HER2-testing in breast and gastric cancers is mandatory for the treatment with trastuzumab. We hypothesized that imaging mass spectrometry (IMS) of breast cancers may be useful for generating a classifier that may determine HER2-status in other cancer entities irrespective of primary tumor site. A total of 107 breast (n = 48) and gastric (n = 59) cryo tissue samples was analyzed by IMS (HER2 was present in 29 cases). The obtained proteomic profiles were used to create HER2 prediction models using different classification algorithms. A breast cancer proteome derived classifier, with HER2 present in 15 cases, correctly predicted HER2-status in gastric cancers with a sensitivity of 65% and a specificity of 92%. To create a universal classifier for HER2-status, breast and nonbreast cancer samples were combined, which increased sensitivity to 78%, and specificity was 88%. Our proof of principle study provides evidence that HER2-status can be identified on a proteomic level across different cancer types suggesting that HER2 overexpression may constitute a unique molecular event independent of the tumor site. Furthermore, these results indicate that IMS may be useful for the determination of potential drugable targets, as it offers a quicker, cheaper, and more objective analysis than the standard HER2-testing procedures immunohistochemistry and fluorescence in situ hybridization.
"These developments, combined with the use of the appropriate computational tools for data processing, have led to the discovery of biomarkers for diverse pathologies, including cancer (Bonnel et al., 2011; Djidja et al., 2009; McCombie et al., 2005; Stauber et al., 2008; Trede et al., 2012). MALDI MSI technology provides access to the molecular profiles of benign and malignant sections of solid tumors (Aichler et al., 2013; Balluff et al., 2010, 2011; El Ayed et al., 2010; Elsner et al., 2012; Flatley et al., 2013; Franck et al., 2009b, 2010; Gustafsson et al., 2012; Jones et al., 2013; Lemaire et al., 2005b, 2007a; Longuespee et al., 2012a, 2012b; McDonnell et al., 2010; Meding et al., 2012a, 2012b; Meding and Walch, 2013; Ray-Coquard et al., 2012; Wisztorski et al., 2013). The application of this method is particularly useful for identifying biomarkers in biopsies from early stages of cancer, when the disease is still treatable and the 5-year survival rate of managed patients remains high (Longuespée et al., 2012a, 2012b; Lowe et al., 2013; Meding et al., 2013). "
[Show abstract][Hide abstract] ABSTRACT: Abstract MALDI mass spectrometry imaging (MALDI-MSI) is currently used for clinical applications, such as biomarker identification, particularly for the study of solid tumors. The ability to map specific compounds that have been determined to be biomarkers and therapeutic targets is relevant for the evaluation of the efficacy of targeted therapies. This article describes a new method called Spectro-ImmunoHistoChemistry (SIHC), which combines the use of specific antibodies against markers and mass spectrometric imaging in the MS/MS mode. SIHC is based on direct primary antibody-antigen recognition, trypsin digestion of the antibody overlaying the markers of interest in the tissue section, and MALDI-MSI of the tryptic peptides generated from the antibody. This approach has both clinical and pharmacological applications. First, it can be used as a cross-validation method to monitor the presence specifically of a marker in a tissue section. Second, SIHC could potentially be used as a novel technology for tracking specific antibodies after in vivo injection for anti-cancer treatments. Additionally, SIHC could enable novel clinical applications of MSI, such as monitoring the efficacy of cytotoxic antibody treatments.
Omics: a journal of integrative biology 12/2013; 18(2). DOI:10.1089/omi.2013.0075 · 2.36 Impact Factor
"However, some limitations have been reported for molecular alterations with heterogeneous expression patterns . We used a TMA that was constructed for the analysis of various biomarkers in gastric cancer . The cores were randomly taken from various areas of the tumors. "
[Show abstract][Hide abstract] ABSTRACT: Her2 expression and amplification occurs in a significant subset of gastro-esophageal carcinomas. Her2 is a client protein of molecular chaperones, e.g. heat shock protein (HSP) 90, rendering targeted therapies against Her2/HSP90 an interesting approach. This study aimed to investigate the role and relationship of Her2 and HSP90 in gastric and gastro-esophageal adenocarcinomas.
