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A review of soluble c-kit (s-kit) as a novel tumor marker and possible molecular target for the treatment of CNS germinoma
Neoplasm
A Review of Soluble c-kit (s-kit) as a Novel Tumor Marker and Possible Molecular Target for the Treatment of CNS Germinoma Hideo Takeshima, M.D., and Jun-Ichi Kuratsu, M.D. Department of Neurosurgery, Faculty of Medicine, Kagoshima University, Kagoshima, Japan
Takeshima H, Kuratsu JI. A review of soluble c-kit (s-kit) as a novel tumor marker and possible molecular target for the treatment of CNS germinoma. Surg Neurol 2003;60:321–5.
KEY WORDS
Germ cell tumor, central nervous system, s-kit, dissemination, cerebrospinal fluid, tumor marker.
BACKGROUND
Although germinomas are the most common central nervous system (CNS) germ cell tumors (GCTs), no specific tumor marker(s) has been identified. In the absence of such a marker, effective treatment planning requires surgical intervention to obtain a histologic diagnosis. The proto-oncogene c-kit is a transmembrane tyrosine kinase receptor that plays a crucial role in the development of germ cells and is aberrantly expressed in a variety of neoplasms. A soluble form of the c-kit (s-kit), composed of only the extracellular domain, has been identified as a functional molecule. METHODS
We immunohistochemically analyzed the distribution of c-kit to determine its expression profile in various histologic subtypes of CNS GCTs. To examine whether s-kit represents a novel clinical marker, its concentration in cerebrospinal fluid (CSF) was assayed by sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS
On the cell surface of germinomas, c-kit was diffusely positive. Some mature teratoma components were weakly immunoreactive for c-kit; syncytiotrophoblastic giant cells were negative. The level of s-kit was significantly higher in germinoma-containing tumors. The CSF concentration of s-kit was correlated with the clinical course; it was markedly higher in patients with subarachnoid dissemination. CONCLUSION
We found that s-kit could be a novel tumor marker for CNS germinomas. In addition, the diffuse expression of c-kit suggests that it may serve as a possible molecular target in the treatment of CNS germinomas. © 2003 Elsevier Inc. All rights reserved.
Address reprint requests to: Dr. Hideo Takeshima, Department of Neurosurgery, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890 – 8520, Japan. Received February 12, 2003; accepted May 14, 2003. © 2003 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010 –1710
entral nervous system (CNS) germ cell tumors (GCTs) are primarily neoplasms of the young; approximately 90% of patients are younger than 20 years [6], and there are geographic differences in the incidence of these tumors. In Western countries, GCTs constitute only 0.3 to 0.5% of all primary intracranial neoplasms and 3% of pediatric tumors. In Asia, on the other hand, they account for at least 2% of all primary intracranial tumors and for 9 to 15% of pediatric tumors [7]. They preferentially arise in midline structures around the third ventricle, in the suprasellar compartment, pineal gland, and the basal ganglia. Several histologically different tumors belong to the GCT family. They include germinomas; malignant nongerminomatous GCTs (including embryonal carcinomas, choriocarcinomas, yolk sac tumors, and mixed types); and teratomas, both immature and mature. Because the histologic subtype affects the response to irradiation and chemotherapy, accurate histologic identification and subclassification of CNS GCTs are essential for assessing the prognosis and for developing effective treatment strategies. Among the histologic CNS GCT subtypes, germinomas are the most common. As they are highly responsive to radiation therapy, the majority of these tumors could be cured by irradiation alone. Until the early 1980s, the vast majority of germinoma patients received 50 to 55 Gy to the local tumor and, as prophylaxis, 30 Gy to the remaining brain and spinal cord. A later study by Shirato et al [22] revealed that a dose as low as 30 Gy was
C
0090-3019/03/$–see front matter doi:10.1016/S0090-3019(03)00430-0
322 Surg Neurol 2003;60:321–5
effective, even in the absence of combined chemotherapy. Currently used radiotherapy regimens have been implicated in cognitive retardation, neuroendocrine deficiency, and physical retardation [9]. Clinical trials with different chemotherapeutic agents have been performed in Japan and other countries [1,14,20] to determine whether the irradiation dose can be further reduced. Because nearly all germinomas can be cured with adjuvant therapy [7,20,25] and since the extent of surgical resection appears not to affect treatment outcomes significantly [19], what is gained from surgery is a tumor tissue specimen for histologic examination. Therefore, an alternative method for accurately diagnosing germinomas would obviate the need for surgery.
