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Mesenchymal Chondrosarcoma: Molecular Characterization by a Proteomic Approach, with Morphogenic and Therapeutic Implications

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

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

 
This study characterizes 3 cases of mesenchymal chondrosarcoma (MC) utilizing a proteomic approach that allows for the detection, visual quantification, cellular compartmentalization, and assessment of the functional state of certain proteins that may promote tumor growth and/or oppose apoptosis. Immunohistochemical procedures were performed to detect the following protein antigens: CD99, interleukin (IL)-1, IL-6, transforming growth factor (TGF)-, conventional (c) protein kinase C (cPKC)-, cPKC-ßII, phosphorylated (p)-PKC-/ßII, c-kit (CD117), platelet-derived growth factor receptor (PDGFR)-, PDGFR-ß, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)-2/neu, cathepsin D, angiotensin-converting enzyme (ACE), angiotensin II type 1 (AT1) receptor, p21ras, the subunit of farnesyl and geranylgeranyl transferase (FT/GGT), phospho (p)-c-Jun N-terminal kinase (p-JNK), p-p38 mitogen-activated protein kinase (MAPK), cyclin D1, c-Jun, Ki-67, bc1-2, TGF-ß1 latency-associated peptide (LAP), TGF-ßRII, and cyclooxygenase (COX)-2. Immunoreactivities were scored from 0 to 3+ positivity using bright-field microscopy. The results showed that malignant mesenchymal chondroblasts exhibit stronger expressions of CD99, IL-1, cPKC-, p-PKC-/ßII, PDGFR-, p-JNK, Ki-67, and bc1-2 antigens than their more mature-appearing chondrocytic counterparts in MC. In conclusion, molecular profiling of mesenchymal chondrosarcoma using a proteomic approach characterized the mesenchymal chondroblasts as possessing pathways that incorporate PKC- and PDGFR- signaling and anti-apoptotic bc1-2 expression. Specific therapies to target the mesenchymal chondroblasts in mesenchymal chondrosarcoma might include interferon-, rapamycin, ciprofloxacin, and STI571.

(received 7 January 2003; accepted 26 January 2003)

Keywords: mesenchymal chondrosarcoma, proteomics, neoplasia, apoptosis

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

 
Mesenchymal chondrosarcoma, first described in 1959 by Lichtenstein and Bernstein [1], is a specific variant of chondrosarcoma. It occurs in multiple bony sites and somatic soft tissues [2] as well as the central nervous system [3,4]. Patients with mesen-chymal chondrosarcomas have relatively poor prognosis, with a 5-yr survival rate ranging from 42 to 55% and a 10-yr survival rate of 28% [2,5].

The goals of this study were (a) to develop a molecular profile of malignant mesenchymal chondroblasts and mature chondrocytic tumor cells in mesenchymal chondrosarcomas using a proteomic approach by immunohistochemistry that allows for detection, visual quantification, cellular compartmentalization, and assessment of the functional state of proteins; (b) to delineate molecular commonalities between mesenchymal chondrosarcoma and mesenchymal chondrogenesis that support the concept of oncogenesis recapitulating ontogenesis; (c) to obtain insights into molecular pathways that control the growth and opposing apoptosis of mesenchymal chondrosarcomas; and (d) to deduce opportunities for therapeutic intervention.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

 
Study population.  With approval of the institutional review board (IRB) of Geisinger Medical Center, 3 patients with mesenchymal chondrosarcoma were identified in our files and included in this study. The authors confirmed the diagnosis in each case, based on examination of hematoxylin-eosin stained slides and immunoreactivity for CD99 antigen. The patients included 2 men and 1 woman, ranging in age from 35 to 52 yr. The 3 tumors were located respectively in (a) soft tissues of the anterior thigh, (b) the rectus muscle, and (c) the maxillary sinus.

Immunohistochemistry.  The general procedure has been previously described [6], with positive controls using tissues with established immunoreactivity and negative controls using each of the study cases. A panel of antibodies was assembled to detect the following protein antigens:

Goat polyclonal anti-human IL-1 antibody (catalog # SC-1253, Santa Cruz Biotechnology, Inc., Santa Cruz, CA) was used to detect the corresponding antigen, a polypeptide (cytokine) that plays a critical role in regulating the immune response.

Mouse monoclonal anti-human IL-6 antibody (clone 1936.14, IgG2b, R&D Systems, Inc., Minneapolis, MN) was used to assess the corresponding antigen, a protein (cytokine) whose signal is mediated through gp130 and the JAK/STAT signal transduction pathway.

Mouse monoclonal anti-human TGF- antibody (clone 9426.21, IgG1, R&D Systems) was used to detect the corresponding antigen, a protein (cytokine) with high affinity for EGFR.

