Expression profiling of GIST: CD133 is associated with <i>KIT</i> exon 11 mutations, gastric location and poor prognosis

Arne, Gabriella; Kristiansson, Erik; Nerman, Olle; Kindblom, Lars‐Gunnar; Ahlman, Håkan; Nilsson, Bengt; Nilsson, Ola

doi:10.1002/ijc.25755

Cited by 34 publications

(23 citation statements)

References 49 publications

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“…The present study further indicated that the expression of CD133 was a considerable factor in predicting the prognosis of GIST, as well as the tumor size, tumor location, mitotic index, depth of invasion and NIH risk classification. The findings coincided with the results of the study by Arne et al (15), in which a univariate survival analysis demonstrated a significant correlation between the presence of the CD133 protein and a shorter overall survival (hazard ratio, 2.23; P=0.027). The multivariate analysis revealed that CD133 provided additional information on patient survival compared with age, gender, NIH risk classification and mutational status.…”

Section: Discussionsupporting

confidence: 91%

“…In addition, studies (27,28) have indicated that CD133 is highly expressed in a variety of malignancies and was often observed to be associated with a poor prognosis. Furthermore, using the TMA method, Arne et al (15) revealed that CD133 was predominantly expressed in gastric GISTs with KIT exon 11 mutations, which was known as a subgroup with a poor prognosis. According to the previous findings, the positive expression of CD133 may be closely associated with survival.…”

Section: Discussionmentioning

confidence: 99%

“…Other studies have indicated that CD133 + tumor cells have a greater potential ability for proliferation, invasion and metastasis compared with that of CD133 − cells (12–14). A study by Arne et al (15) revealed that CD133 was predominantly expressed in gastric GIST with KIT exon 11 mutations using the tissue microarray (TMA) method. This was defined as being a subgroup with a poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

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CD133 and Ki-67 expression is associated with gastrointestinal stromal tumor prognosis

Liu

et al. 2013

Oncology Letters

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CD133+ tumor cells have a greater potential ability for tumorigenesis, proliferation, invasion and metastasis compared with CD133− tumor cells. Ki-67 is associated with cell proliferation in various tumors and has a markedly positive correlation with the prognosis of patients. However, there are a limited number of studies that have investigated the association between the prognosis of gastrointestinal stromal tumors (GISTs) and the two markers. The present study aimed to investigate CD133 and Ki-67 expression in GISTs and to explore their clinicopathological significance in the prognosis of patients with GISTs. A total of 111 GIST patients from the Chinese People’s Liberation Army (PLA) General Hospital were retrospectively followed up and immunohistochemistry was used to detect CD133, Ki-67 and CD117 expression in the tumor samples. The survival rates of the patients were analyzed using the Kaplan-Meier method. The log-rank test, χ2 test and Cox’s proportional hazards model were used to determine the association between CD133, Ki-67, CD117 expression and the prognosis of GIST. The 1-, 3- and 5-year survival rates were 93.0, 89.0 and 82.0%, respectively, in all the patients. However, in the patients with CD133+ or Ki-67+, the 1-, 3- and 5-year survival rates were 81.0, 61.5 and 50.0% and 83.0, 66.6 and 53.0%, respectively. Compared with the negative groups, the survival rates in the positive groups were statistically lower (CD133 log-rank, P=0.028; Ki-67 log-rank, P=0.002). The multivariate Cox analysis revealed that CD133 and Ki-67 expression were considerable factors in the prognosis of GIST patients (CD117, P=0.495; CD133, P=0.036; Ki-67, P=0.003). In conclusion, the positive expression of CD133 and Ki-67 was associated with a poor prognosis of GIST.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CD133 and Ki-67 expression is associated with gastrointestinal stromal tumor prognosis

Liu

et al. 2013

Oncology Letters

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“…Our study also interestingly identified that strong Mcl-1 expression was associated with the favorable prognostic factor of gastric location in the univariate analysis, although this was only of borderline significance in the multivariate analysis ( P = 0.051); the significance of this association is not clear. However, this is similar to another study in which CD133, being more significantly and more frequently expressed in gastric GIST (48%) than in intestinal GIST (4%), was also found to be a significant poor prognostic factor regarding overall survival in GIST [47]. It is notable that CD133, one of the well-recognized cancer stem cell markers in the GI tract, may potentially be involved in drug-resistance in GIST.…”

