|Year : 2012 | Volume
| Issue : 2 | Page : 135-139
Serum platelet-derived growth factor-BB in adult patients with aggressive non-Hodgkin’s lymphoma
Laila F. Youssef1, Emad Eldin Azmy1, Amal A.F. Halim2, Ahmed M. Rabie3, Amal M. El-Gayar1
1 Biochemistry Department, Faculty of Pharmacy, Faculty of Medicine, Mansoura University, Mansoura, Dakahliya, Egypt
2 Clinical Hematology Department, Faculty of Medicine, Mansoura University, Mansoura, Dakahliya, Egypt
3 Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Dakahliya, Egypt
|Date of Submission||15-Feb-2012|
|Date of Acceptance||12-Mar-2012|
|Date of Web Publication||23-Jun-2014|
Emad Eldin Azmy
Clinical Hematology Department, Faculty of Medicine, Mansoura University, 35111 Mansoura, Dakahliya
Source of Support: None, Conflict of Interest: None
The importance of angiogenesis was proved first for solid tumors, and its importance in hematological malignancies was reported later.
Aim of the work
The present study aimed to evaluate the prognostic value of the angiogenesis marker platelet-derived growth factor-BB (PDGF-BB) in patients with aggressive non-Hodgkin’s lymphoma (NHL) and identify its significance on treatment response.
Subjects and methods
The serum level of PDGF-BB was measured in patients with aggressive NHL before and after chemotherapy and compared with that of a healthy control group, and its relationship with certain prognostic parameters was assessed.
Pretreatment serum level of PDGF-BB did not show a significant change as compared with the control group. Its level showed no relation to Ann Arbor stages, International Prognostic Index scores, B symptoms, or extranodal involvement. Chemotherapy led to a considerable increase in serum PDGF-BB level in all NHL patients and in the noncomplete responder subgroup.
From the results mentioned above it could be concluded that PDGF-BB is not vital in the pathogenesis of NHL. Chemotherapy led to elevation of serum PDGF-BB, reflecting activation of angiogenesis, which can be considered one of the mechanisms of conferring chemoresistance to cancer cells or in identification of patients at risk for developing side effects. Future studies are recommended to prove this effect of chemotherapy. If this effect is confirmed, the use of agents blocking the angiogenic pathway of PDGF-BB in combination with chemotherapy may improve the therapeutic effectiveness and sensitize chemoresistant cells.
Keywords: angiogenesis, non-Hodgkin′s lymphoma, platelet-derived growth factor-BB, prognosis
|How to cite this article:|
Youssef LF, Azmy EE, Halim AA, Rabie AM, El-Gayar AM. Serum platelet-derived growth factor-BB in adult patients with aggressive non-Hodgkin’s lymphoma. Egypt J Haematol 2012;37:135-9
|How to cite this URL:|
Youssef LF, Azmy EE, Halim AA, Rabie AM, El-Gayar AM. Serum platelet-derived growth factor-BB in adult patients with aggressive non-Hodgkin’s lymphoma. Egypt J Haematol [serial online] 2012 [cited 2020 Jan 26];37:135-9. Available from: http://www.ehj.eg.net/text.asp?2012/37/2/135/135068
| Introduction|| |
In human lymphomas, the progression of disease is associated with increased angiogenic activity 1.
The platelet-derived growth factor (PDGF) family is composed of four polypeptide chains, PDGF-A, PDGF-B, PDGF-C, and PDGF-D chains, which group together into disulfide-bonded dimers forming five different isoforms: PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD. PDGFs act through two receptors (PDGFR-α and PDGFR-β) 2,3. PDGF signaling has a critical role in carcinogenesis through autocrine and paracrine mechanisms 4.
PDGF was found to be involved in angiogenesis, and it stimulates the angiogenic process both directly and indirectly 4–6. By in-vitro studies it was shown that PDGF-BB significantly increases new capillary network formation 7 and modulates endothelial proliferation and angiogenesis 8; moreover, it was also shown that PDGF-BB has a direct role in lymphangiogenesis and lymphatic metastasis 9.
