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ORIGINAL ARTICLES: TRANSLATIONAL RESEARCH
Diagnostic and prognostic value of heat shock protein 90α in malignant melanoma
Zhang, Tengtenga,,*; Li, Qianqianb,,*; Zhang, Yiyina,,*; Wang, Qianlinga; Wanga, Huia; Gua, KangshengaAuthor Information
Melanoma Research: April 2021 - Volume 31 - Issue 2 - p 152-161
doi: 10.1097/CMR.0000000000000716
OPEN
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Abstract
Malignant melanoma is one of the most common tumours of the skin. Heat shock protein 90α (HSP90α) has been applied in the auxiliary diagnosis of various malignancies, as a tumour marker. This study aims to evaluate diagnostic, therapeutic efficacy and prognostic value of plasma HSP90α levels in malignant melanoma. In this study, higher plasma HSP90α levels and abnormal rates were found in malignant melanoma patients than in healthy controls (92.63 vs. 51.84 ng/mL; P < 0.001 and 68.30 vs. 8.30%; P < 0.001). Plasma HSP90α levels were higher with Breslow thickness >4 mm, a high Clark level (IV + V), abnormal serum lactate dehydrogenase (LDH), distant metastases occurrence and Ki-67≥30% (P < 0.05). The area under the curves (AUCs) of HSP90α was greater than LDH in the training (0.847 vs. 0.677) and validation (0.867 vs. 0.672) cohort. Meanwhile, the sensitivity (76.70%) and negative predictive values (78.80%) of HSP90α were higher. Plasma HSP90α levels were s ignificantly reduced in objective response (81.05 vs. 37.26 ng/mL; P = 0.012) and disease control patients (84.16 vs. 47.05 ng/mL; P = 0.002) post-treatment. Patients with normal HSP90α levels had slightly longer progression-free survival (PFS) than those with abnormal levels (8.0 vs. 3.5 months; P = 0.096). Unfortunately, the trend was not statistically significant. In multivariable analysis, immunotherapy was an independent prognostic factor for PFS. Nevertheless, patients with normal HSP90α levels who received chemotherapy(±targeted therapy) without immunotherapy had significantly longer PFS than patients with abnormal levels (6.0 vs. 2.0 months; P = 0.008). Therefore, HSP90α can be used for auxiliary diagnosis and predict the responses to therapy in malignant melanoma patients.
Introduction
Malignant melanoma is one of the most aggressive tumours worldwide, and its overall 5-year survival rate is very poor [1]. In 2019, the American Cancer Society estimated that more than 95 000 new melanoma patients will be diagnosed and that over 7000 patients will die in the USA [2]. Most melanomas can be classified into four types: acral melanoma, mucosal melanoma, chronic sun-induced damage (CSD) and nonchronic sun-induced damage (non-CSD) [3]. The morbidity and mortality of melanoma are increasing year by year. The most common pathological types in China are acral melanoma, found on acral skin, primarily on the soles of the feet and mucosal melanoma. Due to the high-grade malignancy, strong invasiveness and distant metastatic potential of melanoma, the overall prognosis is poor. Due to the lack of specific tumour markers for the early detection of malignant melanoma, the diagnosis has relied to date on skin screening examinations, histopathology and imaging examination [4]. Cred ible prognostic markers for early stage malignant melanoma patients are absent as well. Therefore, finding a sensitive tumour marker may be benefit to detect patients early and could improve outcomes.
