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Ann Thorac Surg 2009;88:426-431. doi:10.1016/j.athoracsur.2009.04.038
© 2009 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

Placenta Growth Factor Expression Has Prognostic Value in Malignant Pleural Mesothelioma

Eugenio Pompeo, MDa,*, Loredana Albonici, PhDb, Elena Doldo, PhDb, Augusto Orlandi, MDc, Vittorio Manzari, MD, PhDb, Andrea Modesti, MDb, Tommaso C. Mineo, MDa

a Department of Thoracic Surgery, Tor Vergata University, Rome, Italy
b Department of Experimental Medicine and Biochemical Sciences, Tor Vergata University, Rome, Italy
c Department of Anatomic Pathology, Tor Vergata University, Rome, Italy

Accepted for publication April 14, 2009.

* Address correspondence to Dr Pompeo, Department of Thoracic Surgery, Policlinico Tor Vergata University, V le Oxford 81, Rome, 00133, Italy (Email: pompeo{at}med.uniroma2.it).

Presented at the Poster Session of the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26–28, 2009.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Malignant pleural mesothelioma is highly aggressive and recurs rapidly despite radical multimodality treatment. Progression of mesothelioma is thought to be governed by various growth factors, including vascular endothelial growth factor (VEGF). Placenta growth factor (PlGF) belongs to the VEGF family, although no study has yet investigated its expression in mesothelioma. We hypothesized that PlGF is overexpressed in mesothelioma and could have prognostic value in patients treated by extrapleural pneumonectomy.

Methods: We assessed by immunohistochemistry with semiquantitative classification (0 = no staining; 3 = strong staining), the expression levels of PlGF and its cognate receptors VEGF receptor 1, neuropilin-1, and neuropilin-2 in 27 patients with malignant pleural mesothelioma undergoing extrapleural pneumonectomy, in 14 patients with reactive mesothelium, and in 10 patients with normal mesothelium.

Results: Whereas PlGF was not expressed in normal mesothelium, it was overexpressed (grade 3) more frequently in mesothelioma than in reactive mesothelium specimens (11 or 41% versus 1 or 7%, respectively, p = 0.03). Furthermore, in mesothelioma, VEGF receptor 1 and neuropilin-1 and -2 were overexpressed in 18 specimens (67%), 8 specimens (30%), and 9 specimens (33%), respectively. Mean survival after extrapleural pneumonectomy was 17 months. An inverse relationship was found between the degree of PlGF expression and survival in months (R = –0.45, p = 0.01). No correlation was found between tumor stage and survival (R = –0.33) and between tumor stage and PlGF expression (R = 0.07).

Conclusions: We have shown that PlGF can be overexpressed in malignant pleural mesothelioma. In addition, the finding of an inverse relationship between PlGF expression levels and survival suggests a pivotal role of this factor in the recurrence and progression of mesothelioma after extrapleural pneumonectomy.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Malignant pleural mesothelioma is a highly aggressive mesodermally derived tumor that arises in the pleura and is characterized by relentless growth into adjacent structures, resulting in poor prognosis. Although relatively rare, mesothelioma is increasing in incidence in some geographic areas, and it has been estimated that more than 250,000 new cases will occur over the next 30 years in Western Europe [1, 2]. So far, there is no uniformly accepted standard therapy for mesothelioma, but some promising results have been documented by multimodality treatment including extrapleural pneumonectomy [3–5].

The progression of mesothelioma is thought to be driven by tumor-related neoangiogenic factors that lead to the development of new vascular stroma and facilitate tumor growth. This process is governed by a variety of proangiogenic and antiangiogenic factors, among which vascular endothelial growth factor (VEGF) has been studied most extensively [6]. However, investigation on mechanisms underlying progression of mesothelioma suggests that other growth factors besides VEGF could promote tumor angiogenesis [7].

Placenta growth factor (PlGF) is a dimeric glycoprotein, structurally and functionally related to VEGF [8], that binds to VEGF receptor 1 (VEGF-R1) and may modulate VEGF activity [9].

Plasma levels and intratumoral expression of PlGF have been found to correlate with disease progression and survival in different types of tumors, including gastric [10], colorectal [11], breast [12], and nonsmall-cell lung carcinomas [13].

The aim of this study was twofold: firstly, to assess the degree of expression of PlGF and its cognate receptors including VEGF-R1 and neuropilins 1 and 2 in specimens of patients undergoing extrapleural pneumonectomy; and secondly, to investigate the potential relationships existing between PlGF expression and clinical outcome.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
The study group included 27 patients with mesothelioma undergoing extrapleural pneumonectomy at the S. Eugenio hospital (14 patients) and at the Policlinico Tor Vergata (13 patients) between 1997 and 2007. There were 21 men and 6 women with a mean age of 58 ± 12 years (range, 41 to 70). Permission for this retrospective study and authorization for tissue samples reanalysis was obtained from the Institutional Review Boards of each institution where the operations were performed.

