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Cells
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Heat Shock Proteins and Human Cancers
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Heat Shock Proteins and Human Cancers

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (30 June 2025) | Viewed by 10206

Special Issue Editor

Dr. Alexander E. Kabakov

E-Mail Website
Guest Editor
Department of Radiation Biochemistry, A. Tsyb Medical Radiological Research Center, Obninsk, Russia
Interests: heat shock proteins; molecular chaperones; cellular stress; protein folding; cancer; cancer stem cells; radiotherapy; hyperthermia; tumor radioresistance; radiosensitizers; anticancer drugs; DNA damage response; apoptosis; hypoxia in tumors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As the Guest Editor of the announced Special Issue, I am pleased to invite you to submit your manuscripts dedicated to Heat Shock Proteins and Cancer.   

The relationship between heat shock proteins (HSPs) and cancer has been actively studied in recent decades and many remarkable findings have been made in this field. HSPs were shown to promote tumorigenesis, aggressive tumor growth, and tumor resistance to therapeutics; therefore, many current studies focus on the development of HSP-based modalities for theranostics of cancers.

It is now known that HSPs are required for oncogene-mediated malignization and then protect malignant cells from apoptosis, senescence, and immune attack. It is also accepted that HSPs support the viability of tumor cells under stressful conditions in the microenvironment (such as hypoxia, nutrient deficiency, acidosis, and others). Moreover, HSPs contribute to the maintenance of cancer cell stemness and the epithelial-to-mesenchymal transition (which are associated with tumor progression, invasion, and metastases). Excess HSPs can preserve tumor cells from the cytotoxicity of therapeutic agents, including drugs and radiation exposure. Consequently, HSPs are considered to be potential targets for treating or sensitizing human malignancies. Moreover, certain HSPs may be used in cancer-related diagnostics/prognostics or as components of anticancer vaccines.       

This Special Issue primarily aims to present some recent advances in exploring HSPs that may be significant for cancer biology and cancer treatment. We welcome both research articles and reviews covering topics such as HSP-involving mechanisms of tumorigenesis, the role of HSPs in cancer pathogenesis, approaches to inhibitory targeting tumorous HSPs, approaches to HSP-based diagnostics of cancer, HSP-based anticancer vaccines, HSPs and cancer-related exosomes, HSP-containing nanoparticles that are used to fight cancer, etc. Glucose-regulated proteins (GRPs), as members of the HSP family, will also be the cancer-related subject of this Special Issue. 

I look forward to receiving your manuscripts.

Dr. Alexander Kabakov
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • heat shock protein
  • glucose-regulated protein
  • cancer
  • tumorigenesis
  • theranostics
  • anticancer vaccine

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Published Papers (6 papers)

