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Clinical Cancer Research Vol. 5, 237-241, February 1999
© 1999 American Association for Cancer Research

Advances in Brief

SPARC: A Potential Diagnostic Marker of Invasive Meningiomas1

Sandra A. Rempel2, Shugang Ge and Jorge A. Gutiérrez

Henry Ford Midwest Neuro-Oncology Center and the Departments of Neurosurgery [S. A. R., S. G.] and Pathology [J. A. G.], Henry Ford Health Sciences Center, Detroit, Michigan 48202


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
SPARC, a secreted, extracellular matrix-associated protein implicated in the modulation of cell adhesion and migration, was evaluated as a marker for invasive meningiomas. Although the majority of meningiomas are clinically and morphologically benign, ~10% progress into atypical and malignant tumors, according to the standard criteria. However, a subset of meningiomas presents as histomorphologically benign tumors (WHO grade I), but they are clinically invasive. It has been suggested that these tumors should be classified as malignant, and that the patients may require adjuvant therapy and closer follow up. Unfortunately, a significant number of these tumors may not be recognized because the surgical specimen used to assess the grade of a tumor lacks the infiltrative interface with the brain, which is currently necessary to determine its invasive character. Therefore, a marker of heightened invasiveness would greatly facilitate the identification of this subset of patients. In this study, the immunohistochemical expression of SPARC in benign, noninvasive primary meningiomas was compared with its expression in invasive, aggressive, primary and recurrent meningiomas. SPARC was not expressed in the 9 benign, noninvasive tumors, but was highly expressed in the 20 invasive tumors, regardless of the grade. The findings suggest that SPARC is a potential diagnostic marker of invasive meningiomas and is capable of distinguishing the histomorphologically benign noninvasive from the histomorphologically benign but invasive meningiomas, in the absence of the infiltrative interface.


   Introduction
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 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Meningiomas are proposed to arise from the arachnoidal cap cells of the meninges (1) and may progress from benign to malignant tumors (2 , 3) . They are the second most common brain tumor comprising ~15% of intracranial and 25% of the intraspinal primary adult central nervous system tumors (4) . The revised WHO system grades these tumors as benign (grade I), atypical (grade II), and anaplastic/malignant (grade III), based on their histomorphological criteria (5) . One criterion used is invasion, the presence of which is usually associated with the malignant grade. However, there is a subset of meningiomas that is histomorphologically benign but infiltrates the brain, suggesting that their histomorphologically benign features belie their aggressive nature. Patients harboring these morphologically benign but invasive tumors may therefore require closer follow-up and adjuvant chemo- and/or radiation therapy. However, a significant number of these patients may not be recognized and consequently not treated because the specimen used to assess the grade of tumor lacks the infiltrative interface that is presently necessary to determine its invasive character. Therefore, a marker of heightened invasiveness other than the actual demonstration of the invasive edge would greatly facilitate the identification of this subset of patients. SPARC3 may be such a marker.

SPARC (also known as BM-40 and osteonectin; Ref. 6 ) is a developmentally regulated gene that is expressed in a number of cell types (7) . It is secreted into the ECM, where it may modulate cell adhesion through a receptor-mediated event (6) that induces changes in cytoplasmic components associated with focal adhesions (8) , or it may interact directly with ECM components such as vitronectin to modulate cell adhesion (9) . Thus, SPARC expression is associated with the modulation of cell adhesion and migration.

We have recently identified and characterized SPARC as a gene that is overexpressed in the highly infiltrative human astrocytic tumors (grades II–IV; Ref. 10 ). Using an in vivo model, we have demonstrated that increased SPARC expression is observed not only in the tumor mass itself but also in the individual infiltrating astrocytic tumor cells (10) . To further test the hypothesis that increased SPARC expression correlates with tumor cell invasion, we examined its expression in meningiomas that progress from benign to malignant grade. In addition, we hypothesized that increased SPARC expression would be able to differentiate the histomorphologically benign, noninvasive meningiomas from the histomorphologically benign, but invasive meningiomas. To test these hypotheses, we compared SPARC expression in benign, noninvasive, nonrecurrent meningiomas and in invasive, aggressive, recurrent meningiomas.


