Plasma Heat Shock Protein 90alpha as a Biomarker for the Diagnosis of Liver Cancer: An Official, Large-scale, and Multicenter Clinical Trial

Fu, Yan; Xu, Xiao; Huang, Ddongsheng; Cui, Dawei; Liu, Lisheng; Liu, Junwei; He, Zhi Min; Liu, Jingjing; Luo, Yongzhang

doi:10.1016/j.ebiom.2017.09.007

Cited by 93 publications

(111 citation statements)

References 35 publications

(40 reference statements)

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“…Project e‐CAF was conducted on four individual cancer indications in clinical trials, including breast (registered at ClinicalTrial.gov: NCT02324101), lung (registered at the National Medical Products Administration (NMPA), China), liver (registered at ClinicalTrial.gov: NCT02324127), and colorectal cancer (registered at ClinicalTrial.gov: NCT02324114). To validate our observations in the test cohort, we compiled a validation dataset from curated data in project e‐CAF, according to probability theory.…”

Section: Methodsmentioning

confidence: 99%

“…Extracellular Hsp90α (eHsp90α) can promote cell invasion and epithelial‐to‐mesenchymal transition (EMT) processes in multiple cancer cells. Clinical trials have demonstrated that plasma Hsp90α is a more accurate diagnostic biomarker compared with commonly used biomarkers carcinoembryonic antigen (CEA) and fragments of cytokeratin‐19 (CYFRA21‐1) in lung cancer, or alpha‐fetoprotein (AFP) in liver cancer, respectively. In the clinic, a quantitative ELISA kit for plasma Hsp90α has now been approved by the China Food and Drug Administration (CFDA) to be used for patients with lung or liver cancers (see http://www.sfda.gov.cn).…”

Section: Introductionmentioning

confidence: 99%

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A novel pan‐cancer biomarker plasma heat shock protein 90alpha and its diagnosis determinants in clinic

Liu

Zhang

et al. 2019

Cancer Science

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A sensitive and specific diagnosis biomarker, in principle scalable to most cancer types, is needed to reduce the prevalent cancer mortality. Meanwhile, the investigation of diagnosis determinants of a biomarker will facilitate the interpretation of its screening results in clinic. Here we design a large‐scale (1558 enrollments), multicenter (multiple hospitals), and cross‐validation (two datasets) clinic study to validate plasma Hsp90α quantified by ELISA as a pan‐cancer biomarker. ROC curve shows the optimum diagnostic cutoff is 69.19 ng/mL in discriminating various cancer patients from all controls (AUC 0.895, sensitivity 81.33% and specificity 81.65% in test cohort; AUC 0.893, sensitivity 81.72% and specificity 81.03% in validation cohort). Similar results are noted in detecting early‐stage cancer patients. Plasma Hsp90α maintains also broad‐spectrum for cancer subtypes, especially with 91.78% sensitivity and 91.96% specificity in patients with AFP‐limited liver cancer. In addition, we demonstrate levels of plasma Hsp90α are determined by ADAM10 expression, which will affect Hsp90α content in exosomes. Furthermore, Western blotting and PRM‐based quantitative proteomics identify that partial false ELISA‐negative patients secret high levels of plasma Hsp90α. Mechanism analysis reveal that TGFβ‐PKCγ gene signature defines a distinct pool of hyperphosphorylated Hsp90α at Theronine residue. In clinic, a mechanistically relevant population of false ELISA‐negative patients express also higher levels of PKCγ. In sum, plasma Hsp90α is a novel pan‐cancer diagnosis biomarker, and cancer diagnosis with plasma Hsp90α is particularly effective in those patients with high expression of ADAM10, but may be insufficient to detect the patients with low ADAM10 and those with hyperphosphorylated Hsp90α.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel pan‐cancer biomarker plasma heat shock protein 90alpha and its diagnosis determinants in clinic

Liu

Zhang

et al. 2019

Cancer Science

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“…In lung cancer patients, we observed a statistically significant difference between before and after operation, and patients in PD and PR/SD groups [39]. In liver cancer patients, the difference of mean concentration of plasma Hsp90α was also significant between pre and postoperative, and between two interventional therapy groups [43].…”

mentioning

confidence: 96%

“…Due to its low sensitivity, the 2010 American Association for the Study of Liver Diseases (AASLD) guidelines has cancelled the use of AFP as a screening indicator for HCC [42]. However, plasma Hsp90α measurement showed much more precise in distinguishing AFPnegative HCC patients (AUC 0.971, sensitivity 94%, specificity 91%) and AFP-limited liver cancer (AUC 0.971, sensitivity 97%, specificity 90%) from non-liver cancer control, including healthy individuals and patients with non-cancerous liver disease [43]. This quantitative ELISA kit of plasma Hsp90α has now been approved by China Food and Drug Administration (CFDA) to be used in lung cancer and liver cancer patients (see http://www.sfda.gov.cn).…”

mentioning

confidence: 99%

“…The detection of plasma Hsp90α represents an early, convenient, accurate, and fast (e-CAF) "liquid biopsy" means for cancer diagnosis, particularly for patients at early stage. In addition, plasma Hsp90α can also be used to monitor the efficacy of cancer therapy [27,39,43]. A biomarker reflecting the dynamic changes responding to the patients' condition can provide the important clinical guidance for doctors.…”