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Research

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15 pages, 1782 KiB  
Article
HSP110 Regulates the Assembly of the SWI/SNF Complex
by Océane Pointeau, Manon Paccagnini, Natalia Borges-Bonan, Léo Biziorek, Sébastien Causse, Carmen Garrido and Laurence Dubrez
Cells 2025, 14(11), 849; https://doi.org/10.3390/cells14110849 - 5 Jun 2025
Viewed by 596
Abstract
HSP110 is a ubiquitous chaperone contributing to proteostasis. It has a disaggregation activity and can refold denatured proteins. It can regulate fundamental signaling pathways involved in oncogenesis, such as Wnt/β-catenin, NF-κB and STAT3 signaling pathways. In gastric and colorectal cancer, HSP110 has been [...] Read more.
HSP110 is a ubiquitous chaperone contributing to proteostasis. It has a disaggregation activity and can refold denatured proteins. It can regulate fundamental signaling pathways involved in oncogenesis, such as Wnt/β-catenin, NF-κB and STAT3 signaling pathways. In gastric and colorectal cancer, HSP110 has been detected in the nucleus, and nuclear expression has been associated with the resistance of cells to 5-FU chemotherapy. Nuclear translocation of HSP110 is promoted by the exposure of cells to DNA-damaging agents. In a previous work, we demonstrated that nuclear HSP110 participates in the NHEJ DNA repair pathway by facilitating the recruitment of DNA-PKcs to Ku70/80 heterodimers at the site of DNA double-strand breaks. In the present work, analysis of HSP110s’ nuclear interactome revealed an enrichment of components from SWI/SNF chromatin remodeling complexes. We demonstrate that HSP110 is strongly associated with chromatin in temozolomide- and oxaliplatin-treated cells and directly interacts with the core subunit SMARCC2, thereby facilitating the assembly of SWI/SNF complexes. This work expands upon the role of HSP110, which regulates not only proteostasis but also the assembly of critical nuclear macromolecular complexes involved in the adaptive stress response. Full article
(This article belongs to the Special Issue Heat Shock Proteins and Human Cancers)
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24 pages, 3076 KiB  
Article
Strong Hsp90α/β Protein Expression in Advanced Primary CRC Indicates Short Survival and Predicts Response to the Hsp90α/β-Specific Inhibitor Pimitespib
by Sebastian B. M. Schmitz, Jakob Gülden, Marlene Niederreiter, Cassandra Eichner, Jens Werner and Barbara Mayer
Cells 2025, 14(11), 836; https://doi.org/10.3390/cells14110836 - 3 Jun 2025
Cited by 2 | Viewed by 881
Abstract
The prognosis of advanced (UICC IIb-IV) primary colorectal cancer (pCRC) remains poor. More effective targeted therapies are needed. Heat shock protein 90 alpha/beta (Hsp90α/β) expression was immunohistologically quantified in 89 pCRCs and multivariately correlated with survival. Pimitespib (Pim, TAS-116), a Hsp90α/β-specific inhibitor, was [...] Read more.
The prognosis of advanced (UICC IIb-IV) primary colorectal cancer (pCRC) remains poor. More effective targeted therapies are needed. Heat shock protein 90 alpha/beta (Hsp90α/β) expression was immunohistologically quantified in 89 pCRCs and multivariately correlated with survival. Pimitespib (Pim, TAS-116), a Hsp90α/β-specific inhibitor, was tested in pCRC cell lines and patient-derived cancer spheroids (PDCS) and referenced to the pan-Hsp90 inhibitor ganetespib (Gan, STA-9090) and standard-of-care therapies. A total of 26.97% pCRCs showed strong tumoral Hsp90α/β expression (Hsp90α/β > 40%), which correlated with reduced PFS (HR: 3.785, 95%CI: 1.578–9.078, p = 0.003) and OS (HR: 3.502, 95%CI: 