Mouse monoclonal anti-human CD99 antibody (clone: 013, IgG1, Signet Pathology Systems, Inc., Dedham, MA) was used to detect the corresponding cell surface antigen.

Mouse monoclonal IgG1 anti-human cPKC-(H-7) and cPKC-ßII (F-7) antibodies (catalog # SC-8393 and SC-13149, respectively, Santa Cruz Biotechnology) were used to assess the corresponding antigens, which are isozymes in the PKC superfamily of signaling molecules that play a key role in an array of physiological processes including growth and differentiation of tissue.

Rabbit polyclonal anti-human p-PKC/ßII antibody (catalog # 9375L, Cell Signaling Technology, Inc., Beverly, MA) was used to detect the corresponding phosphorylated antigen with an epitope common to both isozymes in the PKC superfamily of signaling molecules.

Rabbit polyclonal anti-human c-kit (CD117) antibody (code # A4502, DAKO Corp., Carpinteria, CA) was used to detect the corresponding antigen, a protein that functions as a transmembrane tyrosine kinase receptor.

Mouse monoclonal anti-human PDGFR-antibody (clone 35264.11, IgG1k, R&D Systems) was used to detect the corresponding antigen, a protein that functions as a tyrosine kinase receptor and, when activated, as a signal transducer.

Mouse monoclonal anti-human PDGFR-ß(A-3) antibody (IgG2b, catalog # SC-6252, Santa Cruz Biotechnology, Inc.) was used to detect the corresponding antigen, a tyrosine kinase receptor that functions as a signal transducer and a mitogen for mesenchymal and glia-derived cells.

Mouse monoclonal anti-human EGFR antibody (clone 2 – 18C9, DAKO EGFR pharmDx) was used to detect the plasmalemmal expression of the corresponding antigen, a transmembrane protein with an extracellular domain that after interactions with EGF or TGF- generates a tyrosine-kinase-mediated signal resulting in cell proliferation.

Rabbit polyclonal anti-human HER-2/neu antibody (code # K5205, HercepTest®, DAKO) was used to detect the corresponding antigen, a protein membrane receptor tyrosine kinase with homology to the epidermal growth factor receptor.

Rabbit polyclonal anti-human cathepsin D (code # A0561, DAKO) was used to detect the corresponding antigen, a lysosomal enzyme involved in intracellular protein turnover.

Mouse monoclonal anti-human ACE (clone CG2-1193-36-18, Accurate Chemical & Scientific Corp., Westbury, NY) was used to detect the corresponding antigen, an endopeptidase that generates angiotensin II from angiotensin I.

Rabbit polyclonal anti-human AT1 receptor (catalog #SC-579; Santa Cruz Biotechnology) was used to detect the corresponding antigen, a receptor that mediates the effects of angiotensin II, which includes the activation of several transduction pathways.

Mouse monoclonal anti-human p21ras antibody (clone NCC-RAS-001, DAKO) was used to detect the corresponding antigen, a protein encoded by the H-ras gene that functions as a guanine nucleotide-binding (G) protein involved in signal transduction.

Rabbit polyclonal anti-human FT- antibody (catalog # SC-487, Santa Cruz Biotechnology) was used to detect the corresponding antigen, a peptide with an subunit common to farnesyl and geranyl-geranyl transferase, which catalyze the prenylation and activation of ras-related proteins.

Mouse monoclonal anti-human p-JNK antibody (clone G7; catalog # SC-6254, Santa Cruz Biotechnology) was used to assess nuclear expression of the corresponding phosphorylated antigen, which mediates phosphorylation of c-Jun and stimulates its transactivating function.

Mouse monoclonal anti-human p-p38 MAPK (Thr180/Tyr182) antibody (catalog #9216L, Cell Signaling Technology) was used to detect the corresponding phosphorylated antigen, a kinase that mediates cellular inflammatory and stress responses.

Mouse monoclonal anti-human cyclin D1 antibody (clone DCS-6, DAKO) was used to detect the corresponding antigen, a protein that positively regulates the cell cycle in the G1 to S phase.

Mouse monoclonal anti-c-Jun antibody with human immunoreactivity (clone 3, BD Trans-duction Laboratories, Becton, Dickinson and Co., East Rutherford, NJ) was used to assess the nuclear expression of the c-Jun antigen, a protein product of its corresponding proliferation-associated, immediate-early gene and an essential component of the activator protein (AP-1) transcription factor.

Mouse monoclonal anti-human Ki-67 antibody (clone MIB-1, DAKO) was used to detect the corresponding antigen, a non-histone nuclear protein associated with all active phases in the cell cycle (G1, S, G2, and M).

