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  Table of Contents    
ORIGINAL ARTICLE  
Year : 2016  |  Volume : 59  |  Issue : 3  |  Page : 287-293
Do phosphatase of regenerating liver-3, matrix metalloproteinases-2, matrix metalloproteinases-9, and epidermal growth factor receptor-1 predict response to therapy and survival in glioblastoma multiforme?


1 Department of Pathology, Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Neurosurgery, King George's Medical University, Lucknow, Uttar Pradesh, India
3 Department of Radiotherapy and Chemotherapy, King George's Medical University, Lucknow, Uttar Pradesh, India
4 Department of Radiology, Fortis Memorial Research Institute, Gurgaon, Haryana, India

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Date of Web Publication10-Aug-2016
 

   Abstract 

Context: Poor survival of the glioblastoma multiforme (GBM) has been attributed in part to the invasive nature of the lesion making complete surgical removal near impossible. Phosphatase of regenerating liver-3 (PRL-3), matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9), and epidermal growth factor receptor (EGFR-1) play a role in invasive nature of tumor cells. Aims: This study was conducted to evaluate PRL-3, MMP-2, MMP-9, and EGFR-1 (markers) expression in cases to GBM and to correlate their expression with therapy response and survival. Settings and Design: GBM cases (n = 62) underwent surgery followed by radiation (n = 34) and chemoradiation (n = 28). Using WHO Response Evaluation Criteria in Solid Tumors criteria response to therapy was assessed at 3 months and cases followed up for survival. Subjects and Methods: Expression of markers was assessed by immunohistochemistry as a percentage of positive tumor cells in hot spots. Statistical Analysis Used: Kaplan–Meier, ANOVA, Chi-square test, univariate, and multivariate Cox-regression analysis was done. Results: Response to therapy was evident in 54.8% cases of responders with the mean survival of 494.03 ± 201.13 days and 45.2% cases of non responders (278.32 ± 121.66 days) with P = 0.001. Mean survival for the patient's opted chemoradiation was 457.43 ± 222.48 days which was approximately 3 months greater than those who opted radiation alone (P = 0.029). We found PRL-3 overexpression was an independent, significant, poor prognostic factor for survival by multivariate analysis (P = 0.044). Cases negative for MMP's and EGFR showed increased survival, but the difference was insignificant. Conclusion: PRL-3 expression appears to be related to an adverse disease outcome.

Keywords: Epidermal growth factor receptor, glioblastoma multiforme, immunohistochemistry, matrix metalloproteinases, phosphatase of regenerating liver

How to cite this article:
Soni P, Husain N, Chandra A, Ojha BK, Bhatt ML, Gupta RK. Do phosphatase of regenerating liver-3, matrix metalloproteinases-2, matrix metalloproteinases-9, and epidermal growth factor receptor-1 predict response to therapy and survival in glioblastoma multiforme?. Indian J Pathol Microbiol 2016;59:287-93

How to cite this URL:
Soni P, Husain N, Chandra A, Ojha BK, Bhatt ML, Gupta RK. Do phosphatase of regenerating liver-3, matrix metalloproteinases-2, matrix metalloproteinases-9, and epidermal growth factor receptor-1 predict response to therapy and survival in glioblastoma multiforme?. Indian J Pathol Microbiol [serial online] 2016 [cited 2019 Oct 21];59:287-93. Available from: http://www.ijpmonline.org/text.asp?2016/59/3/287/188121



   Introduction Top


One of the distinctive features of glioblastoma multiforme (GBM) is the local invasiveness that accounts for dismal prognosis inspite of therapies such as chemoradiation that have shown supplementary efficacy in improving the survival.[1] Phosphatase of regenerating liver (PRL-3), promotes cancer cell invasion and metastasis,[2] also its expression was increased in high-grade gliomas that effected the matrix metalloproteinases (MMP) expression.[3] Extracellular-matrix degradation results in an increased availability of growth factors such as epidermal growth factors, etc.[4] Overexpression of these markers in brain tumor correlates with infiltrating and metastatic behavior, in general, poor prognosis.[4],[5],[6],[7] This study was aimed at evaluating the protein expression of MMP-2, MMP-9, PRL-3, and epidermal growth factor receptor-1 (EGFR-1) by immunohistochemistry (IHC) in the cases with GBM and to correlate the markers expression with therapy response and survival.