To our knowledge, PDGF was not extensively investigated for its prognostic effect in non-Hodgkin’s lymphoma (NHL) patients, except for a few studies conducted on the circulating levels of PDGF-AB isoform and PDGF-β 10,11. Labidi et al. 12, however, did not specify a particular isoform. In addition, an immunohistochemical study on PDGF-A in primary central nervous system lymphoma was also conducted 13.
| Subjects and methods|| |
Thirty-eight patients with newly diagnosed NHL, aged between 20 and 71 years with a mean age of 49.6±2.2 years, were included in the study. Ten healthy individuals, aged between 28 and 59 years with a mean age of 47.5±2.7 years, were used as controls.
The patients were selected from the Hematology and Medical Oncology unit, Oncology Center, Mansoura University, Egypt, between January and November 2009, with informed consent taken from the studied group. Patients with any of the following criteria were excluded from the study: patients with significant hepatic or renal disorders, pregnant women with NHL, patients aged less than 15 years, and patients with lymphoma as a second neoplasm.
All patients were subjected to thorough clinical examination; complete laboratory and radiological studies including computed tomography scans for chest, abdomen, and pelvis; and bone marrow aspiration and trephine biopsy. Six patients died either before or during chemotherapy. Thirty-two patients received four cycles of CHOP chemotherapeutic protocol and were reevaluated after therapy. The patients were 17 men and 15 women, aged between 20 and 69 years, with a mean of 49.8±2.1 years.
Histology classification was based on the WHO classification of lymphomas; all patients had aggressive diffuse large B cell lymphoma and one had follicular lymphoma grade III. Staging was performed according to the Ann Arbor classification system (four cases were in stage I, five cases were in stage II, 15 cases were in stage III, and eight were in stage IV). Prognostic scoring was performed according to the International Prognostic Index (IPI) [10 patients had no or one risk factor (the low-risk group), 16 patients had two risk factors (the low intermediate risk group), five patients had three risk factors (the high intermediate risk group), and only one patient had four risk factors (the high-risk group)]. The clinical characteristics assessed at diagnosis were B symptoms, extranodal involvement (ENI), and performance status (PS) according to the Eastern Cooperative Oncology Group scale.
The laboratory investigations carried out at diagnosis and after treatment were: (a) hematological evaluation including blood picture (hemoglobin concentration, red blood cell count, white blood cell count, and platelet count) and erythrocyte sedimentation rate; (b) biochemical evaluation including serum activities of aminotransferases (alanine aminotransferase, aspartate aminotransferase) and levels of total bilirubin, albumin, creatinine, uric acid, lactate dehydrogenase, and β2-microglobulin. Angiogenesis marker level (PDGF-BB isoform) was assessed using a commercially available ELISA kit according to the manufacturer’s instructions; ‘RayBio Human PDGF-BB’ ELISA kit from ‘RayBiotech Inc. (Norcross, Georgia, USA)’ was used for assessment.
At the end of treatment, the patient’s status was reevaluated by clinical, laboratory, and radiological parameters. Response was assessed and patients were divided into complete responders (eight patients) and noncomplete responders [those achieving partial response (13 patients), no response (eight patients), and progressive disease (three patients)]. Patient characteristics are presented in [Table 1].
Statistical analysis of the present study results was carried out using GraphPad InStat program, produced by GraphPad Software Inc (San Diego, California, USA). An unpaired t-test was used as a test of significance to compare the means of two different groups (patients and controls or patient subgroups) when the data were sampled from two populations with equal SDs, or the alternate unpaired t-test Welch corrected was used when the populations had different SDs. The paired t-test was used as a test of significance to compare the same individuals before and after treatment. Pearson’s correlation coefficient (r) was used to measure the mutual correspondence of two variables in the same studied group. Data were expressed as mean±SE, and P value less than 0.05 was considered significant.
| Results|| |
It was statistically inappropriate to assess the relationship of the angiogenesis marker according to PS. The analysis of the angiogenic molecule according to ENI was carried out by comparing the ENI presence and absence groups as shown in [Table 1] as only one patient had at least two extranodal sites.