Mouse monoclonal anti-human bcl-2 antibody (clone 124, DAKO) was used to detect expression of the corresponding antigen, a protein that plays a key role in the inhibition of apoptosis.

Goat polyclonal antibody reactive with LAP of human TGF-ß1 (catalog # AB-246-NA, R&D Systems) was used in this study. This antibody against LAP has been shown to react with latent TGF-ß1 in immunohistochemical applications.

Rabbit polyclonal anti-human TGF-ßRII antibody (catalog # SC-220, Santa Cruz Biotech-nology) was used to assess the expression of the corresponding antigen, a glycoprotein designed to mediate a signal from active TGF-ß.

Rabbit polyclonal anti-human PGHS-2 (product # PG 27B, Oxford Biomedical Research, Inc., Oxford, MI) was used to assess expression of the C-terminus of the COX-2 isoenzyme, a protein that is involved in the pathway leading to bcl-2 synthesis, thereby reducing apoptosis.

Scoring of immunoreactivity.  Immunoreactivities of tumor cells in the 3 cases were scored from 0 (negative) to 3+ positivity using bright-field microscopy. Instances in which the chromogenic signal was faint (between negative and 1+) were assigned a ± status and a numerical score of 0.5. The final score in each individual case, for each of the protein analytes, incorporated the range of signals and the relative percentages of positive cells among the malignant mesenchymal chondroblasts or their more mature-appearing chondrocytic counterparts. Each slide was evaluated by both authors, and the scores represent a consensus.

	Results

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

 
The 3 cases all exhibited the characteristic bimorphic feature of mesenchymal chondrosarcoma including densely cellular zones composed of undifferentiated small cells (malignant mesenchymal chondroblasts) and contiguous cartilaginous tissue (Fig. 1, panel A). The latter consisted of chondrocytes with either well-differentiated, benign-appearing, or low-grade malignant cytologic features set in a chondroid matrix. The transition between the small cell and chondroid components was relatively abrupt. Immunoreactivity for CD99 antigen, primarily on the plasmalemmal aspect of mesenchymal chondroblasts (Fig. 1, panel B) in all cases coincided with the classic histopathology, affirming the diagnosis of mesenchymal chondrosarcoma [7].

View larger version (163K): [in this window] [in a new window]   Fig. 1. Bimorphic mesenchymal chondrosarcoma characterized by: A. densely cellular zone (upper field) comprised of mesenchymal-type chondroblasts and chondroid zone (lower field, hematoxylin-eosin); B. strong (3+) plasmalemmal immuno-reactivity for CD99 antigen on mesenchymal-type chondroblasts with weak (±) to no expression in chondroid zone; C. intense (3+) expression of cPKC-, primarily in the densely cellular zones; D. marked cytoplasmic immuno-positivity (3+) for bc1-2 antigen in aggregated mesenchymal-type chondroblasts with lesser expression in some chondrocytic cells (DAB chromogen; original magnifications of A, B,& D x400, C x100).

View larger version (169K): [in this window] [in a new window]   Fig. 2. Bimorphic mesenchymal chondrosarcoma showing: A. moderate (2+) immunoreactivity for PDGFR-antigen; B. intra-nuclear expression (2+) of p-JNK in aggregated mesenchymal-type chon-droblasts; C. mild (1+) intranuclear immunopositivity for p-p38MAPK; D. moderate cytoplasmic immunoreactivity for IL-6 antigen (DAB chromogen; original magnifications x600).

Functional grouping of proteins and assessment of their activated state showed congruency among certain protein analytes in malignant mesenchymal chondroblasts (correlative proteomics). These include expressions of the following: CD99 (2+ to 3+ plasmalemmal [Fig. 1, panel B]), IL-1 (1 to 2+, granular, vesicular, and cytoplasmic [Fig. 3, panel A]), plasmalemmal expression (translocation) of PKC- (2+ to 3+; Fig. 3, panel B), p-PKC-/ßII (± to 2+; Fig. 3, panel C), and Ki-67 (0–30%; Fig. 3, panel D).