   Subjects and Methods Top


Sixty-two histopathologically confirmed cases of GBM by the WHO criteria were included in the study from the Department of Pathology and Neurosurgery, King George Medical University, Lucknow, India. There were 46 males and 16 females with a mean age of 45.96 years (range 1–85 years). All the cases initially underwent surgery (near total surgical excision to avoid confounding due to variation in surgical procedure) followed by the treatment. Cases were divided into two treatment groups: (i) Radiation (n = 34), 60 Gy for 6 weeks to the tumor site with a 2–3 cm margin. (ii) Adjuvant chemoradiation (n = 28), patients received 100 mg/m 2 temozolomide (TMZ) daily during radiotherapy then 150–200 mg/m 2 upto 6 adjuvant cycles for 5 out of 28 days. Randomization of cases was not possible, and stratification was dependent on the financial capability of patient to afford adjuvant chemotherapy along with radiotherapy. The study was approved by the Institutional Ethics Committee. Consent was obtained from the patients or their nearest kin after explaining the biopsy procedure.

Tumor volumetric measurement was done to calculate treatment response. Response to treatment given was assessed by magnetic resonance imaging (MRI)/computed tomography scans done at the time of patient's admission with neurologic symptoms and was assessed by comparing the preoperative scans with the post operative ones, done after 3 months of therapy completion. Cases were graded as complete responder (CR), partial responder (PR), progressive disease (PD), and stable disease (SD). Using the Response Evaluation Criteria in Solid Tumors guidelines [8] response was defined as: Complete response: 100% of reduction, i.e., disappearance of all target lesions, partial response: > 30% reduction in the sum of longest diameter (LD) of target lesions; PD > 20% increase in the sum of LD of target lesions; SD: Treatment result lies between partial response and PDs. Further, for the purpose of analysis, the CRs and PR groups were clubbed into a responder group while SD and PD groups into a nonresponder group. The cases were followed up till death to estimate patient's survival. All 62 patients had died at the time of analysis. Overall, survival (OS) was defined as the time interval between initial surgery and the day of the patient's death.

Formalin-fixed paraffin embedded tissue was freshly cut (3–4 μm thick) and fixed overnight at 56°C. The sections were mounted on coated slides (tissue bond, biocare), deparaffinized with xylene, and gradually rehydrated. IHC was performed by the standard protocol. Following peroxidase blocking with 3% H2O2/methanol for 30 min, antigen retrieval was achieved in Pascal (Dako Cytomation, California) in sodium citrate buffer (pH 6.0). Sections were incubated overnightat 4°C, separately with polyclonal antibody to PRL-3 human antigen (Sigma, USA) at a dilution of 1:100, monoclonal antibody against human MMP-2 and MMP-9 antigen (Santa Cruz Biotechnology Inc., USA) at a dilution range of 1:25 and 1:100, respectively and polyclonal antibody against EGFR-1 antigen (Biogenex, Hyderabad, India) ready to use. Then, the specimens were briefly washed in tris buffer saline (pH 7.4) and incubated at room followed by treatment with polymer-based secondary antibody (Envisionkit, Dakopatts, Denmark) for 30 min. Antigen-antibody interaction was visualized using diaminobenzidine according to the company instructions. After washing with water, specimens were counter stained with hematoxylin. Negative (by omitting primary antibody) and positive controls were run with all batches.

For evaluation of PRL-3, MMP-2, MMP-9, and EGFR-1 (markers) immunoreactive tissue, each immunostained slide with each of the four markers was received by an experienced pathologist and percentage positive expression of tumor cells was counted in 10 HPF. Patients were divided into positive and negative for each marker used in the study. The cut off value for the cases negative for PRL-3 was considered <5%,[9] MMPs <25%,[10] and for EGFR <10%.[11] For statistical analysis, the SPSS software by IBM Chicago USA, version 16 was used. Survival analysis was calculated according to the Kaplan–Meier, with log-rank test. The association between survival and different clinical parameters were evaluated using ANOVA and Chi-square test. To identify the predictors of good survival, we used univariate and multivariate Cox-regression analysis. All effects were quantified by odds ratio estimates with 95% of confidence intervals. Differences were considered statistically significant when P < 0.05 and highly significant when P ≤ 0.01


