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

Abstract

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 ...