Tumor Markers for CNS GCTs Ushio et al [24] reported neoadjuvant therapy as effective in the treatment of malignant GCTs such as yolk sac tumors, embryonal carcinomas, and mixed GCTs containing yolk sac tumor components. Their treatment regimen involves preoperative chemotherapy combined with irradiation followed by radical tumor removal. Because it is not possible to obtain a histologic diagnosis before the inception of their treatment, the preoperative diagnosis is made with specific and sensitive tumor markers. Tada [23] reported that to date, -HCG and ␣-fetoprotein (AFP) have proven to be the most useful markers. AFP is synthesized by yolk sac endoderm, fetal hepatocytes, and embryonic intestinal epithelium and -HCG is a glycoprotein secreted by syncytiotrophoblasts. Elevated levels of these markers constitute compelling presumptive evidence that a CNS mass is a germ cell tumor, and the pattern of marker elevation is somewhat predictive of the histologic components of the tumor. Although placental alkaline phosphatase (PLAP) may represent a tumor marker for germinomas, it does not specifically differentiate among GCT subtypes. Immunohistochemically, PLAP is positive in 75 to 100% of germinomas and in 33 to 86% of nongerminomatous GCTs [23]. PLAP is a cellsurface glycoprotein elaborated by syncytiotrophoblasts and produced by primordial germ cells and its low secretion titer makes detection difficult. To make neoadjuvant therapy a reality in patients with germinomas, the identification of novel, specific tumor markers is necessary. In suspect cases where all tumor markers are negative, craniotomy
Takeshima and Kuratsu
must be performed to obtain histologic verification of the tumor type.
S-Kit, A Novel Marker for Germinomas The proto-oncogene c-kit encodes a transmembrane tyrosine kinase receptor for the stem cell factor (SCF) that belongs to the platelet-derived growth factor receptor superfamily [27]. Physiologically, the c-kit protein is expressed in normal human tissues such as skin, breast, bone marrow, brain, and testis [12,26]. In particular, c-kit plays a significant role in the development of germ cells. During testicular development, SCF/c-kit interaction plays an important role in primordial germ cell migration and survival and in spermatogonial adhesion, proliferation, and survival [13,16,17]. Alteration of c-kit expression has been reported in a variety of human neoplasms such as malignant melanomas [10], breast cancers [5], small cell and nonsmall cell lung cancers [18,21], and testicular germ cell tumors [2]. The soluble form of the c-kit receptor (s-kit), consisting of only the extracellular ligand-binding domain, that can be generated by proteolytic cleavage or by alternative splicing [3] has been identified (Figure 1). Clinically, serum levels of s-kit correlate with distinct subtypes of hemopoietic disorders of the French-American-British (FAB) classification and reflect the pathologic state of acute myeloid leukemia [8]. Their preferential location along the ventricular system, i.e., in the pineal and suprasellar region, places CNS GCTs in contact with the CSF. Therefore, if these tumors express s-kit, its presence in the CSF may make it a useful tumor marker. We have immunohistochemical evidence of the expression and localization of c-kit in the CNS of patients with GCTs [15]. Our study indicated that germinoma cells primarily express c-kit, especially on their surface. Syncytiotrophoblastic giant cells (STGC), on the other hand, were negative for c-kit. The level of s-kit was significantly higher in CSF samples from patients with germinoma-containing GCTs. Also, the concentration of s-kit in CSF was correlated with the clinical course. It was significantly higher in samples obtained before treatment and in samples obtained at the time of recurrence than in samples from patients in remission and was remarkably high in patients with subarachnoid tumor dissemination. Our findings strongly suggest that the concentration of s-kit in CSF may be a useful clinical marker
s-kit, A Novel Marker for CNS Germ Cell Tumor
1
Surg Neurol 323 2003;60:321–5
A schematic drawing that shows biologic role of c-kit and generation of s-kit.
for germinomas, especially for detecting recurrence or subarachnoid dissemination [15].