Heat shock proteins (HSPs) are highly conserved polypeptide proteins in evolution and include HSP40, HSP60, HSP70, HSP90 and HSP110 [5,6]. HSPs have been shown to be associated with cell stress, proteostasis, cell differentiation and regulatory pathways, including cell cycle control, protein folding and degradation, and cellular signalling events. Some cancer proteins require HSP90 machinery and chaperones for their maturation and function, such as protein kinases, transcription factors and signal transduction proteins. These proteins play important roles in tumour development and progression, and are a part of HSP90 client proteins [7]. Heat shock protein 90α (HSP90α), a member of the HSP family, has been shown to be overexpressed in cancer cells and involved in the induction of tumour angiogenesis, apoptosis, invasion and metastasis [8]. Currently, the abnormal expression of HSP90α has been detected in the tissues and blood of patients with various malignancies (including blood system tumours [9], oropharyngeal squamous cell carcinoma [10], digestive system tumours [11–15], breast cancer [16], lung cancer[17], etc.). A high level of HSP90α has also been detected in the tumour tissues of patients with malignant melanoma [18] HSP90 inhibitors cause critical proteins that are related to the development and promotion of tumours, and bind to the N-terminal domain nucleotide binding pocket to inhibit ATPase activity [19]. As an ATP-dependent protein, HSP90α therefore is used as a potential therapeutic target in many clinical trials. Several HSP90α inhibitors are currently being investigated, such as geldanamycin[20], 17-AAG [21], AT13387 [22], AUY922 [23], STA-9090 [24] and BIIB021[25]. Multiple experiments have shown that HSP90α inhibitors have antitumour effects [26].
At present, a study discovered that the baseline serum HSP90 levels in cutaneous malignant melanoma were significantly higher than control subjects. However, HSP90 levels were not associated with clinical parameters and long-term survival [27]. There are no studies on plasma HSP90α in acral and mucosal melanoma alone. Therefore, the aim of this study was to determine the level of plasma HSP90α in acral and mucosal patients and evaluate its diagnostic, therapeutic efficacy and prognostic value. In this study, first, plasma HSP90α levels between malignant melanoma patients and healthy controls were compared. Second, the relationship between plasma HSP90α levels and clinicopathological parameters in malignant melanoma patients was evaluated. Third, the diagnostic efficacy of plasma HSP90α level in malignant melanoma was explored. Then, the correlation between plasma HSP90α changes and short-term efficacy of treatment was analysed. Eventually, a correlation between plasma HSP90α l evels and long-term prognosis was performed.
Materials and methods
Patient samples
A total of 60 patients diagnosed with malignant melanoma were enrolled at the First Affiliated Hospital of Anhui Medical University (Hefei, China) between April 2018 and September 2020. The melanoma patients included 49 with acral melanoma and 11 with mucosal melanoma. Meanwhile, 60 healthy controls were also enrolled. The median age of the study group was 57.0 years with a range of 30–80 years and that of the control group was 54.5 years with a range of 27–86 years. The subject inclusion criteria were as follows: (1) malignant melanoma confirmed pathohistologically; (2) no prior systemic treatments, including targeted therapy, immunotherapy, chemotherapy, biological therapy, and so on; (3) no other malignancies existed; and (4) no other dermatological diseases or inflammatory diseases, including autoimmune diseases, tuberculosis and active infectious diseases. The healthy control inclusion criteria were as follows: (1) no malignancies existed; (2) no active dermatologica l diseases; (3) no inflammatory diseases, including autoimmune diseases, tuberculosis and active infectious diseases; and (4) no evidence of clinically significant cardiac, endocrine, hematologic, renal, pulmonary, gastrointestinal and neurologic disease. All malignant melanoma patients and healthy controls were randomly assigned to two groups: a training and a validation cohort.
The clinical data were obtained from the patients' files, including age, sex, Breslow thickness, ulcerations, Clark level, lymph node metastasis condition, clinical stage, vascular invasion, serum lactate dehydrogenase (LDH) level, distant metastases, Ki-67 level and mitotic rate. All patients underwent tumour staging according to the American Joint Committee on Cancer standard (2018 version). This experiment was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Anhui Medical University. Each subject signed an informed consent form before participating in the study.
Plasma HSP90α detection
A 4-mL blood sample (EDTA-K2 anticoagulant) was collected on an empty stomach from all enrolees, which was then centrifuged at 3000 r/min for 10 min, and plasma was obtained and separated. The plasma supernatant was transferred to a polypropylene tube (EP tube) that was centrifuged once more (3000 r/min for 10 min), and the new plasma sample was then frozen at −20 °C. Ninety-six well plates from a kit (Protgen Ltd, Yantai, People Republic of China) were preincubated at 37 °C for 30 min for ELISA analysis of the test samples. First, standard (50 μL) and diluted samples (50 μL) were added to the microplates, and then anti-Hsp90α-HRP-conjugated antibodies (50 μL) were added to the plates for incubation at 37 °C for 60 min. Immediately, the plates were cleaned six times, chromogenic solutions A (50 μL) and B (50 μL) were added to each micropore, and the reaction was stopped by using stop buffer after incubation for 20 min at 37 °C. Finally, the optical density was measured at 450 nm (620 nm as the reference wavelength) with a spectrophotometer. The protein content in each sample was calculated according to the standard curve of the optical density value.
