Ann Thorac Surg 2006;82:1904-1906
© 2006 The Society of Thoracic Surgeons
Case Reports
Autocrine Growth by Granulocyte Colony-Stimulating Factor in Malignant Mesothelioma
Motohiro Nishimura, MD, PhDa,
Kyoko Itoh, MD, PhDb,
Kazuhiro Ito, MD, PhDa,
Masashi Yanada, MDa,
Kunihiko Terauchi, MDa,
Shinji Fushiki, MD, PhDb,
Junichi Shimada, MD, PhDa,*
a Department of Thoracic Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
b Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine, Kyoto, Japan
Accepted for publication February 2, 2006.
* Address correspondence to Dr Shimada, Kajii-cho 465, Kamigyo-ku, Kyoto, 602-8566 Japan. (Email: shimajun{at}beige.plala.or.jp).
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Abstract
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We report the first case of a malignant mesothelioma expressing not only granulocyte-colony stimulating factor (G-CSF), but also its receptor. A 59-year-old male carpenter underwent a panpleuropneumonectomy, but the tumor relapsed and spread rapidly, accompanied by leukocytosis. The white blood cell count reached 147,000/mm3 (96.2% neutrophils), and the concentration of serum G-CSF was 77 pg/mL. An autopsy demonstrated that some of the tumor cells produced G-CSF, but more tumor cells and endothelial cells in the tumor expressed G-CSF receptor. It was hypothesized that an autocrine loop involving G-CSF and the G-CSF receptor greatly accelerated the tumor growth.
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Introduction
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Granulocyte-colony stimulating factor (G-CSF) is produced by a variety of human cell types including monocytes, macrophages, endothelial cells, fibroblasts, and neutrophils. It is well known that some malignant tumors produce G-CSF. Six cases of malignant mesotheliomas producing G-CSF have been previously reported, but the expression of G-CSF receptor has not been documented. Here we report the first case of a malignant mesothelioma expressing not only G-CSF but also its receptor.
A 59-year-old male carpenter was admitted to our university hospital because of chest pain. Chest roentgenogram and computed tomographic chest scans revealed pleural effusion in the right thorax and irregular pleural thickening. The white blood cell count was 15,300/mm3 with a differential count of 69.6% neutrophils. Peripheral blood analysis also demonstrated elevated levels of C-reactive protein (9.0 mg/dL). At that time no bacterial infection was identified and various microbiological cultures were negative. The patient underwent a right thoracotomy and a biopsy of the pleural tumor. The pathologic diagnosis of the tumor was a poorly differentiated malignant mesothelioma of an epithelioid type. A panpleuropneumonectomy was then performed. The diaphragm was partially resected because of tumor invasion and was reconstructed by a polyethylene sheet. The resected specimen was shown to be a sarcomatoid mesothelioma. The white blood cell count normalized (8,000/mm3) after the surgical removal of the tumor, and the patient was discharged. One month later, he had marked leukocytosis (white blood cell count 49,100/mm3; 85.2% neutrophils) develop again without a high fever. Microbiological cultures (including pleural exudates) failed to demonstrate any organisms. The white blood cell count reached 147,000/mm3 (96.2% neutrophils) and the concentration of serum G-CSF was 77 pg/mL (normal range, < 18.1 pg/mL). After 7 days the patient complained of dyspnea and abdominal distension. The cytology of the ascites revealed a recurrence of malignant mesothelioma. The concentration of G-CSF in the ascites was 24,800 pg/mL. The abdominal tumor enlarged rapidly and spread into the surrounding tissues accompanied by leukocytosis. The patient died 4 weeks after the second admission. An autopsy was performed 3 hours after death. The pericardial, abdominal, and pelvic cavities were entirely occupied by the tumor showing a gelatinous, soft, and whitish mass. Disseminated nodular tumors were also found in the bilateral chest wall, diaphragm, and left lung. Histologically the tumor was a highly cellular sarcomatoid mesothelioma composed of interwoven bundles of spindle cells (Fig 1A). The tumor contained large amounts of hyaluronidase-digestive hyaluronic acid in the tumor cells and stroma, which was positively stained with Alcian blue. Some of the tumor cells showed granular immunoreactivity for human G-CSF in their cytoplasm (Fig 1B). However, more of the tumor cells and endothelial cells in the tumor showed intense immunoreactivity for G-CSF receptor in their cytoplasm and cell membrane (Fig 1C) than G-CSF itself.
