Co expression of SCF and KIT in gastrointestinal stromal tumours (GISTs) suggests an autocrine/paracrine mechanism

Théou–Anton, Nathalie; Tabone, Séverine; Brouty‐Boyé, Danièle; Saffroy, Raphaël; Rönnstrand, Lars; Lemoine, Antoinette; Emile, J.

doi:10.1038/sj.bjc.6603063

Cited by 43 publications

(41 citation statements)

References 31 publications

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“…Interestingly, we observed that the KIT inhibitor imatinib partially relieved this blockade and restored KIT expression at the cell surface, suggesting that the constitutional activation of mutated KIT is responsible for the intracellular retention of the protein. Moreover, we previously showed that SCF was detectable in most GISTs, and might therefore contribute to its activation (48). Several tyrosine kinase inhibitors are currently used to treat patients with cancer, and belong to two main types: antibodies directed against surface receptors and small specific inhibitors.…”

Section: Discussionmentioning

confidence: 99%

KIT Mutations Induce Intracellular Retention and Activation of an Immature Form of the KIT Protein in Gastrointestinal Stromal Tumors

Tabone‐Eglinger

Subra

Sayadi

et al. 2008

Clinical Cancer Research

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Purpose: Gastrointestinal stromal tumors (GIST) are frequently associated with gain-of-function mutations of KIT, which can be inhibited by imatinib both in vitro and in vivo. The survival of patients with GIST, following imatinib therapy, has been correlated with the nature of mutations but not with KITexpression. Experimental Design: Subcellular localization, activation, and trafficking of the mature and the immature forms of KIT were investigated in GIST samples and in NIH3T3 cells infected with two different GIST-type exon 11^mutated human KIT cDNA. Results: Paranuclear dot expression of KIT was more frequent in GISTs with homozygous KIT mutations than in those with heterozygous (P = 0.01) or no mutations (P < 0.01). Activation of the immature 125 kDa form of KITwas detected in most GISTs with KIT mutations but not in GISTs without KIT mutations. In NIH3T3 cells, mutant KIT was mainly retained within endoplasmic reticulum and Golgi compartments in an immature constitutively phosphorylated form, whereas the wild-type KIT was expressed at the plasma membrane, in a mature nonphosphorylated form. Imatinib-induced inhibition of the phosphorylation of immature and mature mutant KIT proteins resulted in the restoration of KITexpression at the cell surface. Conclusions: These results show that GIST-type KIT mutations induce an activation-dependent alteration of normal maturation and trafficking, resulting in the intracellular retention of the activated kinase within the cell. These observations likely account for the absence of correlation between response to imatinib and KIT expression using immunohistochemistry and may deserve to be investigated in other tyrosine kinase^activated tumors.

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Section: Discussionmentioning

confidence: 99%

KIT Mutations Induce Intracellular Retention and Activation of an Immature Form of the KIT Protein in Gastrointestinal Stromal Tumors

Tabone‐Eglinger

Subra

Sayadi

et al. 2008

Clinical Cancer Research

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“…Only 5 of 32 cases (16%) showed coexpression of KIT and SCF. Interestingly, however, autocrine/paracrine stimulation is postulated to be one of the mechanisms by which KIT activation occurs in GISTs, 42 small cell lung carcinomas 43 and gliomas, 44 and autocrine stimulation maybe responsible for KIT activation in these five cases of Merkel cell carcinoma that are KIT þ /SCF þ.…”

Section: Discussionmentioning

confidence: 99%

Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

Kartha

Sundram

2008

Modern Pathology

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Merkel cell carcinoma is a rare and aggressive form of skin cancer of neuroendocrine origin. Its treatment involves wide excision and radiotherapy but no effective therapy exists for advanced disease. Upregulation of the platelet-derived growth factor receptor family of tyrosine kinases, PDGFRA and KIT, has a crucial role in cancer development. Several studies have shown expression of the tyrosine kinase receptor KIT (CD117) in Merkel cell carcinoma. In this study, we examined the expression and mutational status of KIT and PDGFRA in 14 primary and 18 metastatic Merkel cell carcinoma. The expression of KIT and PDGFRA and their respective ligands, stem cell factor (SCF) and PDGFA, was assessed by immunohistochemistry. In addition, we analyzed KIT exons 9, 11, 13 and 17, and PDGFRA exons 10, 12 and 18 for the presence of activating mutations. We found that only 53% of cases of Merkel cell carcinoma expressed KIT, which was mostly seen as diffuse weak staining, and SCF expression was observed only in 31% of cases. In contrast, 87 and 81% of cases expressed PDGFRA and PDGFA, respectively. We observed coexpression of SCF and KIT in only 5 of 32 cases (16%) whereas 25 of 31 cases (81%) showed coexpression of PDGFRA and its ligand PDGFA. While we documented silent mutations in exon 17 of KIT and exons 10, 12 and 18 of PDGFRA, we were not able to identify any known activating mutations. Our results indicate that there is no correlation between positive immunostaining and occurrence of activating mutations in KIT and PDGFRA. Moreover, the presence of KIT/SCF and PDGFRA/PDGFA coexpression in a proportion of cases may indicate an autocrine/paracrine stimulation loop. We think therefore that imatinib mesylate is less likely to be an effective therapy for Merkel cell carcinoma, unless activating mutations exist in other exons of these receptor kinases.