For malignant melanoma patients, plasma HSP90α levels were detected before the initial treatment and dynamically monitored after treatment. The reference range of HSP90α in our laboratory was 0–82.00 ng/mL; a value of HSP90α >82.00 ng/mL was considered abnormal.
Efficacy evaluation criteria
All patients received systemic therapy and the efficacy was evaluated after two cycles of treatment. The therapeutic effect was divided into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) according to the Response Evaluation Criteria In Solid Tumours: Revised guideline (version 1.1) [28]. Objective response was defined as CR + PR, and disease control was defined as CR + PR + SD. For long-term prognosis, progression-free survival (PFS) was assessed, which is defined as the time from the data of randomisation to first documented disease progression or death, whichever occurred first. In this study, plasma HSP90α levels and PFS data were obtained in 42 patients pre- and post-treatment; the follow-up data were missing for the remaining patients as they were not rehospitalized or were lost to follow-up.
Statistical analysis
Statistical analyses were performed using SPSS 21.0 software (SPSS, Chicago, Illinois, USA) and GraphPad Prism software version 6.0 (GraphPad, La Jolla, California, USA). HSP90α values do not follow a normal distribution and so are expressed as medians and interquartile ranges, and differences were assessed by the Mann–Whitney U test. Enumeration data are expressed as percentages, and comparisons between two groups were performed by the chi-square test. Receiver operating characteristic (ROC) curves were produced to calculate the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and Youden index for a malignant melanoma diagnosis. The PFS curve was plotted with the Kaplan–Meier method, and the log-rank test was used to assess the PFS between survival curves. A Cox proportional hazards regression model was used for multivariable analysis to estimate prognostic factors for PFS. A value of P < 0.05 was considered statistically significan t.
Results
Plasma heat shock protein 90α levels in all participants
Plasma HSP90α levels in patients with malignant melanoma were significantly higher than those in healthy controls (92.63 vs. 51.84 ng/mL; P < 0.001) (Table 1 and Fig. 1a). Particularly, the plasma HSP90α level for patients with mucosal melanoma and acral melanoma was 140.78 ng/mL (62.04–239.20) and 90.14 ng/mL (71.65–130.11), respectively (Fig. 1b). However, this difference was not statistically significant (P = 0.144). According to the definition, the abnormal rate of HSP90α in malignant melanoma patients was higher than that in the control group (68.30 vs. 8.30%; P < 0.001) (Table 1).
Table 1 - Comparison of plasma heat shock protein 90α levels between malignant melanoma patients and healthy controls
Group Plasma HSP90α levels
[ng/mL, M(P25–P75)] HSP90α abnormal (%) HSP90α normal (%) Number
Malignant melanoma patients 92.63 (70.80–140.77) 41 (68.30%) 19 (31.70%) 60
Healthy controls 51.84 (42.56–61.42) 5 (8.30%) 55 (91.70%) 60
HSP90α, heat shock protein 90α.
Fig. 1
Fig. 1: Plasma heat shock protein 90α (HSP90α) levels in different participants (a) Plasma HSP90α levels in malignant melanoma patients were higher than those in healthy controls (92.63 vs. 51.84 ng/mL; P < 0.001). (b) Plasma HSP90α levels for different pathological types (140.78 vs. 90.14 ng/mL; P = 0.144).