   Results Top


Protein expression of PRL-3, MMP-2, MMP-9, and EGFR-1 was studied in a total of 62 cases of GBM. PRL-3 was detected in 53 (85.5%), MMP-2 in 49 (79.0%), MMP-9 in 52 (80.6%), and EGFR in 47 (75.8%) tumor cases. MRI scans of the responder and nonresponder cases are shown in [Figure 1]c, [Figure 1]d, [Figure 1]h, and [Figure 1]i. Based on the IHC analysis, MMP-2, MMP-9, and EGFR-1 were expressed in cytoplasmic membrane of the tumor cells which were scored as positive [Figure 1]a, [Figure 1]b and [Figure 1]g. PRL-3 showed both cytoplasmic and nuclear staining [Figure 1]f and [Figure 1]e. Infiltrating tumor cells in the adjacent parenchyma expressed all these four antigens. ANOVA was performed to estimate the distribution of mean survival according to basic characteristics, markers expression, and clinicopathological parameters [Table 1]. Mean MMP-2 and MMP-9 protein expression were 2.46 ± 1.33 and 2.75 ± 1.14 for negative cases and 55.92 ± 19.16 and 58.26 ± 20.60 for positive cases, respectively. Mean survival for the MMP-2 and MMP-9 negative cases was 487.38 ± 286.39 and 485.25 ± 247.18 in days as compared to the positive cases 372.53 ± 166.42 and 375.34 ± 184.07 in days, respectively [Table 1] and [Figure 2]a and [Figure 2]b. The Pearson correlation analysis performed also revealed significant and positive (direct) correlation between MMP-2 and MMP-9 (r = 0.66, P < 0.001) [Table 2].
Figure 1: On immunohistochemistry dispersed cytoplasmic expression of (a) matrix metalloproteinases-2, (b) matrix metalloproteinases-9, (f) phosphatase of regenerating liver-3 and (g) EGFR-1 (e) phosphatase of regenerating liver-3 with dispersed nuclear expression (DAB × 100 × digital magnification).(c) magnetic resonance imaging of 23-year-old male with GBM in left-frontal region before surgery (d) after treatment (responder) (h) 42-year-old-male with GBM in left-parietal region before surgery (i) nonresponder

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Table 1: Distribution of mean survival according to basic characteristics, markers expression, clinico-pathological parameters

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Figure 2: Kaplan–Meier estimates of OS in GBM patients (a) matrix metalloproteinases-2, (b) matrix metalloproteinases-9, (c) epidermal growth factor receptor-1 and (d) phosphatase of regenerating liver-3 with respect to positive and negative cases (e) treatment (R vs. R + T), (f) response (complete responder vs. partial responder vs. stable disease vs. progressive disease)

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Table 2: Correlation between markers expression (n=62)

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There were 69.2% and 66.7% responders in the MMP-2 and MMP-9 negative cases, respectively [Supplementary Table 1]. Mean EGFR-1 protein expression was observed to be 3.07 ± 1.22 for negative cases and 67.51 ± 22.91 for positive cases. Mean survival for EGFR-1 negative cases was 468.47 ± 253.28 in days while for positive cases, it was 373.68 ± 177.47 in days [Table 1] and [Figure 2]e. There were 73.3% of responders in the EGFR-1 negative cases [Supplementary Table 1] and [Figure 2]c. Mean PRL-3 protein expression was found to be 3.00 ± 1.32 for negative cases and 60.09 ± 21.63 for positive cases. Mean survival for PRL-3 negative cases was comparatively higher and better than the other markers studied, i.e., 566.33 ± 243.81 in days while for positive cases, it was 367.79 ± 179.22 in days, [Table 1]. The percentage responders were observed to be highest (77.8%) for PRL-3 negative cases [Supplementary Table 1] and [Figure 2]d.



[Table 3] summarizes the basic characteristics (age, sex, Karnofsky performance status [KPS], and site of tumor), expression of all four markers (MMP-2, MMP-9, EGFR-1, and PRL-3) by IHC and clinicopathological parameters (treatment, treatment response, and survival) as percentage. Using the “Chi-square test”, we analyzed the association of all markers individually in relation to basic characteristics and clinicopathological parameters [Supplementary Table 1]. Based on the calculated mean age of 40 years, we divided the sample into younger (≤40 years) and older (>40 years) age groups. Our results showed improved prognosis in patients of the younger age group. Males had comparatively better survival than females. The calculated median for preoperative KPS was 60. We observed that the cases with KPS >60 had survival significantly greater than in cases with KPS ≤60 with P = 0.042.
Table 3: Basic characteristics, markers expressions, and clinicopathological parameters

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We tested for an association of each marker with survival. Of all the four markers studied through IHC PRL-3 negative cases was found to have statistically significant survival with P = 0.005. Survival benefit of 3.69 months was observed in patients opting for chemoradiation versus radiation alone (P = 0.029) [Figure 2]e. Survival was found to be highly significantly associated with response group (CR, PR, SD, and PD). As would be expected, CRs had the highest survival of 600.53 ± 216.70 days, with a significant survival decrease in SD and PD group. Kaplan–Meier analysis was used to estimate the OS with respect to positive and negative expression of each marker [Figure 2]f.