C-Kit as a Molecular Target in the Treatment of CNS Germinoma Recent advances in molecular medicine have improved our understanding of cellular signal transduction pathways and have provided a new molecular target for drug therapies. C-kit may serve as a molecular target in the treatment of germinomas because most germinoma cells highly express c-kit on their surface. S-kit receptors may act as receptor antagonists because they block the binding of SCF to c-kit receptors [11]. This characteristic may make it possible to use recombinant s-kit as a decoy receptor for inhibiting the SCF/c-kit signal pathway. Alternatively, some of the small molecular compounds already in clinical use, such as tyrosine kinase receptor blockers, are promising. Among them, STI571, an inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor tyrosine kinase, is a compound currently used in patients with chronic myeloid leukemia. A recent report showed that in vitro, STI571 inhibited c-kit autophosphorylation and activation of MAP-kinase and of Akt without altering the total protein levels of c-kit, MAP-
kinase, or Akt in vitro [4]. These results provided the rationale for proceeding with the testing of STI 571 as an antitumor agent in patients with germinomas. These new treatment modalities involve molecules that act specifically on tumor cells without affecting normal cells and are expected to reduce the serious side effects elicited by the administration of cytotoxic drugs and to allow reduction of the irradiation dose. REFERENCES 1. Balmaceda C, Heller G, Rosenblum M, et al. Chemotherapy without irradiation—a novel approach for newly diagnosed CNS germ cell tumors: results of an international cooperative trial. The First International Central Nervous System Germ Cell Tumor Study. J Clin Oncol 1996;14:2908 –15. 2. Bokemeyer C, Kuczyk MA, Dunn T, et al. Expression of stem-cell factor and its receptor c-kit protein in normal testicular tissue and malignant germ-cell tumours. J Cancer Res Clin Oncol 1996;122:301–6. 3. Heaney ML, Golde DW. Soluble cytokine receptors. Blood 1996;87:847–57. 4. Heinrich MC, Blanke CD, Druker BJ, Corless CL. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 2002;20:1692–703. 5. Hines SJ, Organ C, Kornstein MJ, Krystal GW. Coexpression of the c-kit and stem cell factor genes in breast carcinomas. Cell Growth Differ 1995;6:769 –79. 6. Hoffman HJ, Otsubo H, Hendrick EB, et al. Intracranial
324 Surg Neurol 2003;60:321–5
7. 8.
9.
10. 11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21. 22. 23.
germ-cell tumors in children. J Neurosurg 1991;74: 545–51. Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg 1985;63:155–67. Kawakita M, Yonemura Y, Miyake H, et al. Soluble c-kit molecule in serum from healthy individuals and patients with haemopoietic disorders. Br J Haematol 1995;91:23–9. Kiltie AE, Gattamaneni HR. Survival and quality of life of paediatric intracranial germ cell tumour patients treated at the Christie Hospital, 1972–1993. Med Pediatr Oncol 1995;25:450 –6. Lassam N, Bickford S. Loss of c-kit expression in cultured melanoma cells. Oncogene 1992;7:51–6. Lev S, Yarden Y, Givol D. A recombinant ectodomain of the receptor for the stem cell factor (SCF) retains ligand-induced receptor dimerization and antagonizes SCF-stimulated cellular responses. J Biol Chem 1992;267:10866 –73. Matsuda R, Takahashi T, Nakamura S, et al. Expression of the c-kit protein in human solid tumors and in corresponding fetal and adult normal tissues. Am J Pathol 1993;142:339 –46. Matsui Y, Toksoz D, Nishikawa S, Williams D, Zsebo K, Hogan BL. Effect of Steel factor and leukaemia inhibitory factor on murine primordial germ cells in culture. Nature 1991;353:750 –2. Matsutani M, Ushio Y, Abe H, et al. Combined chemotherapy and radiation therapy for central nervous system germ cell tumor: preliminary results of a phase II study of the Japanese Pedriatric Brain Tumor Study Group. Neurosurg Focus 1998;5:1–5. Miyanohara O, Takeshima H, Kaji M, et al. Diagnostic significance of soluble c-kit in the cerebrospinal fluid of patients with germ cell tumors. J Neurosurg 2002; 97:177–83. Packer AI, Besmer P, Bachvarova RF. Kit ligand mediates