Pretreatment and post-treatment serum levels of PDGF-BB showed no significant difference as compared with the control group. In all NHL patients, post-treatment serum level of PDGF-BB showed a significant increase as compared with the pretreatment level (P=0.0002). After stratification into complete responders and noncomplete responders, serum level of PDGF-BB in complete responders did not show a significant change after treatment, whereas noncomplete responders showed a highly significant increase after treatment (P=0.0001). Data are shown in [Table 2] and [Figure 1].
|Table 2: Pretreatment and post-treatment serum levels of PDGF-BB in all NHL patients, complete responders, and noncomplete responders|
Click here to view
|Figure 1: Pretreatment and post-treatment serum PDGF-BB concentration in NHL patients, complete responders, and noncomplete responders as compared with the control group and with each other. **Significance (P<0.001). NHL, non-Hodgkin’s lymphoma; PDGF-BB, platelet-derived growth factor-BB.|
Click here to view
Serum PDGF-BB level did not change according to Ann Arbor stages, IPI scores, B symptoms, or ENI. Data are shown in [Table 3] and [Figure 2]. Pretreatment PDGF-BB level did not show any significant correlation with any of the analyzed parameters. Data are shown in [Table 4].
|Table 3: Serum levels of LDH, β2-M, and PDGF-BB based on certain clinical characteristics|
Click here to view
|Table 4: The correlation between pretreatment serum PDGF-BB and some parameters in NHL patients|
Click here to view
|Figure 2: Pretreatment serum PDGF-BB based on some clinical characteristics. ENI, extranodal involvement; IPI, International Prognostic Index; PDGF-BB, platelet-derived growth factor-BB.|
Click here to view
| Discussion|| |
The PDGF antagonists may become important for treatment of cancer and prevention of lymphatic metastasis, as PDGF family stimulates tumor progression through different pathways 9.
It should be noted that there is little information regarding PDGF-BB isoform in NHL. Its pathogenic and prognostic roles are not obvious yet and there is a shortage in the volume of data pertaining to its function in NHL.
Güler et al. 10 observed that PDGF-AB had much higher values compared with the control group, and there was no statistical relationship between high PDGF values and age, sex, PS, ENI, stage, IPI score, lactate dehydrogenase level, and β2-microglobulin level. In the study by Labidi et al. 12 the serum level of PDGF was higher in follicular lymphoma patients than in healthy controls but it did not influence the outcome. However, they did not specify a particular isoform and the patients in his study were at different clinical statuses (diagnosis, complete remission, or first relapse).
In the present study, no significant variation was detected when serum PDGF-BB level in NHL patients was compared with that of the control group. Also, no significant differences were detected between patients with advanced stages and those with lower stages, nor between the lower-risk group and the intermediate and high-risk group. Also, PDGF-BB level did not vary according to the presence or absence of B symptoms, nor according to the presence or absence of ENI.
PDGF, TGF-β, and angiogenin, factors that mediate normal angiogenesis, were probably involved in tumor neovascularization, but their roles in this condition are not well characterized and thus are assumed to play minor roles 14.
Hence, it could be assumed that the contribution of PDGF-BB in normal angiogenesis may overcome their contribution in NHL angiogenesis. Nevertheless, within the confines of the current study, this finding weakens the probability that PDGF-BB may have a role in the pathogenesis of NHL.
In the present study, comparing PDGF-BB value according to treatment response, no significant difference was detected in the pretreatment and post-treatment level in the complete responder group. However, in the noncomplete responder group a highly significant increase was detected at the post-treatment level. In the study by Ria et al. 11 serum levels of PDGF-β decreased significantly after radiotherapy in NHL patients but it did not correlate with age, histotype, or stage. The design of the latter study differs from the current one, as some patients had already undergone previous cycles of chemotherapy before starting radiotherapy and the patients had different histotypes.
No previous studies had reported an elevation in serum PDGF-BB level in lymphoma patients receiving chemotherapy, but in advanced hepatocellular cancer patients an increase in plasma levels for s-E-selectin and PDGF-BB was seen in patients receiving chemotherapy alone, which might reflect activation of angiogenesis 15.
