Biology of Meningiomas

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CHAPTER 7 Biology of Meningiomas

Peter M. Black, Farazana Tariq

INTRODUCTION

Meningiomas are important tumors biologically as well as clinically.¹ Other chapters of this text discuss chromosomal changes and angiogenic molecules as part of their biology. This chapter presents information about growth factors, steroid hormones, and other molecules important for their growth and maintenance. This information may provide better understanding of the pathogenesis of meningiomas and also suggest novel treatment options. This chapter discusses:

• Growth factors and their receptors including platelet-derived growth factor (PDGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF).

• Steroid hormones including estrogen, progesterone, and androgen

• Other factors including somatostatin, dopamine, interferon, interleukins, and endothelin

GROWTH FACTORS AND THEIR RECEPTORS

Growth factors are naturally occurring proteins that play an important role in cellular growth and proliferation. An important early discovery in oncology was the realization that PDGF, a growth factor, was the product of the oncogenic virus v-sis through which the virus caused tumors by stimulating growth.² Growth factors and their receptors important in meningiomas include PDGF, EGF, VEGF, and FGF.

Although genetic changes account for much of the growth derangement in meningiomas,^3,⁴ these growth factors and other changes are also important. Methylation, for example, may keep certain genes biologically inactive.¹ Studies from our laboratory several years ago assessing the clonality of meningiomas suggested that at least some meningiomas are polyclonal—that is, do not arise from the same parent cell, suggesting that environmental factors may also be important in their growth.⁵ Growth factors are almost certainly among those factors.²

Platelet-Derived Growth Factor

There are four different isoforms of PDGF: PDGF-A, PDGF-B, PDGF-C, and PDGF-D; the situation is made more complex by the fact that in human tumors these molecules dimerize as PDGF AA, PDGF BB, and PDGF AB to create active forms.⁶^–⁸ These activate a cellular response through two different cell surface receptors, α and β. On activation by the ligand (PDGF-BB) the PDGF-β receptor dimerizes and undergoes autophosphorylation, leading to activation of signal transduction pathways (Fig. 7-1). Western blot analysis has shown the presence of mitogen-activated protein kinase (MAPK) and activated MAPK in cerebral meningiomas as a transducer of mitogenic signals of PDGF, contributing to the growth of these tumors. A downstream effect of this signal transduction is the regulation of the expression of genes such as the c-fos proto-oncogene that contributes to tumor formation.

FIGURE 7-1 A simplified schematic of PDGF action.

Studies using Northern blot analysis, polymerase chain reaction (PCR), and immunohistochemistry have all demonstrated that meningiomas express transcripts for three members of the platelet-derived growth factor family: PDGF-A, PDGF-B, and PDGFR-B.⁶^–⁸ Although both PDGF-A and PDGF-B are present in meningiomas, PDGF-BB is the major functional ligand as shown by induction of the c-fos proto-oncogene in meningioma cultures.⁹

Expression of PDGF isoforms and the appropriate receptor in some meningiomas suggests that they have an autocrine loop pathway for growth in which the ligand stimulates the receptor in the same cell. This hypothesis is supported by the presence of active c-sis/PDGF-2 proto-oncogene and PDGF-receptor gene and their protein products in meningioma cultures.⁹^–¹¹ The coexpression of mitogen and its receptor contributes to growth and maintenance of human human meningioma cells.^12,¹³ These autocrine loops can be targeted by monoclonal antibodies and may possibly serve as future treatment options for meningiomas.^14,¹⁵ Several drugs have been tested based on this concept. Schrell and colleagues used Suramine, a growth factor scavenger, to inhibit growth-factor-induced proliferation in meningioma cell culture. Suramine causes cell arrest in S and G₂/M phase of the cell cycle. Trapidil is a drug that has an antagonistic action against PDGF and produces dose-dependent inhibition of cultured meningioma cells by blocking mitogenic stimulation.¹³ These and other PDGF antagonists such as Gleevec may be useful in treatment of recurrent or inoperable meningiomas.

There is increased expression of PDGF-BB and PDGF receptor β in atypical meningiomas as compared to benign types. This may be a useful prognostic indicator as well as a target for therapy.