Patients considered eligible for the study were those who did not have lethal postoperative complications and who entered the follow-up program. Indications for extrapleural pneumonectomy included confirmed preoperative diagnosis of mesothelioma of the epithelial or biphasic histotype at stage 3 or less according to the International Mesothelioma Interest Group [14], with a Karnofsky index of 90% or greater, and without major organ dysfunction. All patients had undergone computed tomographic scan of the thorax and upper abdomen and contrast-enhanced magnetic resonance imaging. Resectability was defined by tumor confined to one hemithorax, with the absence of mediastinal organ or full-thickness pericardial or myocardial involvement, absence of multifocal chest wall disease, transdiaphragmatic extension, or spread directly into the spine. Evidence of metastatic mediastinal lymph nodes was considered an absolute exclusion criterion for extrapleural pneumonectomy.

The operation was performed through an extended posterolateral thoracotomy, in most cases through the sixth intercostal space with a counterincision in the eighth space. The procedure included en bloc excision of the lung, pleura, hemipericardium, and hemidiaphragm. The surgical procedure was always followed by adjuvant chemotherapy and radiotherapy. Briefly, chemotherapy regimen usually consisted of four to six cycles of cisplatin and gemcitabine. Radiation therapy usually started after the cycles of chemotherapy. External beam radiotherapy was delivered with an energy ranging from 4 MV to 15 MV. The total radiation doses to the hemithorax and mediastinum were normally 30 Gy and 40 Gy, respectively, fractioned in 1.5 Gy. A boost dose (14 Gy in 2-Gy fractions) was always delivered to areas of gross residual disease or positive resection margins, and metastatic lymph nodes [15].

After discharge, all patients were followed up every 3 months for clinical evidence of disease progression. Progression-free survival was measured from date of operation to clinical-radiologic evidence of tumor progression. Survival was measured from the date of operation until the patient's last follow-up contact or death.

Immunohistochemistry
The immunohistochemical analysis was performed in all the 27 specimens of mesothelioma as well as in 10 specimens of surgical biopsies of normal mesothelium and in 14 specimens of reactive mesothelium (RM). Normal mesothelium biopsies were obtained from patients with no history of pleural-pulmonary disease. Reactive mesothelium biopsies were from patients with histologically proven nonneoplastic disease including empyema, pleural effusion, and chronic pleuritis.

Formalin-fixed paraffin-embedded sections (5 µm) were mounted on sylane-coated slides. Immunohistochemistry was performed with UltraTek HRP kit (ScyTek, Logan, UH) according to manufacturer's instructions. Primary antibodies were incubated in a moist chamber at 4°C overnight. After washing, the sections were incubated with biotinylated polyvalent immunoglobulins followed by HRP-labeled streptavidin and visualized using 3-amino-9-ethylcarbazole chromogen in H2O2 as substrate. Finally, the slides were counterstained with Mayer's hematoxylin. Nonimmune goat or rabbit serum was used as negative control, and the endothelium within the specimens was used as internal positive control.

The immunostained sections were independently evaluated by two pathologists, who recorded immunostaining distribution in mesothelial cells, mesothelioma cells, stroma, endothelial, and inflammatory cells. Mesothelial and mesothelioma cells immunostaining was additionally scored for intensity using a semiquantitative system: 0, no staining; 1, weak staining; 2, moderate staining; and 3, strong staining. The percentage of cells with positive staining was assessed independently and ranked into three categories: 1, less than 30% positive rate; 2, 30% to 60% positive rate; and 3, greater than 60% positive rate. Overexpression was considered by a percentage of positive cells greater than 60% with an intensity level of the immunostaining greater than 2. Disagreement among the readers was resolved by consensus.

Statistical Analysis
Group descriptive statistics are presented as mean ± SD. Because of the limited sample, relationship between factors has been assessed by the nonparametric Spearman correlation coefficients. Proportions among categorical variables were analyzed by two-tailed Fisher's exact test. The impact of PlGF expression on progression-free survival and overall survival were assessed by the Kaplan-Meier method, taking median PlGF level as the cutoff point and dichotomizing results according to values equal to or below, and above the median value. Significance was assessed by the log-rank test. Reported p values are all two-sided. Statistical significance was set at p less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Histologically, malignant pleural mesothelioma was of the epithelial histotype in 24 patients and of the biphasic type in 3 patients. Pathologic tumor staging was stage I in 8 patients, stage II in 6 patients, and stage III in 13 patients. Of these latter, 7 patients had unexpected N2 disease. Follow-up ranged from 4 to 36 months (mean, 17 ± 10).

