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Review
. 2019 Sep 11;20(18):4507.
doi: 10.3390/ijms20184507.

Heat Shock Proteins Are Essential Components in Transformation and Tumor Progression: Cancer Cell Intrinsic Pathways and Beyond

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Free PMC article
Review

Heat Shock Proteins Are Essential Components in Transformation and Tumor Progression: Cancer Cell Intrinsic Pathways and Beyond

Benjamin J Lang et al. Int J Mol Sci. .
Free PMC article

Abstract

Heat shock protein (HSP) synthesis is switched on in a remarkably wide range of tumor cells, in both experimental animal systems and in human cancer, in which these proteins accumulate in high levels. In each case, elevated HSP concentrations bode ill for the patient, and are associated with a poor outlook in terms of survival in most cancer types. The significance of elevated HSPs is underpinned by their essential roles in mediating tumor cell intrinsic traits such as unscheduled cell division, escape from programmed cell death and senescence, de novo angiogenesis, and increased invasion and metastasis. An increased HSP expression thus seems essential for tumorigenesis. Perhaps of equal significance is the pronounced interplay between cancer cells and the tumor milieu, with essential roles for intracellular HSPs in the properties of the stromal cells, and their roles in programming malignant cells and in the release of HSPs from cancer cells to influence the behavior of the adjacent tumor and infiltrating the normal cells. These findings of a triple role for elevated HSP expression in tumorigenesis strongly support the targeting of HSPs in cancer, especially given the role of such stress proteins in resistance to conventional therapies.

Keywords: Hsp70; Hsp90; cancer; chaperome; extracellular HSPs; heat shock proteins; molecular chaperones; proteotoxic stress; stress proteins in cancer; tumor signaling.

Conflict of interest statement

The authors declare no conflict of interest

Figures

Figure 1
Figure 1
The central dogma of the heat shock proteins-1 (HSP1) mediated proteotoxic stress response. (1) Cellular stressors such as heat shock, oxidative stress, exposure to heavy metals, or proteasome inhibition, which induce increased levels of non-native protein conformations (proteotoxic stress) leads to the activation of HSF1. (2) HSF1 translocates to the nucleus, and HSF1 trimers rapidly bind to heat shock elements (HSE) in the promoter region of stress-inducible genes and transactivates mRNA expression. (3) Increased cytosolic HSP levels promote the refolding of proteins in non-native conformations to achieve the native functional protein structure. (4) As proteostasis is restored, a negative feedback loop exists, where HSP72 then inhibits the HSF1 activity further.
Figure 2
Figure 2
Integrated Hsp27, Hsp70, and Hsp90 functions promote proteostasis. There are multiple entry points into the cytosolic chaperone network, where substrates can be recruited by Hsp27, Hsp70 co chaperones (e.g., Hsp40 family members), and Hsp90 co chaperones (e.g., Cdc37), or are bound directly by Hsp70 or Hsp90. Unfolded client proteins are relayed from Hsp27 or Hsp40 to the ATP-bound Hsp70 complex under the direction of J domain co-chaperone DNAJ. Binding of the unfolded client triggers the innate ATPase activity of Hsp70 through allosteric interactions, leading to a high affinity complex containing Hsp70, client, and ADP. The complex then undergoes nucleotide exchange facilitated by binding the co-chaperone Bag3. ADP is exchanged for ATP, which lowers the affinity of Hsp70 for the bound client that is released. Alternative destinations for Hsp70 substrates include proteasomal degradation via STUB1/CHIP, or transfer via HOP for further folding by the Hsp90 complex.
Figure 3
Figure 3
A reduced chaperome network is shown with the representation of the physical connections between the chaperome and the various proteins that can powerfully influence tumorigenesis. A summary of the protein–protein interaction network of the major HSPs. In the network, the nodes represent the most important constituents of the chaperome, which are connected with other proteins by edges of varying width. Red nodes are code for the main HSPs and co-chaperones, blue are well known cancer-related genes, the TRiC complex genes are shown in green, and the Prp19/CDC5L complex genes are in grey. The line thickness of the edges indicates the strength of the experimental data supporting a protein–protein interaction. The network was built using the STRING database (https://string-db.org) from the Swiss Institute of Bioinformatics and the European Molecular Biology Laboratory (EMBL).
Figure 4
Figure 4
An overview of cancer cell-autonomous processes mediated by Hsp27, Hsp70, and Hsp90 that promote tumorigenesis. The transforming potential of cancer cell-autonomous events such as oncogenic mutations is commonly dependent on support from intracellular Hsp27, Hsp70, and Hsp90. The activities of key intracellular mitogenic signal transducers are also dependent on intracellular HSPs for sustained pathway activation, and thus HSPs mediate how cancer cells respond to the growth signals emanating from the tumor microenvironment. Similarly, signals from the tumor microenvironment can promote tumor-initiating properties within the carcinoma cells, the molecular features of which have also been closely linked with subpopulations enriched for Hsp72 and Hsf1. Such transforming events require the ability of tumor cells to overcome senescence (oncogene induced senescence—OIS), and the Hsp72 expression is required to overcome this hurdle to tumorigenesis. We also represent here other key tumorigenic processes supported by intracellular HSPs, including the inhibition of programmed cell death (PCD), altered cellular metabolism to favor glycolysis, stimulation of angiogenesis by cancer cells, and invasive and metastatic properties.
Figure 5
Figure 5
The activities of HSPs can promote a tumorigenic stroma. We represent cancer cells (at the top) within an extracellular stroma containing infiltrating cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) that affect the tumor microenvironment in an HSF1/HSP-dependent manner. The interplay between CAF and carcinoma cells is affected by the HSF1 expression in each of these cell types, and the HSF1 activity promotes the secretion of the TGF-β and CXCL12 factors, which lead to the secretion of ECM molecules, such as collagens, that can modulate tumor cell behavior by affecting the structure of the tumor milieu and binding to integrins on the cancer cell surface. TGF-β and CXCL12 can also influence the properties of the cancer cells and the reactivity of tumor infiltrating lymphocytes. Hsp72 has also been shown to be important for the recruitment of TAM, which can secrete growth promoting factors in an HSP-dependent manner.
Figure 6
Figure 6
Tumor cells can modulate the tumor microenvironment by secreting HSPs. Carcinoma cells derived from several tissues have been identified to secrete HSPs into the extracellular space in soluble form or within exosomes. HSP species, including those listed above, are often abundant within the lumen of tumor cell-derived exosomes or within the exosomal membrane. HSPs secreted from carcinoma cells in soluble form or within exosomes can modulate the biology and functions of other cells in the tumor microenvironment. Specifically, secreted HSPs have been shown to modulate the activities of myeloid-derived suppressor cells (MDSCs), dendritic cells, TAMs, natural killer (NK) cells, other/neighboring carcinoma cells, and endothelial cells. Extracellular HSPs can promote tumorigenic processes (listed in red text), including immunosuppressive MDSC activity, carcinoma cell invasion and migration, and angiogenesis. Alternatively, extracellular HSPs can also promote tumor immunity (listed in green text) by stabilizing tumor antigens, stimulating TAMs to secrete inflammatory cytokines, and by mediating antigen processing by antigen presenting cells (APCs).

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