1.292–9.494, p = 0.014). Co-expression of Hsp90α/β > 40% with its clients BRAF-V600E and Her2/neu aggravated the prognosis (BRAF-V600E mutated: PFS, p = 0.002; OS, p = 0.012; Her2/neu score3: PFS, p = 0.029). The prognostic cut-off Hsp90α/β > 40% was also a predictor for response to Pim-based therapy. Pim efficacy was increased in combination with 5-FU, 5-FU + oxaliplatin, and 5-FU + irinotecan (all p < 0.001). Pim induced sensitization to all chemotherapies in HT-29 (p < 0.001), Caco-2 (p < 0.01), and HCT116 (p < 0.05) cells. Pim combined with encorafenib in HT-29 and with trastuzumab in Caco-2 cells was most effective in dual-target inhibition approaches (HT-29: p < 0.005; Caco-2: p < 0.05). The anti-cancer effect and chemosensitization of Pim-based therapy were prospectively confirmed in PDCS directly generated from Hsp90α/β > 40% pCRCs. Protein profiling combined with functional drug testing stratifies Hsp90α/β > 40% pCRC patients diagnosed with UICC IIb-IV for effective Pim-based therapy. Full article
(This article belongs to the Special Issue Heat Shock Proteins and Human Cancers)
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19 pages, 7588 KiB  
Article
Development of a Humanized Antibody Targeting Extracellular HSP90α to Suppress Endothelial-Mesenchymal Transition-Enhanced Tumor Growth of Pancreatic Adenocarcinoma Cells
by Chi-Shuan Fan, Hui-Chen Hung, Chia-Chi Chen, Li-Li Chen, Yi-Yu Ke, Teng-Kuang Yeh, Chin-Ting Huang, Teng-Yuan Chang, Kuei-Jung Yen, Chung-Hsing Chen, Kee Voon Chua, John Tsu-An Hsu and Tze-Sing Huang
Cells 2024, 13(13), 1146; https://doi.org/10.3390/cells13131146 - 4 Jul 2024
Cited by 4 | Viewed by 2427
Abstract
Extracellular HSP90α (eHSP90α) is a promoter of tumor development and malignant progression. Patients with malignancies, including pancreatic ductal adenocarcinoma (PDAC), have generally shown 5~10-fold increases in serum/plasma eHSP90α levels. In this study, we developed a humanized antibody HH01 to target eHSP90α and evaluated [...] Read more.
Extracellular HSP90α (eHSP90α) is a promoter of tumor development and malignant progression. Patients with malignancies, including pancreatic ductal adenocarcinoma (PDAC), have generally shown 5~10-fold increases in serum/plasma eHSP90α levels. In this study, we developed a humanized antibody HH01 to target eHSP90α and evaluated its anticancer efficacy. HH01, with novel complementarity-determining regions, exhibits high binding affinity toward HSP90α. It recognizes HSP90α epitope sites 235AEEKEDKEEE244 and 251ESEDKPEIED260, with critical amino acid residues E237, E239, D240, K241, E253, and K255. HH01 effectively suppressed eHSP90α-induced invasive and spheroid-forming activities of colorectal cancer and PDAC cell lines by blocking eHSP90α’s ligation with the cell-surface receptor CD91. In mouse models, HH01 potently inhibited the tumor growth of PDAC cell grafts/xenografts promoted by endothelial-mesenchymal transition-derived cancer-associated fibroblasts while also reducing serum eHSP90α levels, reflecting its anticancer efficacy. HH01 also modulated tumor immunity by reducing M2 macrophages and reinvigorating immune T-cells. Additionally, HH01 showed low aggregation propensity, high water solubility, and a half-life time of >18 days in mouse blood. It was not cytotoxic to retinal pigmented epithelial cells and showed no obvious toxicity in mouse organs. Our data suggest that targeting eHSP90α with HH01 antibody can be a promising novel strategy for PDAC therapy. Full article
(This article belongs to the Special Issue Heat Shock Proteins and Human Cancers)
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Review