Univariate and multivariate analysis based on the Cox proportional hazard model was performed to test the independent value of each parameter predicting OS [Table 4]. Worse preoperative KPS and treatment given had a significant negative impact on survival (P = 0.039 and P = 0.034, respectively) by univariate analysis. The multivariate analysis demonstrates that response was independent highly significant predictor for survival (P = 0.002). PRL-3 overexpression also observed to be independent, significant, poor prognostic factor for survival (P = 0.044) after response while the prognostic value of MMP's and EGFR-1 expression was not sufficient to reach statistical significance.
Table 4: Predictors of better survival by univariate and multivariate Cox regression analysis

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   Discussion Top


This study has analyzed the expression of EGFR-1, MMP-2, MMP-9, and PRL-3 in relation to treatment response and survival in GBM. The prognostic role of EGFR overexpression in glioblastoma is controversial, with some studies claiming no association with survival [12],[13] and others claiming that this aberration is a negative prognostic factor.[14],[15] EGFR activated by EGF or transforming growth factor-α and the constitutively activated EGFR variant III promote growth signal transduction through activating several downstream signaling pathways and contribute to tumor progression and poor prognosis.[16] In this study, EGFR overexpression was noted in 75.8% samples. Although multivariate Cox regression analysis did not reveal any significant association of EGFR overexpression with survival in this study, but the mean OS was better for patients where tumor did not express EGFR protein. The percentage responders (73.3%) were also greater in the EGFR negative group. There are studies that support the survival benefit of using TMZ or other chemotherapeutic drug in combination to radiotherapy in glioblastoma patients. A study performed by Prados et al.,[17] on 65 GBM cases showed that patients treated with the combination of erlotinib and TMZ during and following radiotherapy had better median survival (19.3 months) than historical controls (14.1 months). Chakravarti et al.[18] investigated the response of malignant gliomas to erlotinib in a phase I trial of erlotinib administered either alone or with the TMZ that resulted in prolonged survival but this confirmation is lacking. Afatinib, a novel drug, either used alone or in a combination of TMZ did not improve the outcome of patients with recurrent glioblastoma, likely because of negligible blood–brain barrier penetration.[19] A recent study has shown that the inhibition of EGFR signaling by Shikonin, a natural naphthoquinone, and its derivatives synergistically kill glioblastoma cells in combination with erlotinib.[20]

MMPs are involved in the pathogenesis of neuroinflammatory diseases (such as multiple sclerosis) as well as in the expansion of malignant gliomas because they facilitate penetration of anatomical barriers (such as the glialimitans) and migration within the neuropil.[21] In this study, MMP-2 and MMP-9 overexpression were noted in approximately 80.0% of samples. The overexpressed range for MMP-2 and MMP-9 protein was 55–59%. Similar to the EGFR-1 results, multivariate Cox regression analysis did not reveal any significant association of overexpressed MMP-2 and MMP-9 with survival. Further, our overexpressed MMP-2 and MMP-9 cases also showed declined survival rate. We found 69.2% and 66.7% responders in the MMP-2 and MMP-9 negative group, respectively. We also observed significant correlation between MMP-2 and MMP-9 by using Pearson's correlation (Pearson coefficient = 0.66, [Table 2]). Two phase II trials of marimastat, matrix metalloproteinase peptidomimetic inhibitor (MMPI), and TMZ for recurrent GBM and anaplastic gliomas have data in support that this combination appears to be effective to increase progression-free survival (PFS).[22],[23] In contrast Levine et al.,[24] conducted a randomized, placebo-controlled phase II trial of prinomastat (a nonpeptidic MMPI, inhibits MMP-2,-3,-9, and-13) with TMZ after radiation therapy in patients with newly diagnosed GBM. Patients were randomized after surgery and radiation therapy to continuous prinomastat with the dose 25 mg orally twice a day or placebo, plus TMZ orally once a day. This trial showed that prinomast added to TMZ compared with TMZ alone did not improve 1-year survival rate (44% vs. 58%) or PFS (4.5 vs. 6 months).