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“…This implies that other vascular cytokines may play a role in this disease. Recently, most GISTs have been shown to express the ligand for Kit, stem cell factor (26). Stem cell factor may play an important role in GIST progression and imatinib efficacy in lieu or in combination with VEGF.…”

Section: Discussionmentioning

confidence: 99%

Association of Intratumoral Vascular Endothelial Growth Factor Expression and Clinical Outcome for Patients with Gastrointestinal Stromal Tumors Treated with Imatinib Mesylate

McAuliffe

Lazar²,

Yang

et al. 2007

Clinical Cancer Research

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Purpose: Imatinib mesylate (imatinib) has revolutionized clinical outcomes of patients with advanced gastrointestinal stromal tumor (GIST). However, the degree of individual benefit varies, and little is known about prognostic factors for these patients. Importantly, selected patients may be treated with an approach to target both Kit and vascular endothelial growth factor receptor (VEGFR) expression. Experimental Design: Using tissue microarray technology, we analyzed 53 imatinib-naive GISTs for vascular endothelial growth factor (VEGF) expression from patients who then received imatinib. In multivariate analyses, we evaluated overall survival (OS) and progression-free survival (PFS) of these patients based on putative prognostic factors, including VEGF expression. In a separate study, 12 matched pre-imatinib and post-imatinib GIST patient specimens and two human GISTcell lines were assessed for VEGF production in response to imatinib. Results: Independent of kit genotype, patients with GIST expressing high VEGF had inferior median PFS (7.1 months versus 29 months, P = 0.42) and median OS (20 months versus not reached at >50 months; P = 0.02) compared with weak or nonexpressers of VEGF. Non^exon 11 kit mutation predicted inferior PFS but not OS. High mitotic rate was marginally predictive of improved OS. Imatinib resulted in decreased production of VEGF in only a subset of GIST patients (2 of 12) and both cell lines. Conclusions: We present a study to address the prognostic factors for patients with GIST in the imatinib era.We present a rationale to consider exploration of a front-line therapy of GISTwith a regimen targeting both Kit andVEGFR based on the presence of tumor VEGF levels.Gastrointestinal stromal tumor (GIST) is the most common mesenchymal malignancy in the gastrointestinal tract. GISTs may arise anywhere in the alimentary tract and rarely in extraintestinal sites (1). GISTs are distinct from smooth muscle tumors and share features with the interstitial cells of Cajal, the putative progenitor cell of GIST (2).Immunostaining of most GISTs shows expression of the receptor tyrosine kinase Kit for which the majority of GISTs encode activating mutations (2, 3). Most mutations in GIST are deletions or insertions residing in exon 11 of the kit gene. Less frequently, mutations can be found in exons 9, 13, or 17 (4). Alternatively, a minority of GISTs encode activating mutations in exons 12 or 18 of the platelet-derived growth factor receptora (PDGFR-a) gene (5).Before the utilization of imatinib mesylate (imatinib, Gleevec; STI571; Novartis) for the treatment of GIST, patients with advanced disease had limited therapeutic options. GISTs are notoriously chemoresistant and radioresistant, with overall responses of <10% to these modalities (6). Likewise, in the era before imatinib, tumor size (z10 cm), mitotic count (z10 of 50 high power field), small bowel disease, mixed morphology, metastases, BCL-2 expression, exon 11 mutation, and vascular endothelial growth factor (VEGF) expression predicted agg...

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Co expression of SCF and KIT in gastrointestinal stromal tumours (GISTs) suggests an autocrine/paracrine mechanism

Cited by 43 publications

References 31 publications

KIT Mutations Induce Intracellular Retention and Activation of an Immature Form of the KIT Protein in Gastrointestinal Stromal Tumors

KIT Mutations Induce Intracellular Retention and Activation of an Immature Form of the KIT Protein in Gastrointestinal Stromal Tumors

Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

Association of Intratumoral Vascular Endothelial Growth Factor Expression and Clinical Outcome for Patients with Gastrointestinal Stromal Tumors Treated with Imatinib Mesylate

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