Canine mast cell tumors express stem cell factor receptor.
01 Feb 2000-American Journal of Dermatopathology (Lippincott Williams & Wilkins)-Vol. 22, Iss: 1, pp 49-54
TL;DR: KIT can be used as a reliable immunohistochemical marker for canine mast cells and undifferentiated mast cell tumors and there is an inverse correlation between the degree of differentiation and the expression of KIT.
Abstract: c-kit protooncogene encodes a type III transmembrane receptor kinase, the stem cell factor receptor, or KIT. The ligand of the KIT. stem cell factor, is a cytokine that stimulates mast cell growth and differentiation. We have studied immunohistochemically KIT expression in 23 canine mast cell tumors (MCTs), 10 histiocytomas, 5 malignant melanomas, and in 2 cell lines derived from mast cells (HMC-1, human and C2, canine). As expected, KIT was detected both in the human mast cell leukemia cell line (HMC- ) and in the canine mastocytoma cell line C2. In normal canine skin, KIT expression was confined to mast cells. All canine MCTs expressed KIT, although the intensity of the staining reaction varied considerably among the 23 neoplasms. Grade III tumors showed the highest expression of KIT, whereas grade I tumors showed the lowest expression of KIT. Two patterns of KIT expression were detected in mast cells. In normal canine mast cells and in some neoplastic mast cells, KIT appeared mainly on the cell membrane. However, in many canine MCTs, KIT is accumulated in the cytoplasm, usually near the cell nucleus. The meaning of these two patterns is not clear. Expression of KIT could not be detected immunohistochemically in any of the other neoplasias investigated. According to our results, it can be concluded that most, if not all, canine MCT express KIT. Furthermore, there is an inverse correlation between the degree of differentiation and the expression of KIT. Moreover, according to our results, KIT can be used as a reliable immunohistochemical marker for canine mast cells and undifferentiated mast cell tumors.
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TL;DR: Studying dogs with cancer is likely to provide a valuable perspective that is distinct from that generated by the study of human or rodent cancers alone, and has been increasingly recognized in the field of cancer research.
Abstract: Naturally occurring cancers in pet dogs and humans share many features, including histological appearance, tumour genetics, molecular targets, biological behaviour and response to conventional therapies. Studying dogs with cancer is likely to provide a valuable perspective that is distinct from that generated by the study of human or rodent cancers alone. The value of this opportunity has been increasingly recognized in the field of cancer research for the identification of cancer-associated genes, the study of environmental risk factors, understanding tumour biology and progression, and, perhaps most importantly, the evaluation and development of novel cancer therapeutics.
582 citations
14 Apr 2008
214 citations
TL;DR: Increased cytoplasmic KIT staining was significantly associated with an increased rate of local recurrence and a decreased survival rate, and a new prognostic classification of canine cutaneous MCTs, according to their KIT-staining pattern is proposed.
Abstract: Cutaneous mast cell tumors (MCTs) are one of the most common tumors in dogs. Currently, prognostic and therapeutic determinations for MCTs are primarily based on the histologic grade of the tumor, but a vast majority of MCTs are of an intermediate grade, and the prognostic relevance is highly questioned. A more detailed prognostic evaluation, especially of grade 2 canine MCTs, is greatly needed. To evaluate the prognostic significance of KIT and tryptase expression patterns in canine cutaneous MCTs, we studied 100 cutaneous MCTs from 100 dogs that had been treated with surgery only. The total survival and disease-free survival time and the time to local or distant recurrence of MCTs were recorded for all dogs. Using immunohistochemistry, 98 of these MCTs were stained with anti-KIT and antitryptase antibodies. Three KIT- and three tryptase-staining patterns were identified. The KIT-staining patterns were identified as 1) membrane-associated staining, 2) focal to stippled cytoplasmic staining with decreased membrane-associated staining, and 3) diffuse cytoplasmic staining. The tryptase-staining patterns were identified as 1) diffuse cytoplasmic staining, 2) stippled cytoplasmic staining, and 3) little to no cytoplasmic staining. Based on univariate and multivariate survival analysis, increased cytoplasmic KIT staining was significantly associated with an increased rate of local recurrence and a decreased survival rate. The tryptase-staining patterns were not significantly associated with any survival parameter. On the basis of these results, we propose a new prognostic classification of canine cutaneous MCTs, according to their KIT-staining pattern, that can be used for the routine prognostic evaluation of canine cutaneous MCTs.