   Materials and Methods
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 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Tissue Samples.
Institutional Review Board-approved informed consent was obtained from all patients. Immediately upon surgical removal, tumor samples were fixed in 10% buffered formalin and embedded in paraffin for pathological diagnosis. Tissue sections (5 µm) were stained with H&E for histopathological evaluation. Two populations of tumors were analyzed. One set was composed of nine tumors from patients without recurrence that were histologically benign and were confirmed noninvasive by histomorphological examination of the tumor/normal tissue interface. The second set was composed of 20 primary and/or secondary invasive, aggressive tumors of all grades derived from 9 patients with recurrences. Invasiveness was assessed by examining the tumor sections for tumor/normal tissue interface and from descriptions within the surgical report.

Tumor Grading.
Meningioma specimens were graded as benign, atypical, or malignant/anaplastic and histologically classified as meningothelial, transitional, fibroblastic, psammomatous, or papillary according to the WHO system (5) . The occurrence (primary or recurrence number) of the tumor was documented.

Immunohistochemistry.
Immunohistochemical analysis was performed as reported previously (10) . Briefly, formalin-fixed, paraffin-embedded 5-µm tissue sections were subjected to routine deparaffinization and rehydration. The subsequent steps were performed at room temperature unless otherwise specified. Sections were incubated for 10 min in 3% hydrogen peroxide, immersed in 10 mM sodium citrate buffer (pH 6.0) and boiled for 10 min, and then cooled for 20 min. Sections were rinsed in PBS solution and incubated with 10% horse serum in PBS for 60 min. The sections were then incubated overnight at 4°C with a 1:4800 dilution (0.74 µg/ml) of primary anti-SPARC antibody (Haematological Technologies Inc., Essex Junction, VT) in PBS. After three washes in PBS buffer, the sections were incubated for 30 min with biotinylated secondary antibody (1:200 dilution in PBS), washed, and incubated for 45 min with the avidin-biotin complex according to the manufacturer’s instructions (Vectastain ABC kit; Vector Laboratories, Burlingame, CA). Finally, the sections were washed, reacted with diaminobenzidine in 0.1 M Tris buffer (pH 7.6) with 0.03% hydrogen peroxide, followed by rinsing in tap water, counterstaining, and mounting. Negative controls were performed omitting the primary anti-SPARC antibody. Sections were blindly reviewed and scored by a neuropathologist. Staining intensity was graded as negative (-), weak (+), moderate (2+ to 3+) or strong (4+ to 5+) for 0% staining, <20% of cells staining, 20–50% of cells staining, and >50% of cells staining, respectively. In addition, tumor cells were characterized as having diffuse cytoplasmic staining and/or intense, perinuclear cytoplasmic staining patterns.


   Results
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
The summary of occurrence, grade, histology, invasiveness, and SPARC intensity and staining patterns is presented in Table 1Citation . All major histological subtypes and grades were represented.


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  		Table 1 Grade, histomorphological type, invasive features, and SPARC expression levels and pattern in meningiomas

 
The different patterns of SPARC expression found in the meningiomas are illustrated in Fig. 1Citation . The histologically benign tumors were either SPARC negative (Fig. 1A)Citation or SPARC positive (Fig. 1B)Citation . Atypical (Fig. 1C)Citation and malignant/anaplastic meningiomas (Fig. 1D)Citation were also SPARC positive.



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  		Fig. 1. Immunohistochemical localization of SPARC in meningiomas of all grades. SPARC protein was analyzed in benign, noninvasive meningioma (A), benign, invasive meningioma (B), atypical, invasive meningioma (C), and malignant, invasive meningioma (D) using a 1:4800 dilution of anti-SPARC (osteonectin) antibody and detection with a diaminobenzidine reaction as described in "Materials and Methods." SPARC protein was present in all of the invasive tumors (B–D), regardless of grade, but not in the noninvasive tumor (A). When present, SPARC was localized to the cytoplasm of the meningeal tumor cells and the interstitium. SPARC expression was also found in tumor endothelial cells (arrow). x40.

 
To determine whether a correlation existed between SPARC expression and tumor invasiveness and aggressiveness, SPARC expression was examined in histomorphologically benign, noninvasive tumors selected from patients having nonrecurrent disease and compared with that of multiple tumors from a set of patients having aggressive, recurrent disease with documented invasion. SPARC expression was found to be negative in all of the nine benign, noninvasive tumors (Table 1)Citation . In contrast, SPARC expression was increased in all of the invasive tumors of the recurrent group, regardless of histological grade (Fig. 1, B, C, and DCitation ; Table 1Citation ).