survival of type A spermatogonia and dividing spermatocytes in postnatal mouse testes. Mol Reprod Dev 1995;42:303–10. Pesce M, Farrace MG, Piacentini M, Dolci S, De Felici M. Stem cell factor and leukemia inhibitory factor promote primordial germ cell survival by suppressing programmed cell death (apoptosis). Development 1993;118:1089 –94. Pietsch T, Nicotra MR, Fraioli R, Wolf HK, Mottolese M, Natali PG. Expression of the c-Kit receptor and its ligand SCF in non-small-cell lung carcinomas. Int J Cancer 1998;75:171–5. Sawamura Y, de Tribolet N, Ishii N, Abe H. Management of primary intracranial germinomas: diagnostic surgery or radical resection? J Neurosurg 1997;87: 262–6. Sawamura Y, Shirato H, Ikeda J, et al. Induction chemotherapy followed by reduced-volume radiation therapy for newly diagnosed central nervous system germinoma. J Neurosurg 1998;88:66 –72. Sekido Y, Obata Y, Ueda R, et al. Preferential expression of c-kit protooncogene transcripts in small cell lung cancer. Cancer Res 1991;51:2416 –9. Shirato H, Nishio M, Sawamura Y, et al. Analysis of long-term treatment of intracranial germinoma. Int J Radiat Oncol Biol Phys 1997;37:511–5. Tada M. Tumor markers. In: Sawamura Y, Shirato H,
Take`e`shima and Kuratsu
24.
25.
26. 27.
Tribilet N, eds. Intracranial Germ Cell Tumors. Wien: Springer-Verlag, 1998:146 –53. Ushio Y, Kochi M, Kuratsu J, Itoyama Y, Marubayashi T. Preliminary observations for a new treatment in children with primary intracranial yolk sac tumor or embryonal carcinoma. Report of five cases. J Neurosurg 1999;90:133–7. Wara WM, Fellows CF, Sheline GE, Wilson CB, Townsend JJ. Radiation therapy for pineal tumors and suprasellar germinomas. Radiology 1977;124: 221–3. Witte ON. Steel locus defines new multipotent growth factor. Cell 1990;63:5–6. Yarden Y, Kuang WJ, Yang-Feng T, et al. Human protooncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. Embo J 1987;6:3341– 51.
COMMENTARY
Takeshima and Kuratsu summarize the role that the receptor tyrosine kinase, c-kit, plays as a tumor marker for CNS germinomas. KIT is a 976 amino acid single pass transmembrane receptor for Stem Cell Factor (SCF) found on chromosome 4q12. It was first described as a human homolog to the sarcoma causing v-kit gene in Hardy-Zuckerman 4 feline sarcoma virus. The discovery that W mutant mice harbor a KIT mutation indicated its possible importance in human development. Specifically, there are three cell types in which KIT is critical for normal tissue development: pleuripotent hematological stem cells, migrating melanoblasts, and primordial germ cells. As such, these mice have white coats and are anemic and sterile. Patients with the related condition, piebaldism, have been shown to carry c-kit mutations. With the recent evidence that disruption and excess signaling from embryologically important pathways can lead to oncogenesis in those tissues later in life, it is not surprising that the homologous gene product from an oncovirus is associated with tumors of blood, melanocytes, and germ cells, as is the case with c-kit. The authors describe the current diagnostic and management approaches to germ cell tumors. As they mention, there is no role for surgical intervention beyond obtaining tissue for diagnostic purposes in germinomas. Many tumors that occur in regions favored by germ cell tumors can be diagnosed with serum/CSF markers such as b-HCG and a-fetoprotein. Placental alkaline phosphatase (PLAP) is not specific enough to make the diagnosis of germinoma on serum/CSF samples alone. This highlights the importance of the authors’ recent findings. Their paper in J Neurosurg 2002;97:177 describes the significance of the level of soluble c-kit (s-kit) in the CSF of 32 patients with germ cell
A Review of Soluble c-kit (s-kit) as a Novel Tumor Marker and Possible Molecular Target for the Treatment of CNS Germinoma Hideo Takeshima, M.D., and Jun-Ichi Kuratsu, M.D. Department of Neurosurgery, Faculty of Medicine, Kagoshima University, Kagoshima, Japan
Takeshima H, Kuratsu JI. A review of soluble c-kit (s-kit) as a novel tumor marker and possible molecular target for the treatment of CNS germinoma. Surg Neurol 2003;60:321–5.