PRL-3 overexpression was high in our study at 85.5% of cases. PRL-3 overexpression significantly correlated with diminishing survival. While PRL-3 negative cases had significantly better survival (P = 0.005). Our results for multivariate analysis revealed PRL-3 overexpression is an independent, significant, poor prognostic factor for survival.

The Kaplan–Meier analysis of subgroups showed significantly better survival in the patients treated with chemoradiation compared to those on radiotherapy alone. The concurrent and adjuvant use of TMZ with radiation have clearly improved OS as reported in other studies.[1] As can be expected cases with complete response to therapy (27.4%) showed a greatest mean OS of 600.53 ± 216.70. PRs (27.4%) was 387.53 ± 111.24 days, cases with SD (24.2%) was 254.47 ± 78.00 days and PD (21.0%) with an OS of 305.85 ± 157.08 days. Common pathways regulated by these markers responsible for tumor invasion and metastasis. As tumor invasion proceeds through multiple steps, including tumor cell interaction with ECM ligands, hydrolytic digestion of the matrix by the release of proteolytic enzymes followed by migration of tumor cells through the area of destruction. Growth factors and cytokines affect MMP-9 and MMP-2 expression through RAS/MAPK (ERK) and phosphatidylinositol 3-kinase (PI3K)/AKT signaling [Figure 3]. PRL-3 expression in gliomas is also affected by MMP's activity.[4] Metastasis in colon cancer is reported to be controlled by integrin β1-ERK1/2-MMP-2.[25] It is reported that up-regulation of PRL-3 activates the Src kinase, which initiates a number of downstream signaling cascades ending at phosphorylation of ERK1/2, STAT3 (transcription factor that is a direct substrate of Src), and p130Cas, an adaptor protein, through down-regulation of Csk, a negative regulator of Src [Figure 3].[26] For EGFR signalling ERK1/2 are activated by phosphorylation of tyrosine and threonine residues. Dual phosphorylation is necessary for full activation of ERK1/2. When ERK1/2 is activated, it migrates into the nucleus and phosphorylates transcription factors which affect the expression of many genes and ultimately promote cell growth [Figure 3].[27] All four markers thus generally activate ERK1/2 signaling there by inducing cell growth, differentiation, apoptosis, and metastasis.
Figure 3: Pathways of signalization through epidermal growth factor receptor-1, matrix metalloproteinases-2, matrix metalloproteinases-9 and phosphatase of regenerating liver-3 in glioblastoma multiforme

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PRL-3 also promotes epithelial-mesenchymal-transition and cell survival by acting upstream of PI3K.[28] PI3K signaling regulates many processes, such as cell survival, cell proliferation, and cell motility.[29] PRL-3 was reported to post transcriptionally downregulate PTEN protein levels.[30] PTEN counteracts PI3K activity by converting phosphatidyl inositol triphosphate PI (3, 4, 5) P3 into PI (4,5) P2; thus, its downregulation leads to the activation of PI3K signaling. PRL-3 has been described to act on p53 via PI3K/AKT signaling.[31] PI3-K/PTEN/AKT cascade for PRL-3 is similar to that of EGFR and reported to be one of the most significant signal pathways in tumor cells.[32] Nuclear factor NFkB is an important mediator in the regulation of TP53 and in the AKT signaling pathway. Both the above-mentioned signaling pathways lead to impaired apoptosis and thus promoting cell survival, enhanced proliferation, angiogenesis, necrosis, and treatment refractoriness, and are universally contributed by MMP's, PRL-3 and EGFR [Figure 3] suggesting a causative relationship between their receptor dysregulation and the pathobiology of many cancers.


   Conclusion Top


The survival benefit and better response were observed in cases on concomitant TMZ therapy. MGMT gene methylation was not studied in our cases. Results may be better in subgroups stratified on the basis of MGMT methylation. While all four markers include MMP-2, MMP-9, EGFR-1 and PRL-3 were overexpressed in a fai rnumber of GBM in our study and a direct significant correlation with survival was observed only with PRL-3.

Acknowledgment

Author wish to acknowledge and thank Indian Council of Medical Research for providing fellowship support for SRF to Priyanka Soni.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Correspondence Address:
Prof. Nuzhat Husain
Department of Pathology, Ram Manohar Lohia Institute of Medical Sciences, Lucknow - 226 010, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.188121

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

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