Section: Discussionsupporting

confidence: 88%

Anti-apoptotic effects of osteopontin through the up-regulation of Mcl-1 in gastrointestinal stromal tumors

et al. 2014

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BackgroundOsteopontin (OPN) is a secreted phosphoprotein expressed by neoplastic cells involved in the malignant potential and aggressive phenotypes of human malignancies, including gastrointestinal stromal tumors (GISTs). Our previous study showed that OPN can promote tumor cell proliferation in GISTs. In this series, we further aim to investigate the effect of OPN on apoptosis in GISTs.MethodsThe expression of apoptotic and anti-apoptotic proteins in response to OPN was evaluated. In vitro effects of OPN against apoptosis in GIST were also assessed. GIST specimens were also used for analyzing protein expression of specific apoptosis-related molecules and their clinicopathologic significance.ResultsUp-regulation of β-catenin and anti-apoptotic proteins Mcl-1 with concomitant suppression of apoptotic proteins in response to OPN was noted. A significant anti-apoptotic effect of OPN on imatinib-induced apoptosis was identified. Furthermore, Mcl-1 overexpression was significantly associated with OPN and β-catenin expression in tumor tissues, as well as worse survival clinically.ConclusionsOur study identifies anti-apoptotic effects of OPN that, through β-catenin-mediated Mcl-1 up-regulation, significantly antagonized imatinib-induced apoptosis in GISTs. These results provide a potential rationale for therapeutic strategies targeting both OPN and Mcl-1 of the same anti-apoptotic signaling pathway, which may account for resistance to imatinib in GISTs.

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“…In order to construct a PDGFRA activation predictive model, public expression series from patients with GISTs with and without activating PDGFRA mutations were retrieved from the National Center for Biotechnology Information/Genbank GEO and ArrayExpress databases and authors' website [24], [25], [26], [27], [28], [29], [30], [31], [32]. An overview of the incorporated data sets is provided in Supplemental Table 1.…”

Section: Methodsmentioning

confidence: 99%

Characterization and Targeting of Platelet-Derived Growth Factor Receptor alpha (PDGFRA) in Inflammatory Breast Cancer (IBC)

et al. 2017

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PURPOSE: Inflammatory breast cancer (IBC) is arguably the deadliest form of breast cancer due to its rapid onset and highly invasive nature. IBC carries 5- and 10-year disease-free survival rates of ~45% and <20%, respectively. Multiple studies demonstrate that in comparison with conventional breast cancer, IBC has a unique molecular identity. Here, we have identified platelet-derived growth factor receptor alpha (PDGFRA) as being uniquely expressed and active in IBC patient tumor cells. EXPERIMENTAL DESIGN: Here we focus on characterizing and targeting PDGFRA in IBC. Using gene expression, we analyzed IBC patient samples and compared them with non-IBC patient samples. Further, using IBC cells in culture, we determined the effect of small molecules inhibitors in both in vitro and in vivo assays. RESULTS: In IBC patients, we show more frequent PDGFRA activation signature than non-IBC samples. In addition, the PDGFRA activation signature is associated with shorter metastasis-free survival in both uni- and multivariate analyses. We also demonstrate that IBC cells express active PDGFRA. Finally, we show that PDGFRA targeting by crenolanib (CP-868-596), but not imatinib (STI571), two small molecule inhibitors, interferes with IBC cell growth and emboli formation in vitro and tumor growth in vivo. CONCLUSIONS: Our data suggest that PDGFRA may be a promising target for therapy in IBC.

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Expression profiling of GIST: CD133 is associated with KIT exon 11 mutations, gastric location and poor prognosis

Cited by 34 publications

References 49 publications

CD133 and Ki-67 expression is associated with gastrointestinal stromal tumor prognosis

CD133 and Ki-67 expression is associated with gastrointestinal stromal tumor prognosis

Anti-apoptotic effects of osteopontin through the up-regulation of Mcl-1 in gastrointestinal stromal tumors

Characterization and Targeting of Platelet-Derived Growth Factor Receptor alpha (PDGFRA) in Inflammatory Breast Cancer (IBC)

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