KEY WORDS
Germ cell tumor, central nervous system, s-kit, dissemination, cerebrospinal fluid, tumor marker.
BACKGROUND
Although germinomas are the most common central nervous system (CNS) germ cell tumors (GCTs), no specific tumor marker(s) has been identified. In the absence of such a marker, effective treatment planning requires surgical intervention to obtain a histologic diagnosis. The proto-oncogene c-kit is a transmembrane tyrosine kinase receptor that plays a crucial role in the development of germ cells and is aberrantly expressed in a variety of neoplasms. A soluble form of the c-kit (s-kit), composed of only the extracellular domain, has been identified as a functional molecule. METHODS
We immunohistochemically analyzed the distribution of c-kit to determine its expression profile in various histologic subtypes of CNS GCTs. To examine whether s-kit represents a novel clinical marker, its concentration in cerebrospinal fluid (CSF) was assayed by sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS
On the cell surface of germinomas, c-kit was diffusely positive. Some mature teratoma components were weakly immunoreactive for c-kit; syncytiotrophoblastic giant cells were negative. The level of s-kit was significantly higher in germinoma-containing tumors. The CSF concentration of s-kit was correlated with the clinical course; it was markedly higher in patients with subarachnoid dissemination. CONCLUSION
We found that s-kit could be a novel tumor marker for CNS germinomas. In addition, the diffuse expression of c-kit suggests that it may serve as a possible molecular target in the treatment of CNS germinomas. © 2003 Elsevier Inc. All rights reserved.
Address reprint requests to: Dr. Hideo Takeshima, Department of Neurosurgery, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890 – 8520, Japan. Received February 12, 2003; accepted May 14, 2003. © 2003 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010 –1710
entral nervous system (CNS) germ cell tumors (GCTs) are primarily neoplasms of the young; approximately 90% of patients are younger than 20 years [6], and there are geographic differences in the incidence of these tumors. In Western countries, GCTs constitute only 0.3 to 0.5% of all primary intracranial neoplasms and 3% of pediatric tumors. In Asia, on the other hand, they account for at least 2% of all primary intracranial tumors and for 9 to 15% of pediatric tumors [7]. They preferentially arise in midline structures around the third ventricle, in the suprasellar compartment, pineal gland, and the basal ganglia. Several histologically different tumors belong to the GCT family. They include germinomas; malignant nongerminomatous GCTs (including embryonal carcinomas, choriocarcinomas, yolk sac tumors, and mixed types); and teratomas, both immature and mature. Because the histologic subtype affects the response to irradiation and chemotherapy, accurate histologic identification and subclassification of CNS GCTs are essential for assessing the prognosis and for developing effective treatment strategies. Among the histologic CNS GCT subtypes, germinomas are the most common. As they are highly responsive to radiation therapy, the majority of these tumors could be cured by irradiation alone. Until the early 1980s, the vast majority of germinoma patients received 50 to 55 Gy to the local tumor and, as prophylaxis, 30 Gy to the remaining brain and spinal cord. A later study by Shirato et al [22] revealed that a dose as low as 30 Gy was
C
0090-3019/03/$–see front matter doi:10.1016/S0090-3019(03)00430-0
322 Surg Neurol 2003;60:321–5
effective, even in the absence of combined chemotherapy. Currently used radiotherapy regimens have been implicated in cognitive retardation, neuroendocrine deficiency, and physical retardation [9]. Clinical trials with different chemotherapeutic agents have been performed in Japan and other countries [1,14,20] to determine whether the irradiation dose can be further reduced. Because nearly all germinomas can be cured with adjuvant therapy [7,20,25] and since the extent of surgical resection appears not to affect treatment outcomes significantly [19], what is gained from surgery is a tumor tissue specimen for histologic examination. Therefore, an alternative method for accurately diagnosing germinomas would obviate the need for surgery.