Relationship between plasma heat shock protein 90α levels and clinicopathological parameters in malignant melanoma patients
The relationships between plasma HSP90α levels and age, sex, Breslow thickness, ulcerations, Clark level, lymph node metastasis condition, clinical stage, vascular invasion, serum LDH level, distant metastases, Ki-67 level and mitotic rate in malignant melanoma patients were analysed. Plasma HSP90α levels were higher with Breslow thickness >4 mm (P = 0.010), a high Clark level (IV + V) (P = 0.009), abnormal serum LDH level (P < 0.001), distant metastases occurrence (P = 0.049) and Ki-67 ≥ 30% (P = 0.009) (Table 2 and Fig. 2). However, it was not associated with age, sex, ulcerations, lymph node metastasis condition, clinical stage, vascular invasion or mitotic rate in malignant melanoma patients (P > 0.05) (Table 2 and Fig. 3).
Table 2 - Relationship between plasma heat shock protein 90α levels and clinicopathological parameters in malignant melanoma patients
Clinicopathological
parameters Variables Number HSP90α values
[ng/mL, M (P25–P75)] P value
Age >60 26 87.85 (59.35–128.25) 0.245
≤60 34 97.76 (79.06–150.48)
Sex Male 32 91.69 (65.23–124.63) 0.135
Female 28 92.89 (83.60–206.95)
Breslow thickness ≤4 mm 37 86.14 (67.7–113.67) 0.010
>4 mm 23 126.40 (87.53–200.36)
Ulcerations No 30 88.41 (69.81–118.46) 0.294
Yes 30 105.31 (75.47–172.19)
Clark level IV + V 42 109.91 (79.06–192.14) 0.009
I + II + III 18 84.16 (64.99–91.17)
Lymph node metastasis condition No 18 92.89 (70.53–109.26) 0.402
Yes 42 91.69 (69.81–169.63)
Clinical stage I + II 12 92.89 (74.80–136.14) 0.853
III + IV 48 91.69 (69.56–140.77)
Vascular invasion No 42 91.34 (69.81–129.99) 0.488
Yes 18 106.15 (74.85–159.87)
Serum LDH level Abnormal 20 194.17 (128.28–269.52) <0.001
Normal 40 85.30 (62.78–103.04)
Distant metastases No 32 88.41 (70.80–113.22) 0.049
Yes 28 118.80 (71.80–229.49)
Ki-67 ≥30% 31 108.61 (90.14–200.36) 0.009
<30% 29 83.03 (63.51–117.73)
Mitotic rate <1 31 87.53 (65.97–108.61) 0.105
≥1 29 115.81 (76.24–194.17)
HSP90α, heat shock protein 90α; LDH, lactate dehydrogenase.
Fig. 2
Fig. 2: Relationships between plasma heat shock protein 90α (HSP90α) levels and Breslow thickness, Clark level, serum lactate dehydrogenase (LDH) level, distant metastases and Ki-67 level. Plasma HSP90α levels were higher with Breslow thickness >4 mm (P = 0.010; a) a high Clark level (IV + V) (P = 0.009; b) abnormal serum LDH level (P < 0.001; c) distant metastases occurrence (P = 0.049; d) and Ki-67≥30% (P = 0.009 e).
Fig. 3
Fig. 3: Plasma heat shock protein 90α (HSP90α) levels of malignant melanoma patients were not associated with other clinical parameters, including age (P = 0.245; a), sex (P = 0.135; b), ulcerations (P = 0.294; c), lymph node metastasis condition (P = 0.402; d), clinical stage (P = 0.853; e), vascular invasion (P = 0.488; f) and mitotic rate (P = 0.105; g).
Heat shock protein 90α in the diagnosis of malignant melanoma
A total of 60 patients and 60 healthy controls were divided into two groups, including a training and a validation cohort. There was no difference in clinical parameters between the two cohorts (Tables 3 and 4). Serum LDH is the unique tumour marker associated with malignant melanoma in the blood, which has an important reference value for tumour staging. Therefore, in this study, ROC curves and the area under the curve (AUC) were generated and calculated to evaluate and compare the diagnostic value of HSP90α and LDH in malignant melanoma patients.