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26 pages, 935 KiB  
Review
Modulation of Heat Shock Proteins Levels in Health and Disease: An Integrated Perspective in Diagnostics and Therapy
by Elena Mikhailova, Alexandra Sokolenko, Stephanie E. Combs and Maxim Shevtsov
Cells 2025, 14(13), 979; https://doi.org/10.3390/cells14130979 - 25 Jun 2025
Viewed by 804
Abstract
Heat shock proteins belong to a highly conserved family of chaperone proteins, and in addition to their participation in the regulation of cellular proteostasis (folding of polypeptides and proteins, disaggregation of incorrectly folded peptides, and participation in autophagy processes), also play a significant [...] Read more.
Heat shock proteins belong to a highly conserved family of chaperone proteins, and in addition to their participation in the regulation of cellular proteostasis (folding of polypeptides and proteins, disaggregation of incorrectly folded peptides, and participation in autophagy processes), also play a significant immunomodulatory role in both innate and adaptive immunity. Changes in the HSP level, both downwards (e.g., in neurodegenerative diseases) and upwards (e.g., autoimmune, oncological diseases), underlie the pathogenesis of many somatic and oncological pathologies. In this review, we consider the main physiological mechanisms of HSP level regulation and also analyze pharmacological, genetically engineered methods of modulating the chaperone level, citing the advantages and disadvantages of a particular method of influence. In conclusion, modulation of the HSP level, according to numerous preclinical studies, can have a significant impact on the course of various pathological conditions, which, in turn, can be used to develop new therapeutic approaches, when the effect on the level of chaperones can be used as monotherapy or as an adjuvant method of action. Full article
(This article belongs to the Special Issue Heat Shock Proteins and Human Cancers)
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35 pages, 3153 KiB  
Review
More than Just Protein Folding: The Epichaperome, Mastermind of the Cancer Cell
by Haneef Ahmed Amissah, Maxwell Hubert Antwi, Tawfeek Ahmed Amissah, Stephanie E. Combs and Maxim Shevtsov
Cells 2025, 14(3), 204; https://doi.org/10.3390/cells14030204 - 30 Jan 2025
Cited by 2 | Viewed by 1969
Abstract
The epichaperome, a dynamic and integrated network of chaperone proteins, extends its roles beyond basic protein folding to protein stabilization and intracellular signal transduction to orchestrating a multitude of cellular processes critical for tumor survival. In this review, we explore the multifaceted roles [...] Read more.
The epichaperome, a dynamic and integrated network of chaperone proteins, extends its roles beyond basic protein folding to protein stabilization and intracellular signal transduction to orchestrating a multitude of cellular processes critical for tumor survival. In this review, we explore the multifaceted roles of the epichaperome, delving into its diverse cellular locations, factors that modulate its formation and function, its liquid–liquid phase separation, and the key signaling and crosstalk pathways it regulates, including cellular metabolism and intracellular signal transduction. We further highlight techniques for isolating and identifying epichaperome networks, pitfalls, and opportunities. Further, we review the profound implications of the epichaperome for cancer treatment and therapy design, underscoring the need for strategic engineering that hinges on a comprehensive insight into the comprehensive structure and workings of the epichaperome across the heterogeneous cell subpopulations in the tumor milieu. By presenting a holistic view of the epichaperome’s functions and mechanisms, we aim to underscore its potential as a key target for novel anti-cancer strategies, revealing that the epichaperome is not merely a piece of protein folding machinery but a mastermind that facilitates the malignant phenotype. Full article
(This article belongs to the Special Issue Heat Shock Proteins and Human Cancers)
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35 pages, 3587 KiB  
Review
Tumor Dormancy and Reactivation: The Role of Heat Shock Proteins
by Haneef Ahmed Amissah, Stephanie E. Combs and Maxim Shevtsov
Cells 2024, 13(13), 1087; https://doi.org/10.3390/cells13131087 - 23 Jun 2024
Cited by 5 | Viewed by 2675
Abstract
Tumors are a heterogeneous group of cell masses originating in various organs or tissues. The cellular composition of the tumor cell mass interacts in an intricate manner, influenced by humoral, genetic, molecular, and tumor microenvironment cues that dictate tumor growth or suppression. As [...] Read more.
Tumors are a heterogeneous group of cell masses originating in various organs or tissues. The cellular composition of the tumor cell mass interacts in an intricate manner, influenced by humoral, genetic, molecular, and tumor microenvironment cues that dictate tumor growth or suppression. As a result, tumors undergo a period of a dormant state before their clinically discernible stage, which surpasses the clinical dormancy threshold. Moreover, as a genetically imprinted strategy, early-seeder cells, a distinct population of tumor cells, break off to dock nearby or extravasate into blood vessels to secondary tissues, where they form disseminated solitary dormant tumor cells with reversible capacity. Among the various mechanisms underlying the dormant tumor mass and dormant tumor cell formation, heat shock proteins (HSPs) might play one of the most important roles in how the dormancy program plays out. It is known that numerous aberrant cellular processes, such as malignant transformation, cancer cell stemness, tumor invasion, metastasis, angiogenesis, and signaling pathway maintenance, are influenced by the HSPs. An accumulating body of knowledge suggests that HSPs may be involved in the angiogenic switch, immune editing, and extracellular matrix (ECM) remodeling cascades, crucial genetically imprinted strategies important to the tumor dormancy initiation and dormancy maintenance program. In this review, we highlight the biological events that orchestrate the dormancy state and the body of work that has been conducted on the dynamics of HSPs in a tumor mass, as well as tumor cell dormancy and reactivation. Additionally, we propose a conceptual framework that could possibly underlie dormant tumor reactivation in metastatic relapse. Full article
(This article belongs to the Special Issue Heat Shock Proteins and Human Cancers)
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