Vascular Endothelial Growth Factor

VEGF is an important proangiogenic growth factor that plays an important role in unregulated tumor growth by enhancing the growth of blood vessels into the tumor. Reverse transcriptase polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry have been used to analyze the expression of VEGF in meningiomas. These studies have shown an increased expression of VEGF isoforms and the mRNA stability factor HuR in meningiomas. Figure 7-2 describes the mechanism by which VEGF exerts its intracellular effect. Elevated levels of VEGF in meningiomas are associated with increased amount of peritumoral brain edema (PTBE) and higher histologic grades.¹⁶^–¹⁸ Abe and Black demonstrated that peritumoral brain edema can be diffuse or localized.¹⁸ The diffuse type is that associated with leaky endothelial cells in the meningioma and is the most likely to be associated with aggressive growth.¹⁹

FIGURE 7-2 A simplified schematic of VEGF action.

Preoperative embolization leads to hypoxic conditions in meningiomas which may enhance the expression of hypoxia inducible factor and mRNA stability factor which in turn increase the expression of VEGF in meningiomas.^20,²¹ Levels of VEGF are up-regulated in meningioma tissue by both hypoxia inducible factor and HuR. Although no correlation is present between VEGF levels and histologic subtypes of meningiomas, enhanced expression of flt-1 bound VEGF is found in some meningiomas.²² One study showed no relationship between tumor recurrence and VEGF levels,²³ but it appears that expression of VEGF and its receptors leads to a more aggressive meningioma. Antibodies to VEGF could be used as an important pharmacologic agent to treat high-grade meningiomas, and at the present time Avastin is being used for this purpose in some centers (Patrick Wen, Dana-Farber Brigham Women’s Cancer Center, personal communication).

Epidermal Growth Factor

EGF and its receptors are important in many types of systemic tumor including lung carcinoma. Several studies have shown the presence of activated EGF-R in meningioma cells.^23,²⁴ Activated EGF-R interacts with and phosphorylates Shc, an SH2 domain-containing adapter protein that transduces the mitogenic signals from EGF-R through activation of the Ras signaling pathway.²⁵ Present data suggest that EGF-R regulates phospholipase C gamma 1 activity in meningioma cells, which is thought to have antiapoptotic activity in tumor cells.²⁶ Levels of EGF-R diminish postoperatively depending on the extent of resection. Measurement of serum EGFR may possibly be used as a tool for follow up of patients after surgery and perhaps to detect recurrence.²⁶ Immunohistochemical studies have shown that EGF-R immunoreactivity can be used as a predictor of short-term survival in meningioma patients. Lack of EGF-R in patients with an atypical meningioma is a strong indicator of short-term survival.²⁷ EGFR antagonists may also play an important role in treating patients with recurrent or high-grade meningiomas.

Fibroblast Growth Factor

FGF has both angiogenic and mitogenic properties and may be involved in autonomous growth and tumorigenesis of meningioma cells. Immunohistochemical studies have shown the presence of basic FGF and FGF-R in human meningioma cells.²⁸^–³⁰ The presence of both ligand and receptor again supports the hypothesis of an autocrine mechanism in meningiomas that can be used to formulate treatment.

FGF signaling is also important for the growth and migration of endothelial and tumor cells, and this property can be used to establish therapeutic strategies against meningioma cells. One of these efforts is arming oncolytic herpes simplex virus (HSV) with a dominant negative FGF-R. This helps to destroy both tumor cells and tumor endothelial cells in experimental models and may provide a future therapeutic possibility for meningiomas.³¹ A general problem with targeted therapies against this or other growth factors is that a specific meningioma may use several pathways, which makes single-targeted therapy less useful.

HORMONES AND MENINGIOMAS

There is substantial evidence that sex hormones may play an important role in meningioma growth. Meningiomas occur more often in women than in men: 65% of all intracranial and 85% of intraspinal meningiomas occur in women.¹ Observation of increased growth of meningiomas in pregnancy and the luteal phase of the menstrual cycle along with regression in postpartum period strongly support the role of steroid sex hormones in meningioma epidemiology. Many studies have demonstrated the presence of steroid hormones in meningiomas, and therapeutic agents have been used as treatment options for meningiomas based on these findings.