Tumor Markers for CNS GCTs Ushio et al [24] reported neoadjuvant therapy as effective in the treatment of malignant GCTs such as yolk sac tumors, embryonal carcinomas, and mixed GCTs containing yolk sac tumor components. Their treatment regimen involves preoperative chemotherapy combined with irradiation followed by radical tumor removal. Because it is not possible to obtain a histologic diagnosis before the inception of their treatment, the preoperative diagnosis is made with specific and sensitive tumor markers. Tada [23] reported that to date, -HCG and ␣-fetoprotein (AFP) have proven to be the most useful markers. AFP is synthesized by yolk sac endoderm, fetal hepatocytes, and embryonic intestinal epithelium and -HCG is a glycoprotein secreted by syncytiotrophoblasts. Elevated levels of these markers constitute compelling presumptive evidence that a CNS mass is a germ cell tumor, and the pattern of marker elevation is somewhat predictive of the histologic components of the tumor. Although placental alkaline phosphatase (PLAP) may represent a tumor marker for germinomas, it does not specifically differentiate among GCT subtypes. Immunohistochemically, PLAP is positive in 75 to 100% of germinomas and in 33 to 86% of nongerminomatous GCTs [23]. PLAP is a cellsurface glycoprotein elaborated by syncytiotrophoblasts and produced by primordial germ cells and its low secretion titer makes detection difficult. To make neoadjuvant therapy a reality in patients with germinomas, the identification of novel, specific tumor markers is necessary. In suspect cases where all tumor markers are negative, craniotomy
Takeshima and Kuratsu
must be performed to obtain histologic verification of the tumor type.
S-Kit, A Novel Marker for Germinomas The proto-oncogene c-kit encodes a transmembrane tyrosine kinase receptor for the stem cell factor (SCF) that belongs to the platelet-derived growth factor receptor superfamily [27]. Physiologically, the c-kit protein is expressed in normal human tissues such as skin, breast, bone marrow, brain, and testis [12,26]. In particular, c-kit plays a significant role in the development of germ cells. During testicular development, SCF/c-kit interaction plays an important role in primordial germ cell migration and survival and in spermatogonial adhesion, proliferation, and survival [13,16,17]. Alteration of c-kit expression has been reported in a variety of human neoplasms such as malignant melanomas [10], breast cancers [5], small cell and nonsmall cell lung cancers [18,21], and testicular germ cell tumors [2]. The soluble form of the c-kit receptor (s-kit), consisting of only the extracellular ligand-binding domain, that can be generated by proteolytic cleavage or by alternative splicing [3] has been identified (Figure 1). Clinically, serum levels of s-kit correlate with distinct subtypes of hemopoietic disorders of the French-American-British (FAB) classification and reflect the pathologic state of acute myeloid leukemia [8]. Their preferential location along the ventricular system, i.e., in the pineal and suprasellar region, places CNS GCTs in contact with the CSF. Therefore, if these tumors express s-kit, its presence in the CSF may make it a useful tumor marker. We have immunohistochemical evidence of the expression and localization of c-kit in the CNS of patients with GCTs [15]. Our study indicated that germinoma cells primarily express c-kit, especially on their surface. Syncytiotrophoblastic giant cells (STGC), on the other hand, were negative for c-kit. The level of s-kit was significantly higher in CSF samples from patients with germinoma-containing GCTs. Also, the concentration of s-kit in CSF was correlated with the clinical course. It was significantly higher in samples obtained before treatment and in samples obtained at the time of recurrence than in samples from patients in remission and was remarkably high in patients with subarachnoid tumor dissemination. Our findings strongly suggest that the concentration of s-kit in CSF may be a useful clinical marker
s-kit, A Novel Marker for CNS Germ Cell Tumor
1
Surg Neurol 323 2003;60:321–5
A schematic drawing that shows biologic role of c-kit and generation of s-kit.
for germinomas, especially for detecting recurrence or subarachnoid dissemination [15].
