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Brief Communication |
Address correspondence to Robert E. Brown, M.D., Division of Laboratory Medicine, Geisinger Medical Center, Danville, PA 17822-0131, USA; tel: 570 271 6332; fax: 570 271 6105; e-mail rebrown{at}geisinger.edu.
Abstract
Morphoproteomics is defined as the identification by immunohistochemistry of the molecular circuitry of various proteins in a tumor by noting their state of activation (translocation and phosphorylation) and correlative expressions. Such an approach can uncover or confirm potential molecular targets that may be essential to the growth, integrity, and histogenesis of a particular tumor type and that are amenable to specific therapeutic interventions. This communication illustrates the application of such an approach in depicting the mTOR pathway in mesenchymal chondrosarcoma.
(received 7 July 2004; accepted 2 August 2004)
Keywords: mesenchymal chondrosarcoma, morphoproteomics, mTOR pathway
In a previous publication [1], we suggested the possibility of rapamycin as a potential therapeutic option in mesenchymal chondrosarcoma. This was predicated, first, on the observation by Oh et al [2] that rapamycin inhibits protein kinase C (PKC)-alpha (
) and p-38 mitogen-activated protein kinase, leading to inhibition of chondrogenesis by mesenchymal cells (both of these protein analytes were expressed and activated in the malignant mesenchymal chondroblasts in our series), and second, on the reported ability of rapamycin to inhibit the c-Jun N-terminal kinase (JNK) pathway [3], which appears relevant to our demonstration of activated (phosphorylated) JNK in the nuclei of malignant mesenchymal chondroblasts.
Recently, we have assessed the mammalian target of rapamycin (mTOR) pathway using immunohistochemical probes for the detection of phosphorylated (p)-Akt, its upstream effector [4], p-mTOR per se, and p-p70 S6 kinase (p-p70S6K), a downstream effector of p-mTOR [4]. Specifically, we have utilized the following antibodies from Cell Signaling Technology, Inc (Beverly, MA): anti-phospho-Akt (phosphorylated at Ser473); anti-phospho-mTOR (phosphorylated at Ser2448), and anti-phospho-p70 S6 kinase (phosphorylated at Thr389). With continued approval of our institution’s IRB, we have applied these antibodies individually to representative sections from the 3 cases in our original report. This revealed generally stronger cytoplasmic expression of p-Akt and p-mTOR and an equivalent or greater nuclear signal for p-p70S6K in malignant mesenchymal chondroblasts compared to malignant chondrocytes (Fig. 1
).
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). It is noteworthy that platelet-derived growth factor receptor (PDGFR)-alpha (), a potential upstream signal transducer of Akt activation [6,7], and, in mesenchymal cells, of p70S6K signaling [8], was also detected in our cases of mesenchymal chondrosarcoma [1]. In summary, we have been able through morphoproteomic analysis to analyze and delineate the mTOR pathway in mesenchymal chondrosarcoma. These observations strengthen our previous suggestion of incorporating rapamycin-like agents in clinical trials of treatments for this tumor.
Acknowledgements
The author thanks Glen Kauwell and Laurie Kneller for technical assistance and Sharon Coup for secretarial support and assistance with the graphics.
References
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