Extracellular HSP90 Machineries Build Tumor Microenvironment and Boost Cancer Progression

Poggio, Pietro; Sorge, Matteo; Seclì, Laura; Brancaccio, Mara

doi:10.3389/fcell.2021.735529

Cited by 19 publications

(19 citation statements)

References 91 publications

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“…At present, EMT has been considered one of the important mechanisms for the generation of acquired drug resistance to EGFR-TKIs 10 ; 26 . The release of HSP90α from tumor cells and its role in promoting cancer cell survival, migration, invasion, and stemness through autocrine mechanisms is well established 27 . However, less is known whether eHSP90α is involved in the development of EMT and how inhibitors mediate EVs and EMT despite eHsp90 is involved in extracellular matrix remodeling, activation of MMP2 and result in invasion and metastasis 27 .…”

Section: Discussionmentioning

confidence: 99%

“…The release of HSP90α from tumor cells and its role in promoting cancer cell survival, migration, invasion, and stemness through autocrine mechanisms is well established 27 . However, less is known whether eHSP90α is involved in the development of EMT and how inhibitors mediate EVs and EMT despite eHsp90 is involved in extracellular matrix remodeling, activation of MMP2 and result in invasion and metastasis 27 . The secreted HSP90α attenuates the effect of anticancer drugs in NSCLC cells through AKT/GSK3β/β-catenin signaling pathway 28 .…”

Section: Discussionmentioning

confidence: 99%

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GW4869 can inhibit epithelial-mesenchymal transition promoted by extracellular HSP90α in EGFR-mutated NSCLC cells

Wan

Fang

et al. 2022

Preprint

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Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer with the high morbidity and mortality in the world. Meanwhile, the acquired drug resistance against EGFR-mutated NSCLC is increasingly serious. HSP90α might play critical roles in NSCLC, but the effect of GW4869 on extracellular HSP90α remains unclear. We collected plasma samples from 22 NSCLC and 10 healthy individuals, and measured the plasma HSP90α levels by ELISA. Western blot was used to detect the levels of HSP90α, E-cadherin, N-cadherin, and Vimentin in HCC827 and PC9 cells. We found that extracellular HSP90α was upregulated in NSCLC mutated patients and accelerated epithelial-mesenchymal transition (EMT) and invasion/migration capacity in EGFR-mutated NSCLC cells. Meanwhile, we also confirmed that GW4869 inhibited the expression of eHSP90α, EMT and invasion/migration abilities in HCC827 and PC9, and enhanced the antitumor activity of gefitinib in BALB/C nude mice in vivo. These studies suggest that GW4869 can inhibit epithelial-mesenchymal transition promoted by extracellular HSP90α in non-small cell lung cancer, which provides new strategies for delaying the development of acquired resistance to gefitinib for EGFR-mutated NSCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

GW4869 can inhibit epithelial-mesenchymal transition promoted by extracellular HSP90α in EGFR-mutated NSCLC cells

Wan

Fang

et al. 2022

Preprint

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“…Gene expression changes in HS90AA related to chemoresistance (Chu et al, 2013). In addition to that, HSP90AA signaling builds the tumor microenvironment and serves as a therapeutic target (Poggio et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Identification of Differentially Expressed Genes and Key Pathways Associated with PTPN11 Mutation in Acute Myeloid Leukemia

Rangasamy¹,

Santhy²

2022

JSR

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PTPN11 is a prominent oncogene in many tumors, which linked with poor prognosis. But the gene expression profile associated with this gene mutation in AML is not yet fully elucidated. So, the current study was intended to explore the key genes and pathways associated with AML with PTPN11 mutation. Using the TCGA database, we investigated the gene expression profile for PTPN11 mutation and wild type. EdgeR, an R platform, was applied to categorize the differentially expressed genes. GO and KEGG enrichment analysis was accomplished using DAVID and GSEA. PPI network is investigated with STRING database and Cytoscape software. A statistical investigation was employed to examine the expression levels of genes and prognostic values. As a result, in total 3268 gene s were differentially expressed. GO, KEGG pathway and GSEA analysis of up and down-regulated genes represented that gene were enriched in apoptosis and metabolic signaling pathways. Furthermore, ten hub genes GAPDH, HSP90AA, MYC, UBB, HSPA4, EP300, CCDS, POLR2A, EFTUD2, RPL11. GAPDH was identified from the PPI network. A statistical investigation revealed that PTPN11 gene mutation associated with AML patients had a shorter median survival time with an increased risk of death compared with those without mutations.

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“…To provide a common terminology that covers the meanings of “cell surface-bound”, “cell-released”, “cell-secreted” Hsp90α, Isaacs and colleagues recommended “eHsp90” for extracellular Hsp90 which has since become widely accepted by the Hsp90 community [ 23 ]. Over the past 20 years, there have been two dozen excellent review articles on eHsp90, especially eHsp90α [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ], which we use as the stepping-stones for construction of this article.…”

Section: History Of Ehsp90 Discoverymentioning

confidence: 99%

Extracellular Heat Shock Protein-90 (eHsp90): Everything You Need to Know

Jay

Luo

2022

Biomolecules

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“Extracellular” Heat Shock Protein-90 (Hsp90) was initially reported in the 1970s but was not formally recognized until 2008 at the 4th International Conference on The Hsp90 Chaperone Machine (Monastery Seeon, Germany). Studies presented under the topic of “extracellular Hsp90 (eHsp90)” at the conference provided direct evidence for eHsp90’s involvement in cancer invasion and skin wound healing. Over the past 15 years, studies have focused on the secretion, action, biological function, therapeutic targeting, preclinical evaluations, and clinical utility of eHsp90 using wound healing, tissue fibrosis, and tumour models both in vitro and in vivo. eHsp90 has emerged as a critical stress-responding molecule targeting each of the pathophysiological conditions. Despite the studies, our current understanding of several fundamental questions remains little beyond speculation. Does eHsp90 indeed originate from purposeful live cell secretion or rather from accidental dead cell leakage? Why did evolution create an intracellular chaperone that also functions as a secreted factor with reported extracellular duties that might be (easily) fulfilled by conventional secreted molecules? Is eHsp90 a safer and more optimal drug target than intracellular Hsp90 chaperone? In this review, we summarize how much we have learned about eHsp90, provide our conceptual views of the findings, and make recommendations on the future studies of eHsp90 for clinical relevance.

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Extracellular HSP90 Machineries Build Tumor Microenvironment and Boost Cancer Progression

Cited by 19 publications

References 91 publications

GW4869 can inhibit epithelial-mesenchymal transition promoted by extracellular HSP90α in EGFR-mutated NSCLC cells

GW4869 can inhibit epithelial-mesenchymal transition promoted by extracellular HSP90α in EGFR-mutated NSCLC cells

Identification of Differentially Expressed Genes and Key Pathways Associated with PTPN11 Mutation in Acute Myeloid Leukemia

Extracellular Heat Shock Protein-90 (eHsp90): Everything You Need to Know

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