In other types of tumors, the following recent studies have provided evidence that PDGF-BB is involved in cancer cells acquiring resistance against chemotherapeutic agents:
- PDGF-BB protected feline vaccine-associated sarcoma cells from apoptosis induced by serum starvation and doxorubicin, and imatinib (STI571, a tyrosine kinase inhibitor for PDGF receptor) eliminated this protection 16.
- The chemoresistant glioma U87/Pt cells displayed ∼40-fold higher levels of PDGF-B than the chemosensitive U87 cells. U87/Pt cells overexpress PDGF-BB. A therapeutic potential for STI571 was suggested in patients with malignant gliomas refractory to chemotherapy 17.
- A novel mechanism was introduced by Lau et al. 18 by which Akt/hypoxia-inducible factor-1α (HIF-1α)/PDGF-BB form an autocrine signaling loop that confers cisplatin resistance to human hepatocellular carcinoma cell lines and tumorigenic hepatic progenitor cells. Disruption of this autocrine signaling, especially by an HIF-1α blocker or PDGF receptor inhibitor, may improve human hepatocellular carcinoma treatment.
- PDGF-BB partially saved neuroblastoma cells from apoptosis induced by doxorubicin. In vivo, the combination of imatinib with doxorubicin induced a significant growth inhibition of established neuroblastoma xenografts 19.
Although these previous studies differed from the current one in the type of tumor and sometimes the chemotherapy under investigation, these previous results can be taken into account. As to our knowledge, until now there are no studies on this issue in NHL, and the role of PDGF-BB in NHL is not clear yet.
Until further studies are carried out, it is possible to assume that the intense increase in serum PDGF-BB after chemotherapy found in the current study may reflect a reactivation of angiogenesis and make the tumor cells resistant to the damaging action of cytotoxic drugs.
Another possible explanation of this unexpected elevation of serum PDGF-BB after treatment is the systemic toxicity of chemotherapy and the occurrence of yet an unclear side effect, such as fibrosis, as it was shown that overactivity of PDGF was involved in several fibrotic conditions, such as lung and kidney fibroses 20.
These two hypotheses are strengthened by the finding that this elevation was found only in noncomplete responder patients, whereas the complete responder patients showed no significant difference after treatment. Thus, monitoring the PDGF-BB level during treatment may give an indication about the treatment response, and its elevation may refer to a poor response and may indicate gaining a resistance against chemotherapy or identify patients at risk of developing side effects or both.
There is a need for future precise studies to clarify both the significance of PDGF-BB in NHL cells that are refractory to chemotherapy and its role in developing chemotherapeutic side effects in NHL. If its role is confirmed, it will be a suitable target for improving the therapeutic effectiveness by using its inhibitor in combination with chemotherapy in order to sensitize the chemoresistant cells and avoid an expected side effect.
This study is considered one of the few studies analyzing PDGF-BB isoform in NHL. Within the confines of this study, PDGF-BB is not considered vital in the pathogenesis of the disease. The most important finding is that chemotherapy leads to elevation of serum PDGF-BB, reflecting activation of angiogenesis, which can be considered one of the mechanisms of conferring chemoresistance to cancer cells or in identifying patients at risk of developing side effects. Hence, if this effect of chemotherapy is confirmed by future investigations, which we recommend, the combined use of antiangiogenic drug (blocking PDGF-BB pathway) with chemotherapy might be capable of inhibiting the consecutive activation of angiogenesis, which might augment the therapeutic effect, as development of resistance to chemotherapeutic agents is a major problem in the treatment of cancer.