SPARC-positive tumor cells and interstitium were observed at the invading margin of meningiomas that displayed a diffuse infiltrative pattern (11) where tumor cells and adjacent brain cells intermingle, as observed with astrocytic tumors (Fig. 2Citation ; Ref. 10 ), or in meningiomas that penetrate the brain in a nodular fashion (Ref. 11 ; Fig. 3Citation ).



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  		Fig. 2. Diffuse infiltrative invasion at the tumor/brain interface. SPARC protein was immunohistochemically localized as described in Fig. 1Citation . SPARC-positive tumor cells (left) invading adjacent normal brain tissue (right) are shown. Note the intense, perinuclear speckled pattern of SPARC expression (C). Arrows, magnified region. A, x10; B, x20; C, x40.

 


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  		Fig. 3. Nodular invasion at the tumor/brain interface. SPARC protein was immunohistochemically localized as described in Fig. 1Citation . High SPARC expression is observed at the invading tumor edge. SPARC-positive cells are also present throughout the invading nodular mass. A, x10; B, x20; C, x40.

 
Increased SPARC expression was observed in tumor cells invading not only into the brain parenchyma (Figs. 1Citation 2Citation 3Citation ; Table 1Citation ) but also into other tissues such as dura (Fig. 4)Citation , skeletal muscle, and bone (Table 1)Citation .



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  		Fig. 4. Tumor invasion into the adjacent dura. SPARC protein was immunohistochemically localized as described in Fig. 1Citation . Strong SPARC signal is present in sheets of invading tumor. Arrow, magnified region. A, x10; B, x20.

 
We noted both extracellular matrix-associated (interstitial) and intracellular SPARC staining. Two patterns of intracellular staining were observed: one a diffuse, cytoplasmic pattern; and the other a strong, punctate perinuclear pattern.


   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
In this study, we observed that increased SPARC expression is associated with the invasive phenotype in meningiomas, regardless of tumor histological grade. These results suggest that SPARC is a candidate marker to identify those potentially or actually invasive tumors that are otherwise histomorphologically benign and for which there is no tumor/brain invasive interface available for pathological assessment.

SPARC is a secreted, ECM-associated glycoprotein that is implicated in the modulation of cell adhesion, migration, and angiogenesis during development (6) . Increased expression has been associated with other cancer types (12, 13, 14) , suggesting that the inappropriate expression may contribute to cancer progression. We have demonstrated increased SPARC expression in tumor cells and neovessel endothelial cells of astrocytic tumors of all grades (10) . In addition, we have demonstrated SPARC expression in human glioblastoma cells invading rat brain in an in vivo model (10) . We therefore hypothesize that the inappropriate expression of SPARC may play two roles in brain tumor pathobiology, one in angiogenesis and one in tumor invasion. The present demonstration of the lack of SPARC expression in all of the benign, noninvasive meningiomas and the high expression in the tumor cells of aggressive, invasive meningiomas would support this hypothesis. That some of these aggressive tumors were histomorphologically benign suggests that SPARC may be a specific marker of invasion rather than a nonspecific marker of increased aggressiveness related to tumor progression.

For those few tumors having high SPARC expression for which we could not document invasiveness in the initial resection (Table 1Citation , specimens 084, 086, and 088), the aggressiveness of these tumors and the demonstrable invasiveness of the recurrent tumors (Table 1Citation , specimens 085 and 087) support the hypothesis that SPARC may be a useful marker when the interface is not available for evaluation. The usefulness of this protein as a marker is further supported by the observation that increased SPARC expression was observed on sections of the tumor that were of lower grade than that assigned to the whole tumor (Table 1Citation , specimens 079, 008, 077, 081, 085, and 090). These observations suggest that the more histologically aggressive region of the tumor may not be required for the diagnosis of invasiveness. Furthermore, for patient 020, SPARC was highly expressed in the primary, recurrent, and metastatic tumors, an observation consistent with expression associated with the invasive phenotype.

Increased SPARC expression was observed in tumor cells invading not only into the brain parenchyma but also into other tissues such as dura, skeletal muscle, and bone. Although invasion into tissues other than brain is not necessarily considered an indicator of malignancy, increased SPARC expression in tumors invading these tissues is consistent with a correlation of expression with the invasive phenotype.

We noted ECM-associated staining, consistent with the reports that SPARC is a secreted protein. Intracellularly, both a diffuse, cytoplasmic pattern and a strong, punctate perinuclear pattern were observed. The significance of these patterns is not presently understood, but the perinuclear staining observed in the tumors has been observed in normal human fetal astrocytes in culture (data not shown) and in calvaria bone cells in culture (15) and may reflect increases in protein synthesis, processing, secretion, and thus increased function.