Immunohistochemical Analysis of PlGF and Cognate Receptors
Malignant pleural mesothelioma tissue showed strong and diffuse cytoplasmic staining for PlGF. Overall, PlGF was overexpressed in 41% of mesothelioma samples, VEGF-R1 in 67%, neuropilin-1 in 30%, and neuropilin-2 in 33% of samples (Fig 1). Intergroup comparisons as far as immunostaining overexpression (score > 2) is reported in Table 1; this shows that PlGF and VEGF-R1 expression levels were significantly higher in mesothelioma specimens as compared with normal mesothelium specimens in which PlGF immunostaining was not detectable and expression of the VEGFR-1 and coreceptors was low. Instead, expression levels of PlGF and VEGF-R1 in plump cuboidal mesothelial cells of reactive mesothelium specimens were variable but significantly lower than those detected in mesothelioma. On the other hand, neuropilins were found to be expressed in both groups with no significant differences (Table 1).


Figure 1
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  		Fig. 1. (A) Expression of placenta growth factor (PlGF) and vascular endothelial growth factor receptor 1 (VEGF-R1) in human mesothelium and malignant mesothelioma tissues. Shown are representative immunohistochemistry pictures. Immunostaining of PlGF (red color) is absent in normal mesothelium (a), moderate in reactive mesothelium (b), and strong in malignant mesothelioma tissue (c). The immunostaining for VEGF-R1 is weak in normal mesothelium (a) and stronger in reactive mesothelium (b) and mesothelioma (c). (B) Flattened normal mesothelium (a) constitutively expresses moderate levels of both neuropilin-1 (NP-1) and neuropilin-2 (NP-2). A weaker staining for NP-2 is present in plump cuboidal reactive mesothelial cells (b) in respect to NP-1. Conversely, in mesothelioma tissue (c), NP-2 only is upregulated. (Original magnification 200x.)

 

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  		Table 1 Overexpression (Score 3) of Placenta Growth Factor (PlGF) and Its Coreceptors as Assessed by Immunohistochemistry
 
Relationships Between PlGF and Clinical Outcome
Mean follow-up was 18 ± 11 months and ranged from 4 to 40 months. Overall, at the last follow-up, 24 patients had died and 3 patients were still alive (2 free from clinical signs of progression and 1 with radiologic evidence of progression). Mean progression-free survival was 15 ± 11 months, whereas mean survival was 17 ± 10 months.

Spearman correlation analysis of potential prognostic factors showed no significant correlation between survival and age (R = –0.10, p = 0.60), sex (R = –0.07, p = 0.71), tumor stage (R = –0.33, p = 0.08), pathologic N2 status (R = –0.20, p = 0.30), neuropilin-1 expression (R = –0.25, p = 0.19), and neuropilin-2 expression (R = –0.18, p = 0.34). Conversely, an inverse significant correlation was found between survival and the degree of expression of both PlGF (Fig 2) and VEGF-R1 (R = –0.53, p = 0.0038).


Figure 2
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  		Fig 2. Relationship between survival and placenta growth factor (PlGF) expression level. (Dashed lines = confidence intervals.)

 
The estimated 2-year progression-free survival rate was 42% in patients with PlGF expression level below or equal to median value and null in patients with PlGF level above the median value (p = 0.02; Fig 3A). In a similar manner, estimated 2-year survival rates also differed significantly between groups, being 47% in patients with lower PlGF expression and 9% in patients with higher PlGF values (p = 0.02; Fig 3B).


Figure 3
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  		Fig 3. Kaplan-Meier curves comparing (A) progression-free survival and (B) survival according to dichotomized placenta growth factor (PlGF) expression level. (Solid lines = PlGF below median; dashed lines = PlGF above median.)

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
In this study, we have demonstrated by semiquantitative immunohistochemistry analysis that PlGF and its cognate receptors, VEGF-R1 and neuropilin-1 and -2 were expressed in surgical specimens of patients with malignant pleural mesothelioma undergoing extrapleural pneumonectomy. Our main finding is that PlGF was not expressed in normal mesothelium tissue whereas it was overexpressed in as many as 41% of mesothelioma patients. In the same group, we have found an inverse correlation between the degree of expression of PlGF and clinical outcome in the sense that the higher the expression level of PlGF, the worst the survival.

Angiogenesis is involved in several pathologic conditions including inflammation, tumor growth, and metastasis. Tumor growth is known to be dependent on neovascularization that may be governed by an impaired balance between angiogenic and antiangiogenic factors. Among angiogenic factors, VEGF has been reported to be overexpressed in several type of tumors, including malignant mesothelioma [6].