| References|| |
|1.||Ruan J, Hajjar K, Rafii S, Leonard JP. Angiogenesis and antiangiogenic therapy in non-Hodgkin's lymphoma. Ann Oncol. 2009;20:413–424 |
|2.||Fredriksson L, Li H, Eriksson U. The PDGF family: four gene products form five dimeric isoforms. Cytokine Growth Factor Rev. 2004;15:197–204 |
|3.||Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 2008;22:1276–1312 |
|4.||Yu J, Ustach C. Kim HRC. Platelet-derived growth factor signaling and human cancer. J Biochem Mol Biol. 2003;36:49–59 |
|5.||Thommen R, Humar R, Misevic G, Pepper MS, Hahn AWA, John M, et al. PDGF-BB increases endothelial migration and cord movements during angiogenesis in vitro. J Cell Biochem. 1997;64:403–413 |
|6.||Wang D, Huang HJS, Kazlauskas A, Cavenee WK. Induction of vascular endothelial growth factor expression in endothelial cells by platelet-derived growth factor through the activation of phosphatidylinositol 3-kinase. Cancer Res. 1999;59:1464–1472 |
|7.||Sato N, Beitz JG, Kato J, Yamamoto M, Clark JW, Calabresi P, et al. Platelet-derived growth factor indirectly stimulates angiogenesis in vitro. Am J Pathol. 1993;142:1119–1130 |
|8.||Battegay EJ, Rupp J, Iruela Arispe L, Sage EH, Pech M. PDGF-BB modulates endothelial proliferation and angiogenesis in vitro via PDGF β-receptors. J Cell Biol. 1994;125:917–928 |
|9.||Cao Y. Direct role of PDGF-BB in lymphangiogenesis and lymphatic metastasis. Cell Cycle. 2005;4:228–230 |
|10.||Güler N, Yilmaz S, Ayaz S, Yilmaz M, Aki Z, Dagdaş S, et al. The platelet-derived growth factor level (PDGF) in Hodgkin’s disease and non-Hodgkin’s lymphoma and its relationship disease activation. Hematology. 2005;10:53–57 |
|11.||Ria R, Cirulli T, Giannini T, Bambace S, Serio G, Portaluri M, et al. Serum levels of angiogenic cytokines decrease after radiotherapy in non-Hodgkin lymphomas. Clin Exp Med. 2008;8:141–145 |
|12.||Labidi SI, Ménétrier Caux C, Chabaud S, Chassagne C, Sebban C, Gargi T, et al. Serum cytokines in follicular lymphoma. Correlation of TGF-β and VEGF with survival. Ann Hematol. 2010;89:25–33 |
|13.||Karabatsou K, Pal P, Dodd S, Mat A, Haylock B, Aguirreburualde M, et al. Expression of survivin, platelet-derived growth factor A (PDGF-A) and PDGF receptor α in primary central nervous system lymphoma. J Neurooncol. 2006;79:171–179 |
|14.||Papetti M, Herman IM. Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol. 2002;282:C947–C970 |
|15.||Treiber G, Wex T, Malfertheiner P. Impact of different anticancer regimens on biomarkers of angiogenesis in patients with advanced hepatocellular cancer. J Cancer Res Clin Oncol. 2009;135:271–281 |
|16.||Katayama R, Huelsmeyer MK, Marr AK, Kurzman ID, Thamm DH, Vail DM. Imatinib mesylate inhibits platelet-derived growth factor activity and increases chemosensitivity in feline vaccine-associated sarcoma. Cancer Chemother Pharmacol. 2004;54:25–33 |
|17.||Servidei T, Riccardi A, Sanguinetti M, Dominici C, Riccardi R. Increased sensitivity to the platelet-derived growth factor (PDGF) receptor inhibitor STI571 in chemoresistant glioma cells is associated with enhanced PDGF-BB-mediated signaling and STI571-induced Akt inactivation. J Cell Physiol. 2006;208:220–228 |
|18.||Lau CK, Yang ZF, Ho DW, Ng MN, Yeoh GC, Poon RT, et al. An Akt/hypoxia-inducible factor-1alpha/platelet-derived growth factor-BB autocrine loop mediates hypoxia-induced chemoresistance in liver cancer cells and tumorigenic hepatic progenitor cells. Clin Cancer Res. 2009;15:3462–3471 |
|19.||Palmberg E, Johnsen JI, Paulsson J, Gleissman H, Wickström M, Edgren M, et al. Metronomic scheduling of imatinib abrogates clonogenicity of neuroblastoma cells and enhances their susceptibility to selected chemotherapeutic drugs in vitro and in vivo. Int J Cancer. 2009;124:1227–1234 |
|20.||Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. 1999;79:1283–1316 |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]