that in vivo administration of SCF significantly raises the numbers of megakaryocytes, as well as circulating platelet counts. Taken together, these data indicate that SCF may be an important regulator of platelet production under both normal and physiologically disturbed situations.

Kit-stem cell factor (kit ligand) axis in GIST patients treated with imatinib

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10046-10046 ◽  
Author(s):  
J. C. McAuliffe ◽  
A. Lazar ◽  
D. Steinert ◽  
S. Patel ◽  
R. Benjamin ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cell ◽  
Stem Cell Factor ◽  
Expression Patterns ◽  
Progression Free Survival ◽  
Tissue Array ◽  
Adjuvant Imatinib ◽  
Kit Ligand ◽  
Kaplan Meier ◽  
Positron Emission

10046 Background: Gastrointestinal stromal tumors (GISTs) represent the majority of GI mesenchymal neoplasms. Imatinib (Gleevec; STI571; Novartis, Basel, Switzerland) has marked efficacy in the management of GIST; however, little is known of its exact mechanism in GIST. We sought to elucidate expression patterns of stem cell factor (SCF, Kit ligand) and the Kit receptor tyrosine kinase in GIST and tumor-associated endothelial cells (TECs) from patients treated with imatinib. Methods: We constructed a 54 GIST specimen tissue array from patients with GIST surgically resected who received 400–800 mg/day adjuvant imatinib. Arrays were stained for SCF by immunohistochemistry and scored for expression as 0 (none), 1 (weak), or 2 (strong). Expression was correlated to progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier methods. In a second study we collected pre-imatinib core needle biopsies from 15 patients on a phase II prospective, randomized clinical trial of neo-adjuvant and adjuvant imatinib (600mg/day) for the treatment of primary or advanced, resectable GIST. Specimens were stained for phosphorylated-Kit and CD31 and visualized by immunofluorescence and confocal microscopy. Co-localization of markers was correlated to radiographic response by positron emission tomography (PET) and dynamic computed tomography (dCT). Results: 47 of 54 tumors (87%) expressed SCF but there was no significant correlation between SCF expression or intensity with PFS and OS. Interestingly, the majority of GIST tissue from patients on the prospective clinical trial contained pre-imatinib TECs expressing phosphorylated-Kit. 69% and 79% of patients receiving 3–7 days of imatinib responded by PET scan or dCT, respectively. Conclusions: The majority of GISTs express SCF while pre-imatinib TECs were found to express phosphorylated-Kit. Therefore, our results suggest that within the tumor microenvironment there may be Kit/SCF crosstalk between tumor cells and TECs. Whether disruption of this crosstalk plays a role in tumor response or anti-vascular efficacy requires additional investigation. No significant financial relationships to disclose.

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