The role of PlGF as an angiogenic factor has been debated for a long time. However, increasing evidence has shown that upregulation of PlGF and its receptor VEGF-R1 leads the endothelial cell to amplify its responsiveness to VEGF during the angiogenic switch in many pathologic disorders [9]. In fact, overexpression of PlGF in a transgenic mouse model demonstrated that it resulted in a substantial increase in the number, branching, and size of blood vessels [16]. Yet PlGF does not affect only angiogenesis but also promotes tumor cell survival by inhibiting apoptosis and modulates the tumor immune response by suppressing the maturation and antigen-recognition capacity of dendritic cells [17].

Different mechanisms have been proposed to explain PlGF-enhanced pathologic angiogenesis. Possibly, PlGF could synergize with VEGF either by displacing VEGF from VEGF-R1, making more VEGF available to bind and activate VEGF-R2 [9], or by a mechanism of transphosphorylation between VEGF-R1 and VEGF-R2 that activates and transmits angiogenic signals through the VEGF-R2/VEGFR-1 heterodimer receptor complex [18]. Further, PlGF might enhance the angiogenic response to VEGF by forming VEGF/PlGF heterodimers, which have been detected in tumors and are upregulated by hypoxia in vivo (Fig 4) [19].


Figure 4
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  		Fig 4. Hypothetical biological effects of placenta growth factor (PlGF) include displacement of vascular endothelial growth factor (VEGF) from VEGF receptor 1 (VEGF-R1), rendering VEGF more available to bind and activate VEGF-R2; a mechanism of transphosphorylation between VEGF-R1 and VEGF-R2 activating and transmitting angiogenic signals through the VEGF-R2/VEGFR-1 heterodimer receptor complex; and enhancement of the angiogenic response to VEGF by forming VEGF/PlGF heterodimers. The PlGF signaling might be enhanced by the presence of neuropilin-1 (NP-1) and neuropilin-2 (NP-2).

 
It is worth noting that mononuclear phagocytes positive for PlGF were detected both in reactive mesothelium and mesothelioma, indicating that the inflammatory infiltrate can also represent a source of PlGF in these tissues.

In a diabetic wound closure model, PlGF was required for the recruitment of monocytes and macrophages to the closing wound [20]; and in an ischemic hind limb model, PlGF administration increased the number of macrophages around collateral side branches [21]. Therefore, the release of PlGF by mesothelioma cells could drive the recruitment of macrophages in the tumor microenvironment, and, in turn, the recruited macrophages could contribute to tumor progression by releasing PlGF and promoting tumor angiogenesis [22].

Recently, in agreement with our study data, PlGF has been found to be a prognostic factor that correlates with tumor progression and survival in several types of tumors [10–13].

Our results have also shown an upregulation of neuropilin-1 and -2 in 30% and 33% of mesothelioma patients, respectively. It is worth noting that disease progression toward cancer has been correlated also with neuropilins upregulation. In fact, neuropilins levels increase from dysplasia to microinvasive carcinoma [23]. Overexpression of neuropilins has been shown in different types of invasive carcinomas, including nonsmall-cell lung cancer [24]. However, so far it remains unclear whether the overexpression of neuropilins in cancer is associated with increased angiogenesis or whether neuropilins have a direct role in the malignant transformation or metastatic potential of the tumor. Hypothetical biological mechanisms include autocrine, paracrine, and iuxtacrine signaling with tumor cells producing and secreting VEGF, eventually leading to enhanced angiogenic signals in the endothelial cells and inhibition of apoptosis in tumor cells.

Study Limitations
Our study has several limitations. Firstly, the small sample negated the possibility for us to perform a multivariate analysis including other potential independent factors such as tumor stage, adjuvant therapy, and pathologic R status. That implies that our results must be interpreted with caution and await confirmation by larger prospective studies. In addition, the semiquantitative assessment of immunostaining for PlGF may be less precise than assessment of PlGF mRNA by quantitative real-time reverse transcription polymerase chain reaction. Finally, we have included in the analysis patients with biphasic and epithelioid mesothelioma types, a feature that may have biased the results owing to the acknowledged poorer prognosis associated with the former type. However, as far as histogenesis of malignant mesothelioma is concerned, increasing evidence [24] supports the combination theory in which carcinoma and sarcoma cells coexist in variable proportion and are thought to arise from a common stem cell. If this is the case, PlGF might eventually prove to play a prognostic role independently of the conventional histology nomenclature.

In conclusion, we have shown upregulation of PlGF and its cognate receptors in surgical specimens of mesothelioma patients undergoing extrapleural pneumonectomy. Overexpression of PlGF was inversely correlated with outcome, suggesting that this angiogenic factor might be actively involved in the neoplastic process by promoting progression of mesothelioma. We share the belief of Dr Pass [25] that surgeons are eternal optimists and in the case of mesothelioma, there is still need for optimism with good ideas. Maybe some of these ideas will arise from translational efforts between optimists and basic researchers.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This work was supported by a grant from the Department of Surgical Sciences of Tor Vergata University.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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