198 citations
TL;DR: Up-to-date knowledge on the pathogenesis, the Clinical presentation, the clinical prognostic factors, the diagnostic workup including clinical staging, cytological findings, histological findings and the various grading systems which have been evaluated are reviewed.
Abstract: Mast cells (MCs) are well known for their neoplastic transformation in solitary and multiple cutaneous mast cell tumours (MCTs), as well as visceral and systemic mastocytosis. Dogs have a unique risk of developing cutaneous MCTs, and they account for 7% to 21% of all canine skin tumours. The aetiology of canine MCTs is unknown but is probably multifactorial. This article reviews up-to-date knowledge on the pathogenesis, the clinical presentation, the clinical prognostic factors, the diagnostic workup including clinical staging, cytological findings, histological findings and the various grading systems which have been evaluated based on morphology, the assessment of proliferation markers and other factors such as vessel density. Furthermore, detailed information about current treatment protocols for canine cutaneous MCTs is provided.
189 citations
Cites background from "Canine mast cell tumors express ste..."
...Various studies have shown that about 15% to 40% of all canine MCTs are affected by c-kit mutations.(35,44,45,48-54) In addition, a significant association between mutations and tumour grade was demonstrated in two large studies in which 0/24 and 1/12 well-differentiated, 8/58 and 42/119 intermediate grade, and 4/6 and 9/26 high grade tumours, respectively, were affected....
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...Several authors have reported a variety of c-kit mutations in canine MCTs, particularly in exon 11, including different point mutations and tandem duplications in the juxtamembrane coding region.(35,44,45,48-54) However, mutations have not been described in other regions, in particular in the c-kit kinase domain which is the site of the most frequent mutation in human MCTs....
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TL;DR: Canine MCTs are an excellent model for characterizing the role of c-KIT in neoplastic diseases and is a potential target for novel therapeutic agents in clinical trials and the level of KIT expression did not correlate with either c- KIT mutations or changes in protein localization.
178 citations
Cites background from "Canine mast cell tumors express ste..."
...cell tumors (MCTs) [35–39], therefore implicating c-KIT in their pathogenesis....
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References
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TL;DR: The results suggest that p145c‐kit functions as a cell surface receptor for an as yet unidentified ligand, and carboxy‐ and amino‐terminal truncations that occurred during the viral transduction process are likely to have generated the transformation potential of v‐kit.
Abstract: Structural features of v-kit, the oncogene of HZ4 feline sarcoma virus, suggested that this gene arose by transduction and truncation of cellular sequences. Complementary DNA cloning of the human proto-oncogene coding for a receptor tyrosine kinase confirmed this possibility: c-kit encodes a transmembrane glycoprotein that is structurally related to the receptor for macrophage growth factor (CSF-1) and the receptor for platelet-derived growth factor. The c-kit gene is widely expressed as a single, 5-kb transcript, and it is localized to human chromosome 4 and to mouse chromosome 5. A c-kit peptide antibody permitted the identification of a 145,000 dalton c-kit gene product that is inserted in the cellular plasma membrane and is capable of self-phosphorylation on tyrosine residues in both human glioblastoma cells and transfected mouse fibroblasts. Our results suggest that p145c-kit functions as a cell surface receptor for an as yet unidentified ligand. Furthermore, carboxy- and amino-terminal truncations that occurred during the viral transduction process are likely to have generated the transformation potential of v-kit.
1,607 citations
TL;DR: In vivo administration of SCF can reverse the macrocytic anemia and locally repair the mast cell deficiency of Sl/Sld mice and provide biological and physical evidence that SCF is a ligand for the c-kit receptor.
1,485 citations
TL;DR: The identification of the point mutation Asp816Val in c-kit in patients with mastocytosis with an associated hematologic disorder provides insight into how hematopoiesis may become dysregulated and may serve to provide a means of confirming the diagnosis, assessing prognosis, and developing intervention strategies.
