Expression of anaplastic lymphoma kinase in soft tissue tumors: An immunohistochemical and molecular study of 249 cases

Li, Xiaoqiu; Hisaoka, Masanori; Shi, Daren; Zhu, Xiong-Zeng; Hashimoto, Hiroshi

doi:10.1016/j.humpath.2003.12.004

Cited by 98 publications

(78 citation statements)

References 30 publications

(33 reference statements)

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“…Although ALK expression was previously demonstrated in a few ES cell lines and patient samples, these studies lacked the power to accurately determine the frequency of ALK upregulation and its association with patient outcome. 18,19 We demonstrated that MET is ubiquitously expressed in ES. The majority of tumors showed medium to high levels of cytoplasmic MET and apparent membranous staining was detected in several samples as well.…”

Section: Discussionmentioning

confidence: 88%

“…ALK was localized in the cytoplasm without apparent membranous expression, similar to studies in other soft tissue tumors. 17,19 Interestingly, ALK expression was significantly lower in postchemotherapy resection specimens compared to primary tumor biopsies, suggesting that chemotherapy decreases ALK levels. This is an important finding to take into account when combining chemotherapeutics with ALK inhibitors in possible future clinical trials.…”

Section: Discussionmentioning

confidence: 99%

“…16,17 In addition, ALK mRNA and/or protein expression was demonstrated in ES cell lines (4/4) and ES tumor samples (6/10), although the sample size was rather small. 18,19 No correlation between ALK expression and clinical outcome has been described in ES at present.…”

mentioning

confidence: 99%

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Expression and clinical relevance of MET and ALK in Ewing sarcomas

Fleuren

Roeffen

Leenders

et al. 2013

Intl Journal of Cancer

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Because novel therapeutic options are limited in Ewing sarcomas (ES), we investigated the expression, genetic aberrations and clinical relevance of MET and anaplastic lymphoma kinase (ALK) in ES and determined the relevance of targeting these receptors. MET and ALK protein expression was determined immunohistochemically in 31 (50 samples) and 36 (59 samples) ES patients, respectively. Samples included primary tumors, postchemotherapy resections, metastases and relapses. MET and ALK RTK domains were sequenced in respectively 33 and 32 tumors. Five ES cell lines were treated in vitro with the MET/ALKinhibitor crizotinib, the ALK-inhibitor NVP-TAE684 or the MET-inhibitor cabozantinib and analyzed by MTT assays. Modest to high MET and ALK expression was detected in the majority of ES (86 and 69%, respectively). ALK expression was significantly lower in postchemotherapy resections compared to paired untreated primary tumors (p 5 0.031, z 5 22.310, n 5 11). In primary tumors (n 5 20), membranous MET expression significantly correlated with a poor overall survival (OS) (60 vs. 197 months, p 5 0.014). There was a trend toward a poor event-free survival (67 vs. 111 months, p 5 0.078) and OS (88 vs. 128 months, p 5 0.074) in patients with highest ALK levels (n 5 29). ALK or MET RTK domain aberrations were demonstrated in 5/32 (16%) and 3/33 (9%) tumors, respectively. Crizotinib (IC 50 1.22-3.59 lmol/L), NVP-TAE684 (IC 50 0.15-0.79 lmol/L) and cabozantinib (IC 50 2.69-8.27 lmol/L) affected ES cell viability in vitro. Altogether, our data suggest that MET and ALK are potential novel therapeutic targets in ES and targeting these receptors may be of great interest to rationally design future studies in ES.Ewing sarcoma (ES) is the second most common primary malignant bone tumor occurring in children and adolescents. Although multimodal treatment has improved the prognosis of patients with localized ES during the last decades, the final outcome has not improved for patients with metastatic disease and side effects of treatment could be severe. 1,2 This urges the need for novel therapeutic strategies, including targeted therapies directed against molecules involved in the pathogenesis and progression of ES, 3 Although at present some receptor tyrosine kinases (RTKs) have been implicated in ES, predominantly the insulin-like growth factor-1 receptor (IGF-1R), and to a lesser extent also platelet-derived growth factor receptor (PDGFR) and c-KIT, the role of several other receptors remains to be investigated. 4 In this study, we addressed the role of MET and anaplastic lymphoma kinase (ALK) in ES.MET is a RTK known to be deregulated in many cancers. At present, the hepatocyte growth factor (HGF) is the only known ligand for MET. Upon receptor binding, MET undergoes rapid tyrosine phosphorylation and several intracellular signaling cascades are activated, including the phosphatidylinositol 3 (PI3)/Akt kinase and extracellular signal regulated kinase (Erk) pathways. Several studies have shown that HGF/ MET signaling is involved in c...

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Expression and clinical relevance of MET and ALK in Ewing sarcomas

Fleuren

Roeffen

Leenders

et al. 2013

Intl Journal of Cancer

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“…Finally, domains that promote spontaneous dimerization are part of the NPM-ALK fusion protein and are not present in the full-length ALK. Understanding the mechanisms of the full-length ALK is important because of the growing evidence that full-length ALK expression is frequently expressed in human carcinomas (Lawrence et al, 2000;Powers et al, 2002;Stoica et al, 2002;Li et al, 2004;Osajima-Hakomori et al, 2005). We have recently identified ALK as a receptor for PTN and MK (Stoica et al, 2001.…”

Section: Discussionmentioning

confidence: 99%

Recruitment of insulin receptor substrate-1 and activation of NF-κB essential for midkine growth signaling through anaplastic lymphoma kinase

et al. 2006

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Anaplastic lymphoma kinase (ALK) is a transmembrane receptor tyrosine kinase in the insulin receptor superfamily. We recently demonstrated that the growth factors pleiotrophin (PTN) and midkine (MK) are ligands for ALK and that upon ALK activation, insulin receptor substrate-1 (IRS-1) and other substrates are phosphorylated. Here, the role of IRS-1 in ligand-mediated ALK signaling is investigated in interleukin-3 (IL-3)-dependent 32D murine myeloid cells. These cells do not express ALK and IRS family members, and do not respond to exogenously added PTN or MK. We show that expression of ALK plus IRS-1 renders these cells independent of IL-3 owing to the activation of ALK by endogenous MK. Mutational analysis reveals that this transformed phenotype of 32D cells requires kinase-active ALK as well as the interaction of ALK with IRS-1. Furthermore, 32D/ IRS-1/ALK cells display an enhanced activation of mitogen-activated protein kinase and PI3-kinase pathways, and a selective transcriptional activation of nuclear factor (NF)-jB. Small interfering RNA-mediated knockdown of the endogenous MK or p65/NF-jB revealed that both these are rate limiting for the transformed phenotype induced by ALK plus IRS-1. We conclude that the recruitment of IRS-1 to activated ALK and the activation of NF-jB are essential for the autocrine growth and survival signaling of MK.

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“…However, ALK was originally discovered when it was found that the chimeric N-terminal nucleophosmin (NPM) domain/cytoplasmic (catalytic) ALK domain fusion protein (NPM-ALK) is the oncoprotein underlying the pathogenesis of anaplastic large cell lymphomas (ALCL) [5,6]. NPM-ALK results from the (2;5) (p23;q35) chromosomal translocation, however, other translocations also lead to constitutive activation of ALK and other malignancies and furthermore, wild-type ALK has been postulated to be involved in the pathogenesis of rhabdomyosarcomas [7], neuroblastoma and neuroectodermal tumors [8,9], glioblastomas [10], and melanomas [11].…”

Section: Introductionmentioning

confidence: 99%

Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer

Pérez-Piñera

Chang

Astudillo

et al. 2007

Biochemical and Biophysical Research Communications

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Pleiotrophin (PTN, Ptn) is an 18 kDa cytokine expressed in human breast cancers. Since inappropriate expression of Ptn stimulates progression of breast cancer in transgenic mice and a dominant negative PTN reverses the transformed phenotype of human breast cancer cells that inappropriately express Ptn, it is suggested that constitutive PTN signaling in breast cancer cells that inappropriately express Ptn activates pathways that promote a more aggressive breast cancer phenotype. Pleiotrophin signals by inactivating its receptor, the Receptor Protein Tyrosine Phosphatase (RPTP)β/ζ, and, recently, PTN was found to activate Anaplastic Lymphoma Kinase (ALK) through the PTN/RPTPβ/ζ signaling pathway in PTN-stimulated cells, not through a direct interaction of PTN with ALK and thus not through the PTN-enforced dimerization of ALK. Since full-length ALK is activated in different malignant cancers and activated ALK is a potent oncogenic protein, we examined human breast cancers to test the possibility that ALK may be expressed in breast cancers and potentially activated through the PTN/RPTPβ/ζ signaling pathway; we now demonstrate that ALK is strongly expressed in different histological subtypes of human breast cancer; furthermore, ALK is expressed in both nuclei and cytoplasm and, in the "dotted" pattern characteristic of ALK fusion proteins in anaplastic large cell lymphoma. This study thus supports the possibility that activated ALK may be important in human breast cancers and potentially activated either through the PTN/RPTPβ/ζ signaling pathway, or, alternatively, as an activated fusion protein to stimulate progression of breast cancer in humans.

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Expression of anaplastic lymphoma kinase in soft tissue tumors: An immunohistochemical and molecular study of 249 cases

Cited by 98 publications

References 30 publications

Expression and clinical relevance of MET and ALK in Ewing sarcomas

Expression and clinical relevance of MET and ALK in Ewing sarcomas

Recruitment of insulin receptor substrate-1 and activation of NF-κB essential for midkine growth signaling through anaplastic lymphoma kinase

Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer

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