View larger version (163K): [in this window] [in a new window]   Fig. 3. Bimorphic mesenchymal chondrosarcoma with: A. mild to moderate (1 to 2+) expression of IL-1 antigen; B. strong (3+) immunoreactivity for cPKC- along the plasmalemmal aspect in many of the mesenchymal-type chondroblasts; C. corresponding mild (1+) immunopositivity for p-PKC-/ßII antigen in mesenchymal-type chondroblasts; D. a focus illustrating the highest level of Ki-67 antigen expression seen in this series of mesenchymal chondrosarcomas, range of 0 to 30% (DAB chromogen; original magnifications of A,B,C x1,000, D x400).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

Contributions to proliferation of the chondroblasts could also come from IL-6 and TGF-ß1 [21]. At the same time, it is noteworthy that activated (phosphorylated) PKC- serves to phosphorylate bc1-2 [26,31], thereby potentially slowing apoptosis in tumor cells, particularly in the mesenchymal chondroblasts of mesenchymal chondrosarcoma in which both proteins are highly expressed. Parenthetically, JNK has been associated with an inactivating phosphorylation of bc1-2 [32,33] and could counter the effects of PKC-; however, since p-JNK was confined to the nucleus in this study, it is less likely to affect cytoplasmic bc1-2 and obversely could be exerting a stimulatory effect by induction of activator protein-1 (AP1) synthesis [34]. Expression of CD99 appears relevant in this context, given its documented role as a mediator of MAPK (JNK and ERK) activation via a PKC pathway [35,36]. These pathways and events are summarized in Fig. 4.

View larger version (21K): [in this window] [in a new window]   Fig. 4. Cartoon of a mesenchymal chondroblast in mesenchymal chondrosarcoma illustrating the findings in this study (*) and incorporating relevant data from the literature. The molecular pathways created by functional grouping of these proteins provide for a pathogenetic sequence (red color) leading to tumor growth, prevention of apoptosis, and chondrogenic differentiation that involve: (1) activation (+) with plasmalemmal translocation and phosphorylation of PKC- by PDGFR-, IL-1, and CD99; (2) stimulation of tumor growth via activation (+) of mitogen-activated protein kinases including c-Jun-N-terminal kinase (JNK) that leads to DNA synthesis as evidenced by Ki-67 with a contribution by IL-6 and TGF-ß1; (3) phosphorylation of bc1-2 by activated PKC- resulting in a state of anti-apoptosis in the tumor; and (4) expression of p-p38MAPK which, together with PKC- and with the stabilizing influence of bc1-2, promotes chondrogenic differentiation. Opportunities for therapeutic intervention are depicted in blue color and include: (a) ciprofloxacin and interferon (IFN) to inhibit (-) PKC activity, thereby slowing growth and favoring apoptosis of tumor cells; (b) STI571 to inhibit (-) PDGFR- signaling; and (c) rapamycin which potentially inhibits (-) JNK activity and modulates (-) PKC- and p38MAPK signaling pathways.

Finally, the molecular profile that we have developed for mesenchymal chondrosarcoma using a proteomic approach offers new therapeutic options. For instance, interferon (IFN)-, a biological response modifying cytokine, down-regulates PKC- expression while exerting anti-proliferative effects [38] and takes advantage of PKC pathways to produce growth inhibitor/cytolytic effects [39,40]. This mechanism has been proposed to explain the efficacy of IFN- therapy in Langerhans cell histiocytosis [41].

A report by Rubinger et al [42] of successful therapy with IFN-2b in myxoid chondrosarcoma establishes a precedent for its use in this family of tumors. Similarly, because an immunosuppressant agent, rapamycin, blocks the pathway of PKC- and p38MAPK, leading to inhibition of chondrogenesis of mesenchymal cells [12] and because it may lead to reduced JNK activity [43], rapamycin may also offer potential therapeutic benefit. The rationale for targeting the PKC pathway is reinforced by the observations of Multhaupt et al [44] on ciprofloxacin-treated chondrosarcoma cultures; namely, that the malignant cells did not proliferate and apoptosis was induced. Ciprofloxacin inhibits PKC activity [45]. Lastly, in light of the observation by Sulzbacher et al [46] that PDGFR- expression supports the growth of conventional chondrosarcoma and is associated with adverse outcome, their suggestion that it be considered a possible target for novel therapeutic strategies also applies to mesenchymal chondrosarcoma. STI571 (Gleevec) has been shown to inhibit PDGFR- signaling [47,48] and would seem a logical candidate for therapy of mesenchymal chondrosarcoma. These molecular pathways and opportunities for therapeutic intervention are illustrated in Fig. 4.

In summary, molecular profiling of mesenchymal chondrosarcoma using a proteomic approach has characterized the malignant mesenchymal chondroblasts as possessing molecular pathways that incorporate PKC- and PDGFR- signaling and anti-apoptotic bc1-2 expression, and that exhibit commonalities with mesenchymal cells involved in chondrogenesis. Such observations suggest opportunities for specific therapeutic interventions.

	Acknowledgements

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The authors are grateful to Mr. Glen Kauwell and Ms. Laurie Kneller for technical assistance, Ms. Kathy Fenstermacher for secretarial support, and Ms. Diane Latranyi and Dr. Jeffrey Prichard for helping to prepare the graphics.

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