Immunohistochemical determination of HSP90 and Her2 expression was performed on 347 primary resected tumors. Her2 amplification was additionally determined by fluorescence in situ hybridization for all cases. Expression and amplification results were correlated with pathologic parameters (UICC pTNM category, tumor grading) and survival.
Elevated Her2 copy numbers were observed in 87 tumors, 21 of them showing amplification. 174 tumors showed Her2 immunoreactivity/expression. HSP 90 immunoreactivity was found in 125 tumors. There was no difference between gastric carcinomas and carcinomas of the gastroesophageal junction regarding Her2 or HSP90. Both high HSP90 and Her2 expression/amplification were associated with earlier tumor stages (p<0.01), absence of lymph node metastases (p<0.02) and Laurens intestinal type (p<0.001). HSP90 correlated with Her2 expression and amplification (p<0.001 each). Expressions of HSP90 and Her2, but not Her2 amplification were associated with better prognosis (p=0.02; p=0.004; p=0.802). Moreover, Her2 expression was an independent prognostic factor for overall survival in the subgroup of gastric carcinoma patients (p=0.014) besides pT category, pN category and distant metastases.
Her2 expression and gene amplification occurred in a significant subset of cases. Our results suggest a favorable prognostic impact of Her2 expression. This warrants further investigations regarding the significance of Her2 non-amplified tumors showing Her2 immunoreactivity and the definition of Her2 status in gastric cancers. Moreover, the correlation of Her2 expression with the expression of Her2 chaperoning HSP90 may indicate a synergistic regulation. Targeting HSP90 with or without Her2 may offer additional therapeutic options for gastric carcinoma treatment.
PLoS ONE 07/2013; 8(7):e69098. DOI:10.1371/journal.pone.0069098 · 3.23 Impact Factor
"Tandem MS is also of limited use as isolation, and fragmentation efficiency is low for large proteins. Proteins in tissue can be tentatively identified in some cases by additional LC–MS/MS measurements and validated by specific antibodies (Rauser et al. 2010b; Balluff et al. 2010). An alternative approach is to digest proteins directly on tissue and to image the distribution of the resulting tryptic peptides (Groseclose et al. 2007; Lemaire et al. 2007a). "
[Show abstract][Hide abstract] ABSTRACT: Mass spectrometry (MS) imaging links molecular information and the spatial distribution of analytes within a sample. In contrast to most histochemical techniques, mass spectrometry imaging can differentiate molecular modifications and does not require labeling of targeted compounds. We have recently introduced the first mass spectrometry imaging method that provides highly specific molecular information (high resolution and accuracy in mass) at cellular dimensions (high resolution in space). This method is based on a matrix-assisted laser desorption/ionization (MALDI) imaging source working at atmospheric pressure which is coupled to an orbital trapping mass spectrometer. Here, we present a number of application examples and demonstrate the benefit of 'mass spectrometry imaging with high resolution in mass and space.' Phospholipids, peptides and drug compounds were imaged in a number of tissue samples at a spatial resolution of 5-10 μm. Proteins were analyzed after on-tissue tryptic digestion at 50-μm resolution. Additional applications include the analysis of single cells and of human lung carcinoma tissue as well as the first MALDI imaging measurement of tissue at 3 μm pixel size. MS image analysis for all these experiments showed excellent correlation with histological staining evaluation. The high mass resolution (R = 30,000) and mass accuracy (typically 1 ppm) proved to be essential for specific image generation and reliable identification of analytes in tissue samples. The ability to combine the required high-quality mass analysis with spatial resolution in the range of single cells is a unique feature of our method. With that, it has the potential to supplement classical histochemical protocols and to provide new insights about molecular processes on the cellular level.
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