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Fig 1. (A) The tumor showed interwoven bundles of spindle cells and diffuse infiltrates of epithelioid cells (left field) with abundant cytoplasm and irregular nuclei. The infiltration of leukocytes was frequently found in the tumor. (B) Intense granulocyte-colony stimulating factor (G-CSF) immunoreactivity was found in the cytoplasm of many tumor cells. (C) More abundant immunoreactivity for G-CSF receptor was recognized in the cytoplasm of tumor cells and endothelial cells. ([A]: hematoxylin-eosin; [B]: immunohistochemistry for human G-CSF; and [C]: immunohistochemistry for human G-CSF receptor.)
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Comment
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Some types of cancers are known to produce humoral factors, including hematopoietic growth factors. Both normal human mesothelial cells and established human malignant mesothelioma cell lines in culture are known to produce hematopoietic colony-stimulating factors, including G-CSF [1, 2]. Nevertheless, only six cases of malignant mesotheliomas producing G-CSF have been reported in the English literature. All seven of these cases, which includes the present one, document rapid tumor progression with a short survival period. Although the production of G-CSF may contribute to tumor progression, it would be more important to determine whether the tumor cells are able to respond to the G-CSF. In addition to the elevation of G-CSF levels in the serum and ascites, we have demonstrated that some of the tumor cells produced G-CSF, but even more of the tumor cells expressed G-CSF receptor. Our observations would suggest the presence of an autocrine loop involving G-CSF and G-CSF receptor, whereby the tumor growth would be accelerated. It has been reported that G-CSF and granulocyte-macrophage-colony stimulating factor stimulated the proliferation of squamous cell carcinomas of the skin [3] and gliomas [4], which expressed G-CSF and granulocyte-macrophage-colony stimulating factor receptors. In addition to this autocrine effect on the cytokine-producing tumor itself, G-CSF and granulocyte-macrophage-colony stimulating factor induced a microenvironment that promoted tumor progression by modulating the tumor stroma [5]. Both G-CSF and granulocyte-macrophage-colony stimulating factor play a role in angiogenesis by stimulating endothelial cell proliferation and migration [6]. In the present case, the expression of G-CSF receptor was frequently observed in the endothelial cells in the tumor as previously reported [4, 5]. Therefore it may be hypothesized that G-CSF and granulocyte-macrophage-colony stimulating factor may contribute to tumor progression not only by acting on the tumor cells themselves (autocrine), but also by activating or modulating effects, or both, on the tumor stroma (paracrine). The development of novel therapeutic strategies including neutralizing antibodies against G-CSF is required, because the treatment of patients with malignant mesotheliomas still remains poor.
We reported here the first case of a malignant mesothelioma expressing not only G-CSF but also its receptor. It was believed that an autocrine loop involving G-CSF and G-CSF receptor accelerated the tumor growth.
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References
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- Mueller MM, Peter W, Mappes M, et al. Tumor progression of skin carcinoma cells in vivo promoted by clonal selection, mutagenesis, and autocrine growth regulation by granulocyte colony stimulating factor and granulicyte-macrophage colony stimulating factor Am J Pathol 2001;159:1567-1579.[Abstract/Free Full Text]
- Mueller MM, Herold-Mende CC, Riede D, et al. Autocrine growth regulation by granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in human gliomas with tumor progression Am J Pathol 1999;155:1557-1567.[Abstract/Free Full Text]
- Obermueller E, Vosseler S, Fusenig NE, et al. Cooperative autocrine and paracrine functions of granulocyte colony-stimulating factor and granulocyte-macrophage colony stimulating factor in the progression of skin carcinoma cells Cancer Res 2004;64:7801-7812.[Abstract/Free Full Text]
- Bussolino F, Wang JM, Defilippi P, et al. Granulocyte- and granulocyte-macrophage-colony stimulating factors induce human endothelial cells to migrate and proliferate Nature 1989;337:471-473.[Medline]
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Abstract
Introduction