C-Kit as a Molecular Target in the Treatment of CNS Germinoma Recent advances in molecular medicine have improved our understanding of cellular signal transduction pathways and have provided a new molecular target for drug therapies. C-kit may serve as a molecular target in the treatment of germinomas because most germinoma cells highly express c-kit on their surface. S-kit receptors may act as receptor antagonists because they block the binding of SCF to c-kit receptors [11]. This characteristic may make it possible to use recombinant s-kit as a decoy receptor for inhibiting the SCF/c-kit signal pathway. Alternatively, some of the small molecular compounds already in clinical use, such as tyrosine kinase receptor blockers, are promising. Among them, STI571, an inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor tyrosine kinase, is a compound currently used in patients with chronic myeloid leukemia. A recent report showed that in vitro, STI571 inhibited c-kit autophosphorylation and activation of MAP-kinase and of Akt without altering the total protein levels of c-kit, MAP-
kinase, or Akt in vitro [4]. These results provided the rationale for proceeding with the testing of STI 571 as an antitumor agent in patients with germinomas. These new treatment modalities involve molecules that act specifically on tumor cells without affecting normal cells and are expected to reduce the serious side effects elicited by the administration of cytotoxic drugs and to allow reduction of the irradiation dose. REFERENCES 1. Balmaceda C, Heller G, Rosenblum M, et al. Chemotherapy without irradiation—a novel approach for newly diagnosed CNS germ cell tumors: results of an international cooperative trial. The First International Central Nervous System Germ Cell Tumor Study. J Clin Oncol 1996;14:2908 –15. 2. Bokemeyer C, Kuczyk MA, Dunn T, et al. Expression of stem-cell factor and its receptor c-kit protein in normal testicular tissue and malignant germ-cell tumours. J Cancer Res Clin Oncol 1996;122:301–6. 3. Heaney ML, Golde DW. Soluble cytokine receptors. Blood 1996;87:847–57. 4. Heinrich MC, Blanke CD, Druker BJ, Corless CL. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 2002;20:1692–703. 5. Hines SJ, Organ C, Kornstein MJ, Krystal GW. Coexpression of the c-kit and stem cell factor genes in breast carcinomas. Cell Growth Differ 1995;6:769 –79. 6. Hoffman HJ, Otsubo H, Hendrick EB, et al. Intracranial
324 Surg Neurol 2003;60:321–5
7. 8.
9.
10. 11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21. 22. 23.
germ-cell tumors in children. J Neurosurg 1991;74: 545–51. Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg 1985;63:155–67. Kawakita M, Yonemura Y, Miyake H, et al. Soluble c-kit molecule in serum from healthy individuals and patients with haemopoietic disorders. Br J Haematol 1995;91:23–9. Kiltie AE, Gattamaneni HR. Survival and quality of life of paediatric intracranial germ cell tumour patients treated at the Christie Hospital, 1972–1993. Med Pediatr Oncol 1995;25:450 –6. Lassam N, Bickford S. Loss of c-kit expression in cultured melanoma cells. Oncogene 1992;7:51–6. Lev S, Yarden Y, Givol D. A recombinant ectodomain of the receptor for the stem cell factor (SCF) retains ligand-induced receptor dimerization and antagonizes SCF-stimulated cellular responses. J Biol Chem 1992;267:10866 –73. Matsuda R, Takahashi T, Nakamura S, et al. Expression of the c-kit protein in human solid tumors and in corresponding fetal and adult normal tissues. Am J Pathol 1993;142:339 –46. Matsui Y, Toksoz D, Nishikawa S, Williams D, Zsebo K, Hogan BL. Effect of Steel factor and leukaemia inhibitory factor on murine primordial germ cells in culture. Nature 1991;353:750 –2. Matsutani M, Ushio Y, Abe H, et al. Combined chemotherapy and radiation therapy for central nervous system germ cell tumor: preliminary results of a phase II study of the Japanese Pedriatric Brain Tumor Study Group. Neurosurg Focus 1998;5:1–5. Miyanohara