|Year : 2019 | Volume
| Issue : 12 | Page : 1698-1705
Clinical significance of heat shock protein 90α expression as a biomarker of prognosis in patients with gastric cancer
HW Lee1, KM Kim2
1 Department of Pathology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea
2 Division of Gastroenterology, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea
|Date of Submission||02-Feb-2019|
|Date of Acceptance||27-Jul-2019|
|Date of Web Publication||3-Dec-2019|
Prof. K M Kim
Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, 158 Paryong-ro, Masanhoewon-gu, Changwon - 51353
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Heat shock protein 90 (HSP90) possesses two major isoforms – HSP90α and HSP90β. They have essential roles in the protection against stressful conditions. They are also important for the re-establishment of cellular homeostasis. We investigated the clinical significance of HSP90α and HSP90β expression in patients with gastric cancer (GC). Methods: HSP90α and HSP90β expression levels were examined immunohistochemically in surgical specimens obtained from 186 GC patients. The correlations between their expression levels and clinicopathological parameters including patient survival were analyzed. Results: The frequencies of larger tumor size (maximum diameter ≥4 cm) and more prominent tumor invasion (≥pT3) in the high intensity HSP90α expression group were 73.4% and 68.8% higher, respectively, than those in the low intensity group (both P = 0.001). High HSP90α expression level was also significantly associated with lymphatic invasion, lymph node metastasis, and advanced stage (TNM stage ≥III) disease (P = 0.047, P = 0.046, and P = 0.004, respectively). Patients with high HSP90α expression levels demonstrated significantly worse survival than those with low HSP90α expression levels (P = 0.047). In contrast, survival did not differ significantly according to the intensity of HSP90β expression. Conclusions: Our results showed that HSP90α overexpression might be associated with disease progression and poorer survival in patients with GC. Therefore, HSP90α could be used as possible biomarker for the prognosis of GC.
Keywords: Biomarker, gastric cancer, HSP90, immunohistochemistry, prognosis
|How to cite this article:|
Lee H W, Kim K M. Clinical significance of heat shock protein 90α expression as a biomarker of prognosis in patients with gastric cancer. Niger J Clin Pract 2019;22:1698-705
|How to cite this URL:|
Lee H W, Kim K M. Clinical significance of heat shock protein 90α expression as a biomarker of prognosis in patients with gastric cancer. Niger J Clin Pract [serial online] 2019 [cited 2022 Jan 28];22:1698-705. Available from: https://www.njcponline.com/text.asp?2019/22/12/1698/272216
| Introduction|| |
Although worldwide incidence of gastric cancer (GC) has declined over the past few decades following the recognition of certain risk factors such as Helicobacter pylori, it remains the third leading cause of cancer-related death in the world. GC continues to be difficult to cure in Western countries, mainly because most gastric cancer patients are diagnosed at advanced stages., Although tumor-node-metastasis (TNM) classification remains the most powerful prognostic tool for predicting the survival of GC patients, the prognosis of patients can vary even for patients within the same staging, especially at more advanced TNM stages. To predict the survival and prognosis of patients with GC, many biological markers have been or are being evaluated in clinical trials. Biomarkers associated with less favorable prognosis include microsatellite instability (MSI) and the presence of p53 gene mutations., Recently, several additional markers such as microRNAs and human epidermal growth factor receptor-2 (HER2) have also been reported to have possible prognostic values.,, Heat shock proteins (HSPs) are subdivided into several families according to molecular weight. They represent a universal and evolutionarily conserved protein family in response to a variety of environmental stresses or unfavorable conditions. They act as cellular self-protective or defense factor by facilitating the refolding or the elimination of misfolded proteins. Malignant cells have more unfolded proteins than normal cells, leading to higher levels of molecular chaperones such as HSPs. For this reason, overexpression of 70-kilodalton HSP (HSP70), a representative and ubiquitous one among all HSP families, is significantly associated with metastasis, poor prognosis, and resistance to chemotherapy or radiation therapy in various cancers, including GC.,, Similar to HSP70, HSP90 also plays an important role in protecting cells against stressful conditions. It is also important for the re-establishment of cellular homeostasis. Up to date, five HSP90 isoforms have been identified, including two major cytoplasmic isoforms (HSP90α and HSP90β), the endoplasmic reticulum homologue glucose-regulated protein (GRP) 94, and the mitochondrial homologue TNF receptor-associated protein (TRAP) 1. Among these, HSP90β overexpression has been identified as an important prognostic variable in some cancers such as breast cancer. Furthermore, large amounts of HSP90 are expressed in gastric cancer cell lines. However, the role of HSP90 as a marker for the prognosis of GC is relatively less studied compared to HSP70, another emerging biological marker. Therefore, the objective of this study was to evaluate the correlation between HSP90 expression levels, especially those of HSP90α and HSP90β, and clinicopathological parameters including clinical prognosis of GC patients.
| Subjects and Methods|| |
Between January 2002 and December 2015, a total 210 patients who underwent surgical treatment for GC in Samsung Changwon Hospital, Changwon, South Korea, were enrolled in this study. The inclusion criteria were: (1) radical surgical treatment confirming the presence of GC through histopathologic examination, (2) accurate medical records, (3) the absence of any prior history of treatment for other malignancy, and (4) no preoperative chemotherapy or radiotherapy for GC. Ultimately, 186 patients with accurate medical records and pathological specimens available for immunohistochemistry (IHC) analysis of HSP90 were consecutively enrolled in the study. The study protocol was approved by the Ethics Committee of Samsung Changwon Hospital. It was conducted in accordance with the Declaration of Helsinki. Due to the retrospective nature of analyzing existing administrative and clinical data, the need for informed consent was waived by Institutional Review Board of Samsung Changwon Hospital.
Tissue microarray and immunohistochemistry
Immunohistochemistry analysis of HSP90 isoforms (HSP90α, HSP90β, GRP94, and TRAP1) was performed on paraffin-embedded tissue sections according to previously described IHC procedure. Briefly, immunohistochemical staining was performed using Ventana Benchmark XT (Roche-Ventana, Tucson, AZ, USA). Slides of 4-μm-thick tissue sections were baked at 60 degrees Celsius for two hours, dewaxed in xylene, and rehydrated using alcohol gradient. To remove endogenous peroxidase activity, sections were then treated with freshly prepared 0.3% hydrogen peroxide in methanol in the dark for 30 minutes at room temperature. After 30 minutes of preincubation in 10% of normal goat serum to prevent nonspecific staining, samples were incubated overnight with the following primary antibodies: HSP90α (clone D7a, 1:100, Abcam, Cambridge, UK), HSP90β (clone E296, 1:50, Epitomics, Burlingame, CA, USA). An UltraView Universal DAB kit (Roche-Ventana) was used in accordance with the manufacturer's recommendations to detect the localization of the primary antibody followed by counterstaining with hematoxylin (Roche-Ventana). Negative controls without incubating with primary antibodies were also included. Immuno-stained slides were evaluated by two experienced pathologists (H.W.L. and E.H.L.) blinded to clinical information. Discrepant cases were reviewed on a multi-head microscope until a consensus was reached. For each HSP90 isoform, cases were considered as positive when 10% or more of tumor cells expressed the protein. To quantify HSP90 isoforms, respective immunohistochemical staining intensities were scaled according to the following percentages of counted cells in the stain: Negative (score of 0), 0-9%; weakly positive (score of 1), 9-25%; moderately positive (score of 2), 26-50%; or strongly positive (score of 3), 51-100%. Representative examples of immunohistochemical staining for HSP90α and HSP90β are shown in [Figure 1]. The intensities of HSP90α and HSP90β expression were also graded with a two-step scale: Low (0 to 1) and high (2 to 3).
|Figure 1: Representative examples of immunohistochemical staining for: (a) HSP90α and (b) HSP90β demonstrating the intensities of low scores (0: [a1, b1], and 1: [a2, b2]) compared to high scores (2: [a3, b3], and 3: [a4, b4]) as expression levels of each isoform|
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Data collection and assessment of clinicopathologic outcomes
All data for patients with GC samples in the pathology archives were retrospectively reviewed from their medical records. Clinicopathological data including demographic factors, histopathologic type, tumor location and tumor characteristics were evaluated. GC was categorized into four histopathologic types: Tubular, signet ring cell, mucinous, and undifferentiated.
Based on anatomic site, the following four categories were created for tumor locations: Antrum, body, cardia including fundus, and multiple locations. Tumor size was designated into two categories based on the maximum diameter of the surgical specimen: 1) ≥40 mm; 2) <40 mm.
Tumors were dichotomized into intestinal type and diffuse type according to Lauren classification. Tumor stages were classified according to the newly released seventh edition of the American Joint Committee on Cancer/International Union against Cancer Classification (AJCC/UICC) staging system.
All patients who had surgery for GC underwent routine esophagogastroduodenoscopy (EGD) and computed tomography (CT) or magnetic resonance imaging (MRI). They were also subjected to tumor marker level analysis including carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and CA 72-4 at an outpatient clinic every 6 months for the 2 years and annually thereafter to check for local recurrence, lymph node involvement, and distant metastasis. Patient survival data were collected from the National Statistics Service, ensuring that all deaths at the time of assessment were certified. Overall survival (OS) was calculated from the date of surgery to the date of death from any cause or the date of the last follow-up. Recurrence-free survival (RFS) was defined as the interval between the date of surgery and the date of diagnosis of any type of relapse or the last follow-up.
Statistical analyses were performed using PASW Statistics 17.0 (SPSS Inc., Chicago, IL, USA). Relationships between expression status and clinicopathological parameters were evaluated using Chi-square or Fisher exact tests. Overall survival (OS) was compared using the Kaplan-Meier method and log-rank test. A Cox proportional hazards model was used to evaluate HSP90α and HSP90β expression levels and the intensities of staining as prognostic factors for patient survival. A P value <0.05 was considered as statistically significant.
| Results|| |
Baseline demographic and clinical characteristics of the 186 patients included in this study who received surgery for GC are summarized in [Table 1]. The mean patient age was 61.4 ± 10.6 years. The male: female ratio was approximately 7:3. The antrum was the most common location of GC (n = 124, 66.7%), followed by the body (n = 38, 20.4%) and the cardia (n = 5, 2.7%). The remaining 19 (10.2%) tumors extended over more than one anatomical portion of the stomach. One hundred five (56.5%) patients had tumors greater than or equal to 4 cm in maximum diameter. Histologically, GC was characterized as “tubular adenocarcinoma,” “mucinous adenocarcinoma,” “signet ring cell carcinoma”, and “undifferentiated carcinoma” in 155 (83.3%), 26 (14.0%), 3 (1.6%), and 2 (1.1%) of cases, respectively. According to the Lauren classification, intestinal type was noted in 100 (53.8%) cases and diffuse type was found in 85 (46.2%) cases. Pathological T stage was pT1 for 65 (34.9%) tumors, while 28 (15.1%) were at pT2, 38 (20.4%) were at pT3, and 55 (29.6%) were at pT4. Of these tumors, 65 pT1 were early gastric cancers (EGC) while the other 121 (65.1%) were advanced gastric cancers (AGC, ranging from pT2 to pT4). Seventy-eight (41.9%) patients were node negative (pN0) while 108 (58.1%) were node positive (pN1, n = 44, 23.7%; pN2, n = 24, 12.9%; pN3, n = 40, 21.5%). More than half of patients were in final pathologic stage I or II (AJCC/UICC TNM stage: Stage I, n = 73, 39.2%; stage II, n = 44, 23.7%). About one-third (32.3%) of patients were diagnosed with locally advanced (stage III) disease. With score 2 of staining as a cut-off value to define high expression, 62 (34.4%) and 116 (62.4%) patients were placed in the high HSP90α group and the high HSP90β expression group, respectively.
|Table 1: Baseline characteristics of 186 patients who underwent surgical treatment for gastric cancer|
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Influence of HSP90α and HSP90β overexpression levels on clinicopathologic variables associated with prognosis
To evaluate the influence of HSP90α and HSP90β overexpression levels on clinicopathologic outcomes of patients with GC, the incidence of tumor size ≥4 cm, depth of tumor invasion ≥pT3, lymphovascular invasion, lymph node metastasis, TNM stage ≥III, diffuse type, and tumor recurrence were compared between the low intensity group and the high intensity group depending on the degree of HSP90α expression. Results are shown in [Table 2]. The frequencies of larger tumor size (maximum diameter ≥4 cm) and more prominent tumor invasion (≥pT3) in the high intensity HSP90α expression group were 73.4% and 68.8%, respectively, which were significantly higher than those in the low intensity group (both P = 0.001). In addition, high HSP90α expression was significantly associated with lymphatic invasion, lymph node metastasis, and advanced stage (TNM stage ≥ III) disease (P = 0.047, P = 0.046, and P = 0.004, respectively). There was no significant correlation between the intensity of HSP90α expression and other factors such as venous invasion or frequency of diffuse-type carcinoma. In terms of HSP90β overexpression, patients in the high intensity group also tended to have higher incidence of clinicopathologic factors associated with poor prognosis than those in the low intensity group. The incidence rates of depth of tumor invasion ≥pT3 and diffuse type carcinoma in the low intensity group were significantly higher than those in the high intensity group. However, other factors were not significantly different between the two groups.
|Table 2: Correlation of HSP90α or HSP90β expression with various clinicopathologic factors associated with prognosis|
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Survival analysis according to HSP90α and HSP90β overexpression
The median follow-up time for all patients was 95.0 months (range, 1 to 130 months). Regarding mortality, 80 (43.0%) of 186 patients with GC died of the disease during the follow-up. Kaplan-Meier survival curves were constructed according to the intensities of HSP90α and HSP90β expression. Results are shown in [Figure 2]. When the overall 5-year survival rate of GC patients was compared with respect to their HSP90α expression (low vs. high), patients with low HSP90α expression levels had more favorable survival than those with high HSP90α expression levels (5-year survival rate, 70.6% vs. 56.5%, P = 0.047). In contrast, survival did not differ significantly according to the intensity of HSP90β expression (P = 0.084).
|Figure 2: (a-b) Kaplan-Meier survival curves showing cumulative survival of patients who underwent surgical treatment for gastric cancer: (a) Survival curves of patients with low HSP90α expression levels showed significantly better 5-year survival rates than patients with high|
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Impact of clinicopathological factors on RFS in patients with GC
Cox proportional hazard regression analysis was performed to identify prognostic factors influencing RFS in patients with GC. Results of univariate and multivariate analysis using Cox proportional hazards model are summarized in [Table 3]. Univariate analysis revealed the following significant unfavorable variables for RFS: Larger tumor size (≥ 4 cm in maximum diameter, P < 0.001), diffuse-type carcinoma (P = 0.018), prominent tumor invasion (≥ pT, P < 0.001), lymphatic invasion (P = 0.018), lymph node metastasis (P< 0.001), and advanced stage (TNM stage ≥ III, P < 0.001). However, sex, age, presence of venous invasion and status of HSP90α or HSP90β overexpression had no significant prognostic value with respect to RFS of patients with GC. Multivariate analysis showed that older age (≥ 60, OR: 1.763; 95% CI: 1.061-2.932, P = 0.029) and advanced stage (TNM stage ≥ III, OR: 3.872; 95% CI: 1.826-8.212, P < 0.001) were significant and independent poor prognostic factors for RFS.
| Discussion|| |
The objective of this study was to evaluate the correlation between HSP90α and HSP90β expression status and clinicopathologic parameters including survival in GC patients. Despite progress in the diagnosis and treatment for GC, the prognosis of GC remains poor in developing countries because the majority of GC patients in clinical practice have advanced or metastatic disease due to possible absence of specific symptoms. Given this status quo, there is a strong need to clarify the mechanisms governing the pathogenesis, invasion, and metastasis of GC and to identify molecular markers with predictive capability for tumor prognosis. To identify these molecular markers, many key regulators in GC progression have been researched in recent years. However, due to molecular heterogeneity of GC, its detailed mechanisms remain unclear. It is essential to identify the pathologic, prognostic, and predictive factors of GC in order to guide clinical decision-making and the selection of appropriate treatment options.
HSP90 performs a chaperone function by promoting the refolding of proteins damaged by cell stress and suppressing their aggregation. These functions contribute to the regulation of cell signaling, protein traffic, and apoptosis., It has been asserted that cancer cells require higher expression of HSP90 than normal cells because of their prolonged exposure to oncogenic stress. However, whether the expression of HSP90 is associated with tumor invasiveness or prognosis of patients with GC remains controversial., Furthermore, few studies have explored the clinicopathologic significance of each HSP90 isoform as a potential predictive biomarker. HSP90α is inducible by various cellular stresses. It is involved in cell cycle progression or growth factor-mediated signaling. However, HSP90β is intrinsically expressed. It is involved in long-term cellular adaptation. The results of the present study suggest that HSP90α overexpression could be an adverse prognostic factor for the survival of patients with GC. Notably, HSP90α overexpression was confirmed to be correlated with multiple clinicopathological factors associated with unfavorable prognosis. In particular, we found that the frequency of more advanced stage in HSP90α high intensity group was significantly higher than that in the low intensity group. Lymph node metastasis was also identified at significantly higher level in patients with HSP90α overexpression. These findings were in agreement with results of earlier studies showing that HSP90 overexpression is a poor prognostic factor in different types of cancer.,. Patients in the HSP90β high-intensity group also had higher proportions of unfavorable clinicopathologic factors without statistical significance except for the depth of tumor invasion which showed a significant correlation with more advanced T stage and HSP90β overexpression. Several previous studies have shown that HSP90β overexpression is associated with the differentiation and progression of certain cancers, thus contributing to poor postsurgical survival time and lymphatic metastasis., However, the present study failed to reveal any differences in survival rate according to the intensity of HSP90β expression in GC patients. Our finding of a similar prevalence of advanced TNM stage between HSP90β low and high intensity groups might be due to the absence of any significant difference between the two groups. Interestingly, this study demonstrated that the frequency of tumors larger than or equal to 4 cm in diameter (which is not included in the component variables of the classification of TNM stage) was significantly more common in the HSP90α high intensity group than that in the low intensity group. This finding suggests that the distance between the tumor and the resection margin is likely to be smaller in patients with HSP90α overexpression. Despite the lack of evidence that the length of the proximal resection margin can influence the overall survival and local recurrence of GC after curative resection, it can be difficult to achieve an optimum proximal margin length in GC with high HSP90α expression when a surgeon needs a sufficient proximal resection margin due to the larger tumor diameter. When multivariate analysis was performed to identify prognostic factors influencing RFS in patients with GC, RFS was shown to be significantly shorter for older patients and those with advanced TNM stage GC. When the depth of invasion and lymph node metastasis were not concerned, patients with T3 or T4 carcinoma and patients with lymph node metastasis both tended to present with shortened RFS, although these were not independent predictors for RFS in multivariate analysis. We also found that high HSP90α expression was not significantly associated with shorter RFS, which was different from our expectation.
We acknowledge the limitation of this study with regard to determining the value of HSP90 as a predictive marker of gastric cancer survival because of its retrospective study design. In addition, RFS, unlike overall survival rate, did not significantly correlate with HSP90 overexpression. Therefore, more studies are needed before HSP90 can be used as a specific marker to predict gastric cancer prognosis. Considering these, the present study is important because it is one of the very few studies that elucidates the potential role of α isoforms of HSP90 as a prognostic factor in GC patients by showing that HSP90α overexpression is significantly associated with inferior overall survival. Meanwhile, TNM staging remains the most important factor influencing the prognosis of GC patients. However, if overexpression of HSP90, especially HSP90α, is identified in a surgical specimen of GC, we would predict that such patient might have poorer prognosis after resection. Additionally, pre-surgical awareness of this histologic information may affect the choice of treatment strategy.
| Conclusions|| |
The identification of specific novel markers with prognostic value in GC patients is critical. We investigated the prognostic utility of α and β isoforms of HSP90 in GC patients. HSP90α seemed to more relevant to disease progression and survival of GC, whereas HSP90β was less relevant. Our results indicated that HSP90α might constitute a feasible biomarker for predicting prognosis in GC. Therefore, GC cases with high HSP90α expression may require closer monitoring for disease progression. However, additional research studies are required before HSP90α expression could be widely implemented in clinical practice.
We would like to thank Canadian technology writer Nancy Ellen McLennan for her proofreading and syntax support with this article.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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