On the basis of these encouraging preliminary data, immunohistochemical and correlative analyses of a larger number of specimens, including the rarer subtypes, are presently under way to statistically confirm that SPARC expression correlates with the invasive phenotype and is capable of predicting invasive behavior in otherwise histologically benign tumors, thereby providing a much needed diagnostic marker.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported in part by a 1996–1997 Elsa U. Pardee Foundation Grant. Back

2 To whom requests for reprints should be addressed, at Department of Neurosurgery, Room 3096, Education and Research Building, Henry Ford Health Sciences Center, 2799 West Grand Boulevard, Detroit, MI 48202. Phone: (313) 916-8689; Fax: (313) 916-9855; E-mail: nssan{at}neuro.hfh.edu Back

3 The abbreviations used are: SPARC, secreted protein acidic and rich in cysteine; ECM, extracellular matrix. Back

Received 8/11/99; revised 11/25/99; accepted 11/25/99.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

  1. Kepes J. J. Meningiomas. Biology, Pathology, and Differential Diagnosis Sternberg Stephen S. eds. . Masson Monographs in Diagnostic Pathology, : 1-2, Masson Publishing USA, Inc. New York 1982.
  2. Weber R. G., Boström J., Wolter M., Baudis M., Collins V. P., Reifenberger G., Lichter P. Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression. Proc. Natl. Acad. Sci. USA, 94: 14719-14724, 1997.[Abstract/Free Full Text]
  3. Rempel S. A. Molecular biology of central nervous system tumors. Curr. Opin. Oncol., 10: 179-185, 1998.[Medline]
  4. Russell D. S., Rubenstein L. J. 5 . Pathology of the Tumors of the Nervous System, : 1-1012, Edward Arnold London 1989.
  5. Kleihues P., Burger P. C., Scheithauer B. W. The new WHO classification of brain tumors. Brain Pathol., 3: 255-268, 1993.[Medline]
  6. Sage E. H. Terms of attachment: SPARC and tumorigenicity. Nat. Med., 3: 144-146, 1997.[Medline]
  7. Mundlos S., Schwahn B., Reichert T., Zabel B. Distribution of osteonectin mRNA and protein during human embryonic and fetal development. J. Histochem. Cytochem., 40: 283-291, 1992.[Abstract]
  8. Murphy-Ullrich J. E., Lane T. F., Pallero M. A., Sage E. H. SPARC mediates focal adhesion disassembly in endothelial cells through a follistatin-like region and the Ca++-binding EF-hand. J. Cell. Biochem., 57: 341-350, 1995.[Medline]
  9. Rosenblatt S., Bassuk J. A., Alpers C. E., Sage E. H., Timpl R., Preissner K. T. Differential modulation of cell adhesion by interaction between adhesive and counter-adhesive proteins: characterization of the binding of vitronectin to osteonectin (BM40, SPARC). Biochem. J., 324: 311-319, 1997.
  10. Rempel S. A., Golembieski W. A., Ge S., Lemke N., Elisevich K., Mikkelsen T., Gutiérrez J. A. SPARC. A Signal of Astrocytic Neoplastic Transformation and Reactive Response in Human Primary and Xenograft Gliomas. J. Neuropathol. Exp. Neurol., 57: 1112-1121, 1998.[Medline]
  11. Nakasu S., Hirano A., Llena J. F., Shimura T., Handa J. Interface between the meningioma and the brain. Surg. Neurol., 32: 206-212, 1989.[Medline]
  12. Porter P. L., Sage E. H., Lane T. F., Funk S. E., Gown A. M. Distribution of SPARC in normal and neoplastic tissue. J. Histochem. Cytochem., 43: 791-800, 1995.[Abstract]
  13. Bellacene A., Castronovo V. Increased expression of osteonectin and osteopontin, two bone matrix proteins, in human breast cancer. Am. J. Pathol., 146: 95-100, 1995.[Abstract]
  14. Porte H., Chastre E., Prevot S., Nordlinger B., Empereur S., Basset P., Chambon P., Gespach C. Neoplastic progression of human colorectal cancer is associated with overexpression of the stromelysin-3 and BM-40/SPARC genes. Int. J. Cancer, 64: 70-75, 1995.[Medline]
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