O, Takeshima H, Kaji M, et al. Diagnostic significance of soluble c-kit in the cerebrospinal fluid of patients with germ cell tumors. J Neurosurg 2002; 97:177–83. Packer AI, Besmer P, Bachvarova RF. Kit ligand mediates survival of type A spermatogonia and dividing spermatocytes in postnatal mouse testes. Mol Reprod Dev 1995;42:303–10. Pesce M, Farrace MG, Piacentini M, Dolci S, De Felici M. Stem cell factor and leukemia inhibitory factor promote primordial germ cell survival by suppressing programmed cell death (apoptosis). Development 1993;118:1089 –94. Pietsch T, Nicotra MR, Fraioli R, Wolf HK, Mottolese M, Natali PG. Expression of the c-Kit receptor and its ligand SCF in non-small-cell lung carcinomas. Int J Cancer 1998;75:171–5. Sawamura Y, de Tribolet N, Ishii N, Abe H. Management of primary intracranial germinomas: diagnostic surgery or radical resection? J Neurosurg 1997;87: 262–6. Sawamura Y, Shirato H, Ikeda J, et al. Induction chemotherapy followed by reduced-volume radiation therapy for newly diagnosed central nervous system germinoma. J Neurosurg 1998;88:66 –72. Sekido Y, Obata Y, Ueda R, et al. Preferential expression of c-kit protooncogene transcripts in small cell lung cancer. Cancer Res 1991;51:2416 –9. Shirato H, Nishio M, Sawamura Y, et al. Analysis of long-term treatment of intracranial germinoma. Int J Radiat Oncol Biol Phys 1997;37:511–5. Tada M. Tumor markers. In: Sawamura Y, Shirato H,
Take`e`shima and Kuratsu
24.
25.
26. 27.
Tribilet N, eds. Intracranial Germ Cell Tumors. Wien: Springer-Verlag, 1998:146 –53. Ushio Y, Kochi M, Kuratsu J, Itoyama Y, Marubayashi T. Preliminary observations for a new treatment in children with primary intracranial yolk sac tumor or embryonal carcinoma. Report of five cases. J Neurosurg 1999;90:133–7. Wara WM, Fellows CF, Sheline GE, Wilson CB, Townsend JJ. Radiation therapy for pineal tumors and suprasellar germinomas. Radiology 1977;124: 221–3. Witte ON. Steel locus defines new multipotent growth factor. Cell 1990;63:5–6. Yarden Y, Kuang WJ, Yang-Feng T, et al. Human protooncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. Embo J 1987;6:3341– 51.
COMMENTARY
Takeshima and Kuratsu summarize the role that the receptor tyrosine kinase, c-kit, plays as a tumor marker for CNS germinomas. KIT is a 976 amino acid single pass transmembrane receptor for Stem Cell Factor (SCF) found on chromosome 4q12. It was first described as a human homolog to the sarcoma causing v-kit gene in Hardy-Zuckerman 4 feline sarcoma virus. The discovery that W mutant mice harbor a KIT mutation indicated its possible importance in human development. Specifically, there are three cell types in which KIT is critical for normal tissue development: pleuripotent hematological stem cells, migrating melanoblasts, and primordial germ cells. As such, these mice have white coats and are anemic and sterile. Patients with the related condition, piebaldism, have been shown to carry c-kit mutations. With the recent evidence that disruption and excess signaling from embryologically important pathways can lead to oncogenesis in those tissues later in life, it is not surprising that the homologous gene product from an oncovirus is associated with tumors of blood, melanocytes, and germ cells, as is the case with c-kit. The authors describe the current diagnostic and management approaches to germ cell tumors. As they mention, there is no role for surgical intervention beyond obtaining tissue for diagnostic purposes in germinomas. Many tumors that occur in regions favored by germ cell tumors can be diagnosed with serum/CSF markers such as b-HCG and a-fetoprotein. Placental alkaline phosphatase (PLAP) is not specific enough to make the diagnosis of germinoma on serum/CSF samples alone. This highlights the importance of the authors’ recent findings. Their paper in J Neurosurg 2002;97:177 describes the significance of the level of soluble c-kit (s-kit) in the CSF of 32 patients with germ cell