Table 3 - Comparison of clinical parameters in malignant melanoma patients between the training cohort and validation cohort
Characteristics Variables Training cohort
(cases) Validation cohort
(cases) χ2 P value
Age >60 13 13 0.000 1.000
≤60 17 17
Pathological types Acral melanoma 24 25 0.111 0.739
Mucosal melanoma 6 5
Sex Male 16 16 0.000 1.000
Female 14 14
Breslow thickness ≤4 mm 16 21 1.763 0.184
>4 mm 14 9
Ulcerations No 14 16 0.267 0.606
Yes 16 14
Clark level IV + V 22 20 0.317 0.573
I + II + III 8 10
Lymph node metastasis condition No 11 7 1.270 0.260
Yes 19 23
Clinical stage I + II 8 4 0.938 0.333
III + IV 22 26
Vascular invasion No 18 24 2.857 0.091
Yes 12 6
Serum LDH level Abnormal 8 12 1.200 0.273
Normal 22 18
Distant metastases No 19 13 2.411 0.121
Yes 11 17
Ki-67 ≥30% 15 16 0.067 0.796
<30% 15 14
Mitotic rate <1 12 19 3.270 0.071
≥1 18 11
LDH, lactate dehydrogenase.
Table 4 - Comparison of clinical parameters in healthy controls between the training cohort and validation cohort
Characteristics Variables Training cohort
(cases) Validation cohort
(cases) χ2 P value
Age >60 12 9 0.659 0.417
≤60 18 21
Sex Male 15 18 0.606 0.436
Female 15 12
In the training cohort, the AUC of LDH was 0.677, and the maximum value of Youden index was calculated to be 0.334. Accordingly, the sensitivity, specificity, PPV and NPV of LDH were 46.70, 86.70, 77.80 and 61.90% in the diagnosis of malignant melanoma, respectively. In contrast, a higher AUC and Youden index were achieved for HSP90α (AUC = 0.847; Youden index = 0.634) (Fig. 4a). Meanwhile, the sensitivity, specificity, PPV and NPV were 76.70, 86.70, 85.20 and 78.80% for HSP90α (Table 5). In the validation cohort, the AUCs were 0.672 for LDH and 0.867 for HSP90α, respectively (Fig. 4b). Nevertheless, the Youden index were 0.367 and 0.633 for LDH and HSP90α, respectively. Furthermore, the sensitivity, specificity, PPV and NPV were 70.00, 93.30, 91.30 and 75.70% for HSP90α and 36.70, 100.00, 100.00 and 61.20% for LDH (Table 5).
Table 5 - Diagnostic efficacy of plasma heat shock protein 90α and lactate dehydrogenase in malignant melanoma
Group Tumour marker AUC
(95% CI) Youden index Sensitivity
(%) Specificity
(%) Positive predictive value (%) Negative predictive value (%)
Training cohort LDH 0.677 0.334 46.70 86.70 77.80 61.90
HSP90α 0.847 0.634 76.70 86.70 85.20 78.80
Validation cohort LDH 0.672 0.367 36.70 100.00 100.00 61.20
HSP90α 0.867 0.633 70.00 93.30 91.30 75.70
AUC, area under the curves; CI, confidence interval; HSP90α, heat shock protein 90α; LDH, lactate dehydrogenase
Fig. 4
Fig. 4: Receiver operating characteristic curves of heat shock protein 90α (HSP90α) in the diagnosis of malignant melanoma. (a) The area under the curves (AUCs) were 0.677 for lactate dehydrogenase (LDH) and 0.847 for HSP90α, respectively, in the training cohort. (b) The AUCs were 0.672 for LDH and 0.867 for HSP90α, respectively, in the validation cohort.
Therefore, the AUC, sensitivity and NPV of HSP90α were superior to LDH when used in the auxiliary diagnosis of malignant melanoma.
Plasma heat shock protein 90α dynamic changes and therapeutic efficacy
Sixty patients received systemic treatment, including chemotherapy, targeted therapy and immunotherapy. Of all 60 patients, plasma HSP90α levels could be obtained pre- and post-treatment in 42 patients, and the efficacy was evaluated after two cycles of treatment. The therapeutic efficacy of 42 patients included CR (1 patient), PR (7), SD (16) and PD (18). HSP90α levels were significantly reduced in objective response (81.05 vs. 37.26 ng/ml; P = 0.012) and disease control patients (84.16 vs. 47.05 ng/ml; P = 0.002) (Table 6 and Fig. 5) post-treatment. Meanwhile, HSP90α levels were increased post-treatment in PD patients (111.41 ng/ml vs. 139.96 ng/ml; P = 0.242) (Table 6 and Fig. 5).
Table 6 - Changes of heat shock protein 90α levels pre- and post-treatment
Group Pretreatment
[ng/mL, M (P25–P75)] Post-treatment
[ng/mL, M (P25–P75)] Number
CR 90.14 42.92 1
PR 79.12 (65.97–87.53) 35.65 (33.12–43.28) 7
SD 88.79 (62.78–139.61) 62.19 (45.21–102.77) 16
PD 111.41 (84.33–172.19) 139.96 (107.44–184.04) 18
OR 81.05 (66.96–89.49) 37.26 (33.28–43.19) 8
DC 84.16 (65.23–118.44) 47.05 (36.46–75.67) 24
CR, complete response; DC, disease control; OR, Objective response; PD, progressive disease; PR, partial response; SD, stable disease.
Fig. 5
Fig. 5: Changes in heat shock protein 90α (HSP90α) levels for each patient pre- and post-treatment (a–d). HSP90α levels were significantly reduced in objective response (P = 0.012; e) and disease control (P = 0.002; f) patients.
Correlation between plasma heat shock protein 90α levels and progression-free survival
Forty-two patients received systemic therapy, including 14 patients with normal plasma HSP90α levels and 28 patients with abnormal HSP90α levels pretreatment (Table 7). It was shown that patients who had normal plasma HSP90α levels had greater PFS than abnormal patients (8.0 vs. 3.5 months; P = 0.096) (Fig. 6a). However, the trend was not statistically significant. Immunotherapy was an independent prognostic factor for PFS according to multivariable analysis (Table 8). The therapeutic effect for malignant melanoma was significantly improved, and the adverse effects of traditional prognostic factors, such as later tumour stage, ulcer, high LDH level and tumour thickness, were not reflected due to the application of immunotherapy (e.g. immune checkpoint inhibitors). In this study, 20 patients received immunotherapy, and 22 patients only received conventional chemotherapy(±targeted therapy), among whom plasma HSP90α levels were normal in 8 patients and abnormal in 14 patients pretreatment. Patients with normal plasma HSP90α levels who did not undergo immunotherapy had significantly longer PFS than patient with abnormal levels (6.0 vs. 2.0 months; P = 0.008) (Fig. 6b).
Table 7 - Systemic therapy project for 42 malignant melanoma patients
Project Drug HSP90α levels
Normal
patients
(Number) Abnormal
patients
(Number)
Chemotherapy (±targeted therapy) Dacarbazine 2 3
Dacarbazine + Recombinant human endostatina 6 8
Paclitaxel + Carboplatin 0 3
Combined immunotherapy Pembrolizumab 1 2
Pembrolizumab + Dacarbazine 2 1
Toripalimab 2 5
Toripalimab + Dacarbazine 1 5
Toripalimab + Recombinant human endostatin 0 1
HSP90α, heat shock protein 90α.
aRecombinant human endostatin has been approved to be used in the treatment of metastatic melanoma in China [29].
Table 8 - Univariable and multivariable analyses of prognostic factors for progression-free survival in malignant melanoma patients
Characteristics Univariable analysis Multivariable analysis
PFS P value PFS P value
HR 95% CI HR 95% CI
Age 0.788 0.368–1.689 0.540 0.516 0.198–1.346 0.176
Pathological types 2.043 0.734–5.687 0.171 1.160 0.304–4.420 0.828
Sex 1.456 0.668–3.173 0.345 2.330 0.683–7.943 0.177
Breslow thickness 2.205 1.041–4.672 0.039 2.445 0.781–7.653 0.125
Ulcerations 1.353 0.636–2.877 0.432 1.905 0.609–5.961 0.268
Clark level 1.948 0.732–5.181 0.181 1.197 0.284–5.049 0.807
Lymph node metastasis condition 1.179 0.446–3.113 0.740 1.541 0.193–12.318 0.684
Clinical stage 1.020 0.305–3.410 0.974 0.496 0.033–7.388 0.611
Vascular invasion 0.844 0.381–1.872 0.677 0.393 0.108–1.428 0.156
LDH level 6.740 2.542–17.868 <0.001 2.707 0.512–14.311 0.241
Distant metastases 2.187 1.016–4.707 0.045 1.474 0.364–5.960 0.587
Ki-67 1.346 0.637–2.844 0.436 1.068 0.368–3.102 0.903
Mitotic rate 1.033 0.488–2.186 0.932 0.484 0.174–1.344 0.164
Immunotherapy 0.417 0.189–0.919 0.030 0.264 0.088–0.798 0.018a
Plasma HSP90α levels 1.909 0.850–4.287 0.117 3.311 0.771–14.216 0.107
CI, confidence interval; HR, hazard ratio; HSP90α, heat shock protein 90α; LDH, lactate dehydrogenase; PFS, progression-free survival.
aSignificant variables; P < 0.05.
Fig. 6
Fig. 6: Patients who received systemic therapy with normal plasma heat shock protein 90α (HSP90α) levels showed a trend of longer progression-free survival (PFS) than patients with abnormal levels (8.0 vs. 3.5 months; P = 0.096; a). Patients with normal plasma HSP90α levels who received chemotherapy(±targeted therapy) without immunotherapy obtained significantly longer PFS than patients with abnormal levels (6.0 vs. 2.0 months; P = 0.008; b).
Discussion
Melanoma is a malignant tumour with extremely high malignancy potential, most frequently appearing on the skin. Despite increasingly effective treatment measures, the long-term prognosis remains poor, and the 5-year survival rate of metastatic melanoma patients is only 16% previously [30]. With the use of immune checkpoint inhibitors for melanoma treatment, overall survival at 5 years is significantly improved to 52% [31]. According to SEER data, the incidence and mortality rates in Caucasian individuals are higher than those in patients of other ethnic groups [32]. Diagnosis of malignant melanoma depends on clinical manifestations, pathological and medical imaging studies. Therefore, a tumour marker for the early diagnosis of malignant melanoma should be explored for use in clinical practice.
There is currently a lack of specific tumour markers in the diagnosis of malignant melanoma. Serum LDH was previously used as a tumour marker for malignant melanoma, but the sensitivity and specificity were not satisfactory. HSPs are vital proteins with chaperone characteristics that participate in protein folding and transport. HSP90 accounts for 1–2% of total cellular proteins under nonstressed conditions, but is expressed at high levels under conditions of increased stress. Cancer cells are in a constant state of cellular stress due to the presence of mutant proteins and rapid proliferation. Uncontrolled proliferation is the most fundamental characteristic of tumours; meanwhile, increasing protein synthesis and tremendous proteomic changes requires more chaperone activity and protein folding in cancer cells. By correcting the protein synthesis errors, increased HSP90 levels in cancer cells lead to uncontrolled cell proliferation. HSP90 has also been demonstrated that it is essen tial for cell development, survival and metastasis in malignant tumours. A variety of client proteins associated with HSP90, including protein kinases and nuclear receptors, have been explored. Together with client proteins which mediate the transformation of normal cells into cancer cells, HSP90 is involved in the critical activities of tumor progression such as insensitivity of antigrowth signals, evading immune destruction, sustained angiogenesis and escaping apoptosis. Besides, it is showed that HSP90 is a vital promoter of oncogene dependence and increased expression of HSP90 is conducive to the survival of cancer cells under adverse physiological and stress conditions [33]. Several studies suggest that the level of HSP90 expression is associated with the prognosis and treatment of malignant tumours. Therefore, HSP90 used as a biomarker has great potential to improve the detection, diagnosis and prognosis of cancer.
As a relatively new tumour marker, HSP90α has been widely investigated in many studies that revealed the overexpression of HSP90α in tissues of various malignancies. A large-scale and multicentre study confirmed that plasma HSP90α values were significantly higher in patients with cancer than in noncancer controls. HSP90 has been used for adjuvant diagnosis and plays an important role in tumour efficacy monitoring and prognosis. Moreover, over expression of HSP90 was found to be a risk factor for poor prognosis, but treatment targeting HSP90 is effective [6]. An existing study has shown that serum HSP90 levels of cutaneous malignant melanoma were higher than the control subjects. Nevertheless, the matter was found that clinical variables and survival were not relevant to serum HSP90 levels [27]. Acral and mucosal melanoma are the most common pathological types in China, whereas the correlation with plasma HSP90α has not been investigated up to now. Given this background, we explor ed the value of plasma HSP90α in acral and mucosal malignant melanoma.
In this study, the results showed that plasma HSP90α levels and abnormal rates in malignant melanoma patients were significantly higher than those in healthy controls. Similar results were obtained in other tumours, such as lung cancer [34] and cholangiocarcinoma [35]. Mucosal melanoma is the second largest subtype of melanoma in the Asian population. Compared with acral melanoma, mucosal melanoma is more prone to recurrence and metastasis and has a worse prognosis. Among the pathological subtypes, plasma HSP90α levels in mucosal melanoma were higher than those in acral melanoma, although the difference was not statistically significant. Then, the relationship between HSP90α and clinical parameters was explored. Plasma HSP90α levels were higher with Breslow thickness >4 mm, a high Clark level (IV + V), abnormal serum LDH, distant metastases occurrence and Ki-67 ≥ 30%. This result suggested that higher plasma HSP90α levels may be associated with a poor prognosis.
When used as a tumour marker in the auxiliary diagnosis of malignant melanoma, in the training cohort and validation cohort, the AUCs of HSP90α were significantly greater than LDH (0.847 vs. 0.677 and 0.867 vs. 0.672). Moreover, HSP90α has the higher sensitivity and NPV compared with LDH. The results showed that plasma HSP90α could be used as an auxiliary diagnostic agent for malignant melanoma, although its sensitivity and specificity were imperfect. The results are consistent with other experiments, in which the sensitivity and specificity of HSP90α for diagnosis were 72.18 and 78.70%, respectively, in lung cancer [34]. Furthermore, a multicentre study confirmed that the AUC of HSP90α as a novel pan-cancer diagnostic biomarker was 0.895 [35].
According to the analysis of the changes in plasma HSP90α levels pre- and post-treatment, plasma HSP90α levels were decreased in patients with good outcomes (objective response and disease control patients). In contrast, HSP90α levels were increased post-treatment in patients with poor outcomes (PD patients), although this increase was not statistically significant. A similar result was achieved in lung cancer in which postoperative HSP90α levels were reduced compared with preoperative levels and HSP90α levels were significantly elevated in patients who did not respond well to treatment [34]. The association between plasma HSP90α levels and PFS in patients who received systemic therapy was analysed. Patients who had normal plasma HSP90α levels pretreatment tended towards slightly longer PFS than patients with abnormal levels. Unfortunately, the trend was not significantly different. In multivariable analysis, immunotherapy was confirmed to be independent prognostic factor for PFS. Recent advances in the treatment of melanoma with immunotherapy have significantly improved the prognosis of melanoma patients. Several new immunotherapies have been approved for the treatment of untreated advanced melanoma, including nivolumab, pembrolizumab, ipilimumab and toripalimab [36–40]. Because of the benefit from immunotherapy, previous adverse prognostic factors were less important in monitoring prognosis. Therefore, patients with normal plasma HSP90α levels obtained significantly longer PFS than those with abnormal levels when they received chemotherapy (±targeted therapy) without immunotherapy. The results showed that high plasma HSP90α levels were associated with the aggressiveness and poor prognosis of malignant melanoma.
Conclusion
Research concerning plasma HSP90α in malignant melanoma is limited at present. This experiment showed that plasma HSP90α levels play a vital role in the diagnosis and can predict the responses to therapy in malignant melanoma patients as a tumour marker. We hope the result can be confirmed in other experiments. Because of the small sample size in the study, the difference may ultimately be the result of trial bias. Eventually, further evaluation and additional larger studies are needed to explore the application value of plasma HSP90α in melanoma.
Acknowledgements
This work was supported by the Anhui Provincial Natural Science Foundation (1808085MH306, 1908085QH333) and the Anhui Provincial Key Research and Development Project (NO. 202004j07020044).
Conflicts of interest
There are no conflicts of interest.
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Keywords:
diagnosis; heat shock protein 90α; malignant melanoma; therapeutic efficacy
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.
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