Abstract: Both stem cells and mast cells express c-kit and proliferate after exposure to c-kit ligand. Mutations in c-kit may enhance or interfere with the ability of c-kit receptor to initiate the intracellular pathways resulting in cell proliferation. These observations suggested to us that mastocytosis might in some patients result from mutations in c-kit. cDNA synthesized from peripheral blood mononuclear cells of patients with indolent mastocytosis, mastocytosis with an associated hematologic disorder, aggressive mastocytosis, solitary mastocytoma, and chronic myelomonocytic leukemia unassociated with mastocytosis was thus screened for a mutation of c-kit. This analysis revealed that four of four mastocytosis patients with an associated hematologic disorder with predominantly myelodysplastic features had an A-->T substitution at nt 2468 of c-kit mRNA that causes an Asp-816-->Val substitution. One of one patient examined who had mastocytosis with an associated hematologic disorder had the corresponding mutation in genomic DNA. Identical or similar amino acid substitutions in mast cell lines result in ligand-independent autophosphorylation of the c-kit receptor. This mutation was not identified in the patients within the other disease categories or in 67 of 67 controls. The identification of the point mutation Asp816Val in c-kit in patients with mastocytosis with an associated hematologic disorder provides insight not only into the pathogenesis of this form of mastocytosis but also into how hematopoiesis may become dysregulated and may serve to provide a means of confirming the diagnosis, assessing prognosis, and developing intervention strategies.
865 citations
TL;DR: Results suggest that conversion of Asp-816 to Val in human c-kitR may be an activating mutation and responsible for the constitutive activation of c-KitR in HMC-1 cells.
Abstract: The c-kit proto-oncogene encodes a receptor tyrosine kinase. Binding of c-kit ligand, stem cell factor (SCF) to c-kit receptor (c-kitR) is known to activate c-kitR tyrosine kinase, thereby leading to autophosphorylation of c-kitR on tyrosine and to association of c-kitR with substrates such as phosphatidylinositol 3-kinase (PI3K). In a human mast cell leukemia cell line HMC-1, c-kitR was found to be constitutively phosphorylated on tyrosine, activated, and associated with PI3K without the addition of SCF. The expression of SCF mRNA transcript in HMC-1 cells was not detectable by means of PCR after reverse transcription (RT-PCR) analysis, suggesting that the constitutive activation of c-kitR was ligand independent. Sequencing of whole coding region of c-kit cDNA revealed that c-kit genes of HMC-1 cells were composed of a normal, wild-type allele and a mutant allele with two point mutations resulting in intracellular amino acid substitutions of Gly-560 for Val and Val-816 for Asp. Amino acid sequences in the regions of the two mutations are completely conserved in all of mouse, rat, and human c-kit. In order to determine the causal role of these mutations in the constitutive activation, murine c-kit mutants encoding Gly-559 and/or Val-814, corresponding to human Gly-560 and/or Val-816, were constructed by site-directed mutagenesis and expressed in a human embryonic kidney cell line, 293T cells. In the transfected cells, both c-kitR (Gly-559, Val-814) and c-kitR (Val-814) were abundantly phosphorylated on tyrosine and activated in immune complex kinase reaction in the absence of SCF, whereas tyrosine phosphorylation and activation of c-kitR (Gly-559) or wild-type c-kitR was modest or little, respectively. These results suggest that conversion of Asp-816 to Val in human c-kitR may be an activating mutation and responsible for the constitutive activation of c-kitR in HMC-1 cells.
826 citations
TL;DR: Eighty-three cutaneous mast cell tumors in the dog were classified morphologically into three grades, and the neoplasms were excised surgically and dogs were followed for 1500 days.
Abstract: Eighty-three cutaneous mast cell tumors in the dog were classified morphologically into three grades. The neoplasms were excised surgically, and the dogs were followed for 1500 days. Comparison of morphologic grade of tumor with survival time revealed significant differences among the three groups (p less than 0.00010). Comparison of sex and age (above and below ten years) with morphologic grade of tumor revealed no significant differences.
660 citations