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confidence: 99%

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Biomarker-based Diagnosis and Personalized Medicine for Cancer Patients: Trinity of Nucleolin Guided, Endostatin Treatment, and Plasma Hsp90α Monitored

Liu¹,

Fu²,

Luo³

2017

J Cell Signal

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CommentaryCancer is a major public health problem across the society, and is the second leading cause of death globally [1]. Early diagnosis of cancer effectively decreases the mortality associated with cancer metastasis [2]. However, the scarcity of more sensitive biomarker has hampered this important public healthy strategy. In this communication, we will discuss: 1) the topic on plasma Hsp90α as a novel cancer diagnosis biomarker; 2) the present knowledge regarding the underlying regulatory mechanism of Hsp90α translocation to cell membrane and secretion; 3) our strategy for cancer prevention with an emphasis on trinity of nucleolin guided, endostatin treatment, and plasma Hsp90α monitored.The intracellular heat shock protein 90 (Hsp90) is well-known and widely studied as the essential and ubiquitously expressed molecular chaperone [3][4][5][6]. It accounts for 1-2% of cellular proteins in normal cells or 2-7% in tumor cells [7]. In concert with co-chaperones and accessory proteins, Hsp90 mediates remarkably versatile activities including intracellular signal transduction [8,9], protein folding [10], cell apoptosis [11], chaperone mediated autophagy [12], antigen presentation [13], and morphological evolution [14,15]. Until now, more than 300 Hsp90's diverse "clients" have been reported to be involved in these processes in both normal cells and cancer cells [16] (for a comprehensive review of Hsp90's clients, see http:// www.picard.ch/downloads/Hsp90facts.pdf and the database of the Hsp90Int, see http://www.picard.ch/Hsp90Int).However, the discovery of secreted Hsp90 is a relatively recent story. The widely accepted specific isoform which can be secreted is heat shock protein 90alpha (Hsp90α) [17][18][19][20][21][22][23][24][25][26][27][28][29], whereas some researchers have also identified that heat shock protein 90beta (Hsp90β) localize outside of certain cell types [20,30,31]. Work by Jay and colleagues has provided the most compelling evidence that Hsp90α, not Hsp90β, can be detected extracellularly with functional proteomic and specific antiHsp90α antibody [24]. After that, two pools of secreted Hsp90α, including "cell surface-bound" Hsp90α and "extracellular" Hsp90α (eHsp90α), have been characterized from cancer cells [7]. The function of eHsp90α in regulating tumor invasion and metastasis will not be covered in this short communication, which has been well summarized in recent reviews [7,32].Previous work from our group has firstly reported the underlying regulatory mechanism of Hsp90α secretion [27]. Residue Thr-90 phosphorylated by protein kinase A will disrupt the interaction between Hsp90α and proteins containing tetratricopeptide repeat domains, which leads to the exposure and cleavage of C-terminal EEVD motif. This process will initiate the downstream secretion of Hsp90α. PLCγ1-PKCγ signaling axis mediates Hsp90α plasma membrane translocation [28]. Hsp90α has no to-be-secreted signal peptide, and the presently well accepted secretory pathway is through exosome [21,33,34]. Our group reported that ...

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The prominence of potential biomarkers in the diagnosis and management of hepatocellular carcinoma: Current scenario and future anticipation

Mir

Jyothi

Thirunavukkarasu

2021

J of Cellular Biochemistry

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Hepatocellular carcinoma (HCC) is one of the most aggressive and truculent types of cancer. Early detection of HCC is a massive concern that can boost the overall survival rates of HCC patients. As a result, there is a continual quest for advancements in screening, diagnosis, and treatment strategies to enhance the prognosis at its early stages. However, the confluence of inflammation and cirrhosis hampers the early detection of HCC. The analysis of different types of biomarkers such as tissue biomarkers, serum biomarkers, protein biomarkers, autoantibody markers, and improved imaging techniques has played a vital role in ameliorating HCC monitoring responses. Therefore biomarkers that can identify HCC early with a high degree of sensitivity and specificity might be prodigiously serviceable in the diagnosis and treatment of this notorious disorder. This study offers an overview of the contemporary understanding of several types of biomarkers implicated in hepatocarcinogenesis and their applications in monitoring, diagnosis, and prognosis presage. In additament, we address the role of image techniques associated with HCC diagnosis.

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Plasma Heat Shock Protein 90alpha as a Biomarker for the Diagnosis of Liver Cancer: An Official, Large-scale, and Multicenter Clinical Trial

Cited by 93 publications

References 35 publications

A novel pan‐cancer biomarker plasma heat shock protein 90alpha and its diagnosis determinants in clinic

A novel pan‐cancer biomarker plasma heat shock protein 90alpha and its diagnosis determinants in clinic

Biomarker-based Diagnosis and Personalized Medicine for Cancer Patients: Trinity of Nucleolin Guided, Endostatin Treatment, and Plasma Hsp90α Monitored

The prominence of potential biomarkers in the diagnosis and management of hepatocellular